Potential Applications of the Anti-Inflammatory, Antithrombotic and Antioxidant Health-Promoting Properties of Curcumin: A Critical Review

Abstract

The major constituent of turmeric, curcumin, is a bioactive phenolic compound that has been studied for its potential health benefits and therapeutic properties. Within this article, the anti-inflammatory, antioxidant and antithrombotic properties and mechanisms of action of curcumin are thoroughly reviewed and the main focus is shifted to its associated health-promoting effects against inflammation-related chronic disorders. An overview of the cardio-protective, anti-tumor, anti-diabetic, anti-obesity, anti-microbial and neuro–protective health-promoting properties of curcumin are thoroughly reviewed, while relative outcomes obtained from clinical trials are also presented. Emphasis is given to the wound-healing properties of curcumin, as presented by several studies and clinical trials, which further promote the application of curcumin as a bioactive ingredient in several functional products, including functional foods, nutraceuticals, cosmetics and drugs. Limitations and future perspectives of such uses of curcumin as a bio-functional ingredient are also discussed.

1. Introduction

Many long-term medical conditions have been related to oxidative stress, thrombotic incidents and inflammatory consequences. The World Health Organization (WHO) reports that chronic inflammatory non-communicable illnesses, including cancer, obesity, diabetes, heart problems, stroke and chronic respiratory diseases account for three out of every five deaths globally. Thus, it has been determined that the biggest risk to human health is chronic inflammatory disease [1]. Such chronic inflammation-related disorders begin and progress as a result of ongoing, inappropriate inflammatory activation, which is followed by endothelial dysfunction and oxidative damage at the inflammatory sites. Several typical platelet agonists, involving collagen and adenosine diphosphate (ADP), thrombo-inflammatory mediators like platelet-activating factor (PAF) and thrombin, as well as reactive oxygen species (ROS) are usually involved in these processes [2,3].

Treatment for inflammatory diseases comprise corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and biologic pharmaceuticals, among other medication types. However, these medications exhibit a number of side effects and pose various environmental challenges, while using biologic pharmaceuticals is costly. Therefore, despite their usefulness, the scientific community is looking for alternative solutions. One such alternative approach that has gained the attention of researchers is natural products, which have low toxicity and increased pharmacological activity. Among these products, polysaccharides, flavonoids, polyphenols, alkaloids, terpenes, natural pigments, volatile oils from plants and other pharmacological compounds are listed [4,5,6].

A natural product of great scientific interest and research is turmeric, which has gained international recognition for its medicinal properties and originated in Asia. It belongs to a class of compounds known as polyphenols, which own powerful biological effects. Among a large number of compounds isolated from turmeric, curcumin is the most widely studied compound as evidenced by the vast number of references in the literature. Briefly, it is an unflavored, orange–red, photosensitive powder with a molecular weight equal to 368.39 g/mol (chemical formula: C₂₁H₂₀O₆). Although hydrophobic, curcumin dissolves in organic solvents like ethanol and acetone [7,8].

Curcumin is being currently investigated in a number of areas, including medicine, cosmetics and nutrition as a result of its multifaceted biological activity. Targeting several routes and substances, curcumin reduces inflammation. Specifically, it inhibits the nuclear factor kappa B (NF–κB) pathway, a major contributor to inflammation and downregulates the production of inflammatory chemical compounds (interleukins including IL–1β, Il–6 and the tumor necrosis factor α (TNF–α)) and enzymes (inducible nitric oxide synthase (iNOS), cyclooxygenase–2 inhibitor (COX-2) etc.). Additionally, curcumin eliminates free radicals which damage cells in its role as an antioxidant. It also reduces pain perception through antinociceptive actions and promotes tissue regeneration, which aid the healing of wounds. Gram-positive and gram-negative bacterial membranes are highly affected as well by curcumin’s antibacterial activities. It prevents bacteria from adhering to host receptors and limits their growth, virulence factors and biofilm formation. Curcumin prevents platelet aggregation caused by collagen, adrenaline and arachidonic acid (ARA), among other physiological factors. More specifically, platelet aggregation is restrained by curcumin as it inhibits cyclooxygenase (COX), which lowers the production of thromboxane (TX). Furthermore, curcumin effectively suppresses platelet aggregation and TX formation by increasing the lipoxygenase pathway synthesis of 12–hydroxyeicosatetraenoic acid (12-HETE) [9,10,11].

Curcumin has demonstrated potent anticoagulant and antiplatelet aggregation properties, as well as antithrombotic effects. Several studies highlight its beneficial impact on platelets, establishing curcumin as a promising candidate for the treatment of related conditions, given that platelet activation and aggregation are key processes in atherosclerotic thrombosis. The secretion and aggregation of platelets is a complex process, triggered by epinephrine, adenosine diphosphate, PAF, thrombin, collagen and arachidonic acid. Additionally, curcumin is widely used as an anti-inflammatory agent in traditional medicine. In patients with arthritis, it has been found to reduce the production of pro-inflammatory eicosanoids, as well as alleviate edema, morning stiffness, and other symptoms. The oral administration of curcumin also reduced acute inflammation caused by carrageenan in rats. Furthermore, curcumin has been shown to inhibit atherosclerosis and platelet aggregation, while reducing angiogenesis in adipose tissue. In cerebral microcirculation, curcumin significantly decreased platelet and leukocyte adhesion, primarily modulating the endothelium to minimize platelet adhesion. It also improved P-selectin expression and survival rates in mice after cecal ligation and puncture, while altering platelet and leukocyte adhesion and mitigating blood–brain barrier dysfunction [8,12,13]. Curcumin, along with its derivatives (curcuminoids) and more complex curcumin-based compounds, has been shown to inhibit platelet activation and aggregation triggered by PAF-related thrombo-inflammatory signaling. This is achieved by directly blocking the binding of PAF to its receptor (PAFR), as well as through various other mechanisms, such as directly inhibiting the deacetylation of arachidonic acid or indirectly disrupting its interaction with platelet phospholipids. Additionally, curcumin can directly suppress the calcium signaling pathway, antagonize the GP II B/III A receptor, inhibit the cyclooxygenase pathway, and prevent the formation of thromboxane A2, thus blocking platelet aggregation and thrombosis. By regulating multiple processes involved in platelet aggregation, curcuminoids have consistently demonstrated measurable antiplatelet effects. Consequently, curcuminoids could potentially act as therapeutic agents in preventing disorders associated with platelet activation [8,12,14,15]. A summary of curcumin’s great potential and activities is depicted in Figure 1.

Curcumin has been the subject of numerous in vitro and in vivo experiments. This compound has attracted attention in scientific research due to its potential health benefits, including its anti-inflammatory, antioxidant and antithrombotic properties [11]. This article’s main purpose is to provide an extensive examination of these studies.

Due to the fact that curcumin has so many beneficial properties, it may be used in a wide range of ways. For instance, it is a major component utilized in the production of functional foods, pharmaceuticals and cosmetics (Figure 2). In terms of functional foods, turmeric content is accountable for an increase in nutritional value and health-promoting attributes. Turmeric functional foods may be applied to cereal-based foods, milk-based products, beverage enrichment, meat-based consumables, films and coatings. Curcumin displays also vast biological action against a number of conditions, such as autoimmune, neurological, cancer and cardiovascular disorders. Additionally, it affects several cellular targets and pathways as it, for example, controls the action of growth factors, transcription factors, cytokines, (pro)inflammatory mediators and enzymes [7].

In the pharmaceutical industry, curcumin is the leading component in anticancer drug formulations, comprising more than 50% of the global market. It is closely followed by applications in the food and cosmetics industries. In contemporary cosmetology, there is an increasing incorporation of valuable plant-based ingredients into skincare products, with curcumin’s role becoming more prominent due to its potent antioxidant, anti-inflammatory, and anti-aging properties. This trend is expected to significantly boost the financial growth of the cosmetics market in the near future (Figure 2) [7].

Curcumin targets multiple cellular pathways and thus, curcumin–based pharmaceutical products are being explored for the treatment of various pestering diseases. The considerable potential of curcumin for decreasing photodamage to the skin, minimizing signs of aging and being utilized in skin care products for acne-prone skin, is still far from being fully elucidated [16,17,18,19,20,21].

Although curcumin has many advantages with regard to human health, it is important to acknowledge its limits. For example, it confronts difficulties in absorption, distribution, metabolism and excretion (ADME), resulting in a short half-life in the gastrointestinal system. These processes collectively impact the amount of curcumin available for our body to use, limiting its effectiveness. In addition to its low availability, curcumin also has a low water solubility, is unstable in alkaline environments and undergoes rapid metabolism into inactive forms and conjugates, which further reduce its bioactivity. Due to these restrictions, curcumin’s therapeutic potential is hampered, emphasizing the necessity of developing methods to increase its bioavailability, stability and metabolic profile [18,22,23,24]. Numerous tests have demonstrated that curcumin is safe, but because of possible adverse effects, especially regarding larger dosages, prudence is suggested. These complications include the risk of increased oxalate-induced kidney stones, anemia in iron-deficient individuals, liver damage, abnormal cardiac rhythms, drug interaction, allergic reactions and many other side effects [8,11,25]. Within this article, curcumin’s significance for food, cosmetics and pharmaceutical-related applications, as well as its anti-inflammatory, antithrombotic and antioxidant health-promoting properties, will be further evaluated and discussed (Figure 3).

Various extraction procedures, such as Soxhlet extraction, maceration, or contemporary technologies like ultrasonic or microwave extraction, are used to isolate curcumin from turmeric rhizome. Curcumin is extracted, separately using thin-layer chromatography (TLC), and is quantified by high-performance liquid chromatography (HPLC). While modern methods provide advantages like lower temperatures and less solvent usage, Soxhlet extraction is reported to deliver the highest amount of curcumin [9,10].

2. Applications of Curcumin

2.1. Curcumin in Food Industry

The addition of bioactive compounds like curcumin to consumable products has garnered increasing attention, as consumers become more conscious and adopt healthier eating habits. With its appealing bright yellow–orange shade, curcumin has been used as a natural food coloring ingredient. It is frequently preferred in order to enhance the appearance of dishes such as rice, beef, mustards and other food products. Apart from its widespread use as a food coloring, curcumin may also be used in food products as a natural and safe antioxidant and antibacterial agent, replacing artificial, harmful ones [26,27]. Studies on the food uses of curcumin have been widely conducted, many of which are covered in the section that follows and are included in

Table 1. Indicative studies of curcumin in the food industry.

Aim of the Study	Study Design	Results	Reference
The incorporation of curcumin into milk and the observation of its effects, was evaluated in this study (in vitro and in vivo)	Commercial milk products were used together with mucin from porcine stomach type II, pepsin from porcine gastric mucosa, lipase from porcine pancreas type II, and pancreatin from porcine pancreas. Curcumin-loaded milk was prepared using the pH-driven method. Curcumin powder was dissolved at pH = 12.0 for the 0.9% (w/v) solution, which was subsequently mixed with commercial milk of varying fat contents while being continuously agitated at room temperature (1:19 ratio) The curcumin-loaded milk was subsequently adjusted to pH 6.5 and stirred for 30 min in the dark, achieving a final concentration of 0.45 mg/mL, before being stored in a refrigerator at 4 °C.	Curcumin-loaded milk was more chemically stable when exposed to pasteurization, had improved its quality in long-term conditions and had better absorption by the body, suggesting its potential health-promoting benefits. Curcumin can be successfully integrated into milk products with different fat levels, as it interacts with both milk fat droplets and protein micelles. When fat is absent, curcumin primarily binds to protein micelles. Encapsulation of curcumin improved its in vivo bioactivity and in vitro bio-accessibility	[28]
Fortifying zobo with turmeric which improved its nutritional value and health benefits, was the aim of this study (in vitro)	Various ingredients, including dried Zobo calyces, turmeric roots, ascorbic acid, folic acid, chlorogenic acid, trans-ferulic acid and delphinidin- and cyanidin-3-sambubioside were procured. Turmeric paste was prepared by blending 40 g of finely chopped turmeric root with 80 mL of water for 4 min until smooth. Following the preparation of the control samples, four turmeric-fortified Zobo samples were also created: Zobo with boiled turmeric at 2% w/w, Zobo with boiled turmeric at 6% w/w, Zobo with fresh turmeric paste at 2% w/w, and Zobo with fresh turmeric paste at 6% w/w. All samples were prepared using water and H. sabdariffa calyces in a 2:25 weight ratio. All samples were freeze-dried, and measurements were taken for pH, moisture content, ash content, crude protein content, mineral and vitamin levels, as well as chlorogenic and ferulic acid, and anthocyanin determination	Fortifying Zobo with boiled turmeric enhanced its antioxidant and nutritional qualities, particularly in terms of vitamin C, polyphenols and iron, suggesting its potential as a health-promoting beverage. The heat treatment applied increased vitamin C and anthocyanins concentration. Anthocyanin, chlorogenic and ferulic acid, as well as ascorbic acid, were present in the turmeric-fortified Zobo drink. Adding 2% boiled turmeric to street-vended Zobo could provide health benefits for both Nigerian and Mediterranean dietary patterns.	[29]
The aim of this study was to assess the impact of turmeric supplementation on specific quality attributes, oxidative stability, and safety of duck meat burgers (in vitro)	Superficial deep muscles of Peking ducks, culinary elements without breast muscles or bones, turmeric powder and turmeric extract were purchased and used. Duck breast meat with skin was chilled to 0 ± 2 °C and subsequently cut into 3–4 cm cubes A total of 18 kg of raw meat was processed through a meat grinder twice and divided into four different portions. Group I served as the control and consisted of duck meat burgers without turmeric. Groups II–IV contained turmeric-enhanced burgers: Group II with ground turmeric root in dry paste form, Group III with turmeric extract and Group IV with turmeric paste. Meat masses were mixed separately and burgers in a shape of flat disks were formed by thermal treatment at 180 °C. Physical traits and sensory assessments, as well as statistical analysis, were then conducted.	Turmeric supplementation in duck meat burgers effectively reduced lipid oxidation in products stored under refrigeration for 18 days. Maintained microbial stability, and various quality attributes influence such as pH, water retention and color were recorded Desirable aroma, taste and juiciness were also exhibited in turmeric paste meat. Burgers containing turmeric powder were also noted for their appealing aroma and strong flavor.	[30]
Addition of turmeric powder and ascorbic acid to rabbit meat formulations that will affect various quality parameters of burgers, was discussed in this study(in vitro and in vivo)	A total of 36 hybrid rabbits (2.5 ± 0.10 kg) reared under intensive conditions and were fed a commercial pelleted feed, before undergoing the slaughter method. Following 24 h of chilling at 4 ± 0.5 °C, the hind legs were carefully separated from the carcasses and deboned using a standard method. Six batches of meat were prepared, each divided into three formulations: control, turmeric powder and ascorbic acid Six burgers (~50 g) were shaped in petri dishes to produce a total of 36 burgers per formulation, which were packaged and stored at 4 ± 1 °C for 0 and 7 days. Chemical composition, pH, drip loss, cooking loss, color, microbial assay, fatty acid, thiobarbituric acid reactive substances (TBARS), antioxidant properties, radical cation decolorization assay (ABTS+), ferric reducing ability assay (FRAP) and statistical analysis were conducted and determined.	The inclusion of 3.5% turmeric powder positively affected the oxidative stability and quality attributes of rabbit burgers stored under refrigeration. It also altered the meat’s color and provided antioxidant capacity comparable to that of ascorbic acid, particularly in rabbit meat, which is high in polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Turmeric acted as a natural antioxidant which helped prevent the meat from spoiling and potentially extended the shelf life of the burgers. Also, it was considered as a functional food source for its anti-inflammatory and anti-infectious properties.	[31]
An evaluation of the neuroprotective effect and pharmacokinetic profile of turmeric extract and its combination with essential oil, was analyzed further in this study (in vitro and in vivo)	Turmeric rhizomes were extracted using ethyl acetate to yield oleoresin; curcuminoids separated from the oleoresin and turmeric essential oil blended with turmeric extract (TE + EO) were utilized, along with aluminum chloride, curcumin sulfate, hexahydrocurcumin and tetrahydro curcumin. Swiss albino mice were selected as the animal model for the study. The mice were caged and maintained at a room temperature of 22 ± 2 °C and on a 12:12 h dark cycle, and were provided with plenty of food and water. An intraperitoneal route (i.p.) was utilized to give 40 mg/kg/day of aluminum chloride, and the following groups participated in a neurotoxicity study: (1) vehicle control (0.3% carboxymethyl cellulose (CMC)), (2) positive control (AlCl3–treated; 40 mg/kg, i.p.), (3) TE + EO; 25 mg/kg, oral, (4) TE + EO; 50 mg/kg, oral + AlCl3–treated; 40 mg/kg, i.p. For 45 days, mice were given TE + EO orally at a dosage of 50 mg/kg body weight (BW), suspended in 0.3% CMC. Phytochemical analysis, pharmacokinetics, Morris’s water and elevated plus maze test, analysis of curcumin, derivatives and metabolites, biochemical assessments, histopathology and statistical analysis were conducted.	TE + EO exhibited neuroprotective and antioxidant effects against aluminum-induced neurotoxicity, attributed to the improved bioavailability and tissue distribution of free curcumin and its metabolites. TE + EO reversed the effects of chronic exposure to Al, by increasing the expression of antioxidants, which reduces the activation of microglia and subsequent neuronal damage, and by first facilitating greater plasma bioavailability and curcuminoids’ entry into the brain. TE + EO plus showed an enhanced capacity to neutralize free radicals, bind to redox metal ions and pass through the blood–brain barrier. TE + EO is a promising prophylaxis and treatment solution for neurodegenerative diseases, as it reduces neuroinflammation and oxidative stress, and it improves memory in mice exposed to aluminum.	[32]
An investigation on the protective effects of turmeric extract and curcumin against liver injury induced by carbon tetrachloride (CCl4) in rats, was conducted in this study (in vitro and in vivo)	CCl4, curcumin, malondialdehyde (MDA), glutathione (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, triglyceride, HDL and LDL cholesterol were utilized. A total of 70 male Sprague Dawley rats (250–270 g) were selected and i.p. injected with a mixture of CCl4 (0.1 mL/100 g BW) and olive oil (1:1 v/v) every other day for 4 weeks. Turmeric was administered orally to rats at dosages of 100, 200 and 300 mg/kg/BW, while curcumin was administered once daily at a level of 200 mg/kg. All rats were fed a chow diet and maintained at 22–23 °C with a 12-h light/dark cycle. After receiving their final injection of CCl4, the rats in the control group were given the same care and were sacrificed using diethyl ether. Samples of blood and liver were obtained; entire blood was chilled in a centrifuge tube for thirty minutes; all liver tissue samples were preserved at −75 °C. Histologic analysis, blood biochemical marker assays, total lipid, triglyceride and cholesterol levels’ measurements, lipid peroxidation analysis, GSH measurement, Sirius red collaged staining and statistical analysis were conducted	Curcumin and turmeric extract reduced oxidative stress, prevented lipid peroxidation and increased glutathione peroxidase (GPx) activity, shielding the liver from CCl4-induced damage. Curcumin and turmeric extracts inhibited the increase of aminotransferase levels, reversed elevated ALT and AST levels, attenuated CCl4–mediated hepatic lipid accumulation and restored total cholesterol and LDL levels. Both turmeric extract and curcumin treatment, reduced oxidative stress, improved the GSH/oxidized GSH (GSSG) ratio and ameliorated the accumulation of ROS in the liver.	[33]

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Gao et al. [28] performed an experiment in which curcumin was encapsulated in milk fat beads and protein micelles. The researchers used a simulated digestion model to evaluate how curcumin behaved in milk samples after they mimicked human digestion. Milk loaded with curcumin was compared to a simple mix of curcumin powder and milk. Milk loaded with curcumin reportedly remained stable throughout digestion, while curcumin powder in milk did not. Moreover, milk that was loaded with curcumin also released more curcumin that could potentially be absorbed by the body (higher bio-accessibility), as compared to the mix with curcumin powder. This is likely due to curcumin being hidden within fat or protein parts of the milk, which enhance its protection and its easier release during digestion. Interestingly, whole milk with fat did not necessarily improve curcumin absorption compared to skimmed milk. This finding suggested that other factors besides fat might exist in milk and may aid curcumin’s absorption [28].

Another relevant study investigated the potential use of turmeric root in enhancing the nutritional quality of a street-vended Zobo drink, a popular beverage in Nigeria. The obtained results indicated that adding boiling turmeric to Zobo boosted its nutritional value and antioxidant content, as demonstrated by the higher levels of anthocyanins and vitamin C found [29]. Augustyńska-Prejsnar et al. [30] investigated the effects of adding turmeric (powder or paste) to duck burgers. Turmeric paste and powder efficiently reduced lipid oxidation in the burgers throughout an 18-day refrigerated storage period; the burgers with powdered turmeric showed the lowest level of oxidation. Turmeric additives also influenced pH, water retention and the color of burgers, with turmeric paste resulting in the most desirable sensory attributes, including aroma, taste and juiciness. Overall, the study suggested that turmeric additives enhance the oxidative stability and microbiological safety of duck meat burgers, with turmeric paste yielding particularly favorable sensory qualities [30]. Mancini et al. [31] evaluated the impact of adding ascorbic acid and turmeric powder to rabbit meat burgers during refrigerated storage. According to this study’s results, turmeric powder minimizes cooking loss and promotes meat’s antioxidant capacity to that of ascorbic acid [31].

In a series of studies, researchers inquired into the neuroprotective and hepatoprotective effects of turmeric extract and its components in animal models. Banji et al. [32] studied the effects of turmeric extract on aluminum-induced neurotoxicity in Swiss albino mice. It was then found that treatment with turmeric extract plus essential oil significantly reversed aluminum-induced spatial learning and memory impairment, decreased lipid peroxidation, and improved antioxidant enzyme levels, suggesting its high neuroprotective potential [32]. Lee et al. [33] demonstrated that turmeric extract and curcumin mitigated liver damage induced by carbon tetrachloride in rats by reducing serum liver enzyme activities and boosting hepatic glutathione levels [33]. The most important outcomes of each selective indicative study are depicted in Table 1.

2.2. Curcumin in Medicinal Purposes

The rhizome of Curcuma longa L., commonly known as turmeric, has been historically utilized for its medicinal properties across diverse cultural contexts, notably within traditional medical systems including Islamic, Chinese and Ayurvedic traditions. Its therapeutic applications encompass a broad spectrum of maladies ranging from gastrointestinal disturbances to cardiovascular, hepatic, and neurological ailments, as well as inflammatory conditions like arthritis. Central to turmeric’s medicinal efficacy is curcumin, a bioactive compound characterized by its anti-inflammatory, antioxidant and anticancer attributes, along with its capacity to ameliorate metabolic dysregulation, cognitive function and mood disorders [34].

Li et al. [35] sought to evaluate the efficacy of curcumin in mitigating myocardial ischemia-reperfusion (I/R) injury, examining evidence from both animal experimentation and clinical trials. Employing a systematic review and meta-analysis methodology, the investigation encompassed 24 animal studies and four human trials. Results indicated that curcumin exhibited significant reductions in myocardial infarction size, enhancement of cardiac function indices and favorable modulation of various markers indicative of myocardial injury, oxidative stress, apoptosis and inflammation in animal models. Moreover, clinical investigations suggested potential benefits of curcumin in ameliorating cardiac dysfunction, hospital-acquired myocardial infarction and major adverse cardiovascular events (MACE) within short-term observation periods. Overall, all findings underscore the putative cardioprotective attributes of curcumin against myocardial infarction, primarily attributed to its anti-inflammatory and antioxidant properties [35].

In order to determine if curcumin is effective at reducing cardiac ischemia/reperfusion (I/R) injury in animal models, Zeng et al. [36] performed a meta-analysis. A thorough analysis of research published up to January 2023 revealed 37 studies involving 771 animals. Curcumin dramatically decreased the extent of myocardial infarction, enhanced cardiac function and lowered markers of oxidative stress and myocardial injury, according to the analysis. Subgroup analyses revealed dose and treatment condition-related significant differences, but some publication bias was seen. Overall, research in larger animals and human trials are required for the validation of curcumin’s potential cardioprotective properties against myocardial I/R injury in animal models [36].

Wei et al. [37] studied curcumin and its ability to protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury. Their investigation of the protective effects of Cur used a range of analytical methodologies, with a particular emphasis on morphological alterations, cell viability, oxidative stress and apoptosis in H9c2 cardiomyocytes. Under H/R conditions, the researchers saw significant changes in cell shape and decreased viability, coupled with increased apoptosis and elevated levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH), along with decreased superoxide dismutase (SOD) activity. These effects were successfully counteracted by curcumin therapy, which also increased SOD activity, decreased ROS and apoptosis, and restored LDH and MDA levels. Curcumin also reduced the stress on the endoplasmic reticulum (ER) caused by H/R and inhibited the signaling cascade of mitogen-activated protein kinase (MAPK), which includes p38, JNK and ERK1/2. These results underline curcumin’s cardioprotective qualities by showing how it can reduce heart damage via regulating ER stress and MAPK signaling pathways [37].

Dolatabadi et al. [38] investigated the possibility of using curcumin as a medicinal drug to lessen the cognitive and neurological damage brought on by global cerebral ischemia (GCI). In a rat model of GCI, curcumin—which is well known for its anti-inflammatory, antioxidant and neuroprotective qualities—was examined for its impact on neurological deficiencies, memory impairment and spatial neural distribution in the Cornu Ammonis 1 (CA1) area of the hippocampus. Forty-six male Sprague Dawley rats were used in the investigation, and they were divided into four groups at random. The treatment periods for each group were further split into short-term (7 days) and long-term (28 days). At different post-operative days, neurological evaluations were conducted, such as the traction test, passive avoidance task and neurological severity score (NSS). Furthermore, on days 7 and 28 following GCI, the Voronoi tessellation and the novel object identification test were carried out. In comparison to the control and lower dose (50 mg/kg) groups, the results demonstrated that curcumin at a dose of 100 mg/kg dramatically improved neurological scores and decreased memory deficits. In particular, step-through latency times and the novelty preference index showed significant improvements in the high-dose curcumin group, suggesting improved memory performance. Additionally, a 100 mg/kg dose of curcumin maintained neuronal aggregation in the CA1 area at levels similar to those of normal rats. Overall, the study shows that curcumin successfully improves memory and neurological deficits following GCI and restores neuronal distribution in the CA1 region. This is especially true at higher doses and with long-term treatment. These findings suggest that curcumin holds promise as a therapeutic agent for reducing brain complications associated with ischemia [38].

Zhang and Wu [39] aimed to evaluate curcumin’s possible chemoprotective benefits against doxorubicin-induced cardiotoxicity. Doxorubicin administration was linked, in comparison to control groups, to lower cell survival, increased mortality, decreased body weight, heart weight and heart-to-body weight ratio, according to an analysis of in vitro and in vivo investigations. Curcumin co-administration, however, demonstrated a reversal of these effects seen in groups receiving doxorubicin alone. Additionally, doxorubicin caused notable histological and biochemical changes in heart tissue, both of which were substantially lessened by curcumin cotreatment [39].

Sayevand et al. [40] examined how moderate exercise and curcumin supplementation, both known to have protective effects on the heart, might work together to prevent heart damage caused by lack of blood flow (I/R injury). Researchers used rats and assigned them to groups that either received no treatment, exercise alone, curcumin alone, both exercise and curcumin, or just the I/R injury. They looked at genes involved in amyloid plaque formation and markers of heart damage. The obtained results demonstrated that both exercise and curcumin supplementation individually mitigated the mRNA expression of amyloid precursor protein and associated enzymes (β-secretase-1, presenilin-1 and -2), reduced infarct size and elevated neprilysin gene expression in myocardial tissue. Nonetheless, the combined regimen failed to confer additional benefits compared to singular interventions [40].

Neerati et al. [41] studied the potential benefits of curcumin capsules in lowering lipid levels and inhibiting permeability glycoprotein (P-gp), thereby affecting the pharmacokinetics and pharmacodynamics of glyburide, a medication used in type-2 diabetes mellitus management. An open-label, randomized controlled trial involving eight patients with type-2 diabetes on glyburide therapy was conducted over 11 days. Glucose levels decreased, while Area Under first Movement Curve (AUMC) increased, with no instances of hypoglycemia observed. Furthermore, significant reductions in low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and triglyceride levels, along with increased high-density lipoprotein (HDL) content, were noted. Co-administration of curcumin capsules with glyburide demonstrated potential benefits for improving glycemic control and exhibited lipid-lowering and antidiabetic properties, suggesting a potential role for curcumin as a future drug molecule [41].

Han et al. [42] aimed to elucidate the mechanism via which curcumin influenced energy metabolism, focusing on its effects on thermogenesis and obesity. By utilizing a mouse model fed a high-fat diet (HFD), researchers found that curcumin supplementation resulted in reduced weight gain and improved cold tolerance, indicative of enhanced adaptive thermogenesis. These effects were contingent upon the presence of uncoupling protein 1 (Ucp1), a pivotal regulator of thermogenesis. Analysis of the gut microbiota (GM) revealed that curcumin induced alterations in microbial composition in HFD-fed mice. Moreover, curcumin influenced bile acid (BA) metabolism, elevating levels of deoxycholic acid (DCA) and lithocholic acid (LCA), as potent ligands for G protein-coupled membrane receptor 5 (TGR5). Mechanistically, curcumin activated the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in thermogenic adipose tissue through the modulation of the GM and TGR5. These findings underscore the potential of targeting the GM to modulate thermogenesis and combat obesity [42].

In rats that had been overfed early in the neonatal period, Zhu et al. [43] investigated the effects of curcumin (CUR) supplementation on white adipose tissue (WAT) browning and thermogenesis. Metabolic imprinting resulting from early overfeeding has been linked to reduced energy expenditure and increased WAT accumulation over the course of a lifetime. The purpose of the study was to ascertain whether CUR may mitigate these effects by stimulating thermogenic mechanisms and encouraging WAT browning. For 10 weeks, rats with small litters (SL) were fed either a regular diet or a diet supplemented with 1% or 2% CUR. When compared to SL rats that were not treated, the study’s conclusion showed that the rats administered 2% CUR had decreased body weight, decreased WAT growth, and improved blood lipid levels and glucose tolerance. In subcutaneous adipose tissue (SAT), CUR supplementation significantly enhanced heat production and browning-related gene expression; these effects were more noticeable at the 2% dose. Overall, by increasing energy expenditure and SAT browning, CUR supplementation reduced body fat and metabolic diseases [43].

Du et al. [44] explored how curcumin (CUR) affects postnatal overfed rats, a model for early-life overnutrition, which raises the risk of obesity and metabolic diseases. Male rats were divided into normal (NL) and overfed small litters (SL). From weaning, SL rats received either a normal diet or a 2% CUR diet starting at weaning (W3), puberty (W6), or end of puberty (W8) for 10 weeks. Results showed that CUR starting at weaning (SL-CURW13) or early puberty (SL-CURW16) significantly reduced body weight and fat gain, and improved glucose and lipid levels, with SL-CURW13 being the most effective. CUR had no effect and began at the end of puberty (SL-CURW18). The findings emphasize how early CUR intervention prior to puberty can significantly ameliorate the consequences of early-life overnutrition [44].

The effects of supplementing with curcumin throughout pregnancy and lactation on the offspring of obese mice were studied by Santos et al. [45]. Three groups of pregnant and nursing female mice were used: hyperglycemic (high-sugar diet), curcumin (high-sugar diet combined with curcumin) and control (normal diet). The offspring were subsequently given a 12-week high-sugar diet. The results indicated that, compared to those from hyperglycemic dams, the offspring of curcumin-supplemented dams experienced decreased weight increase and food consumption. They also showed decreased insulin, glucose and cholesterol levels, as well as enhanced glucose tolerance. Adipose tissues had higher expression levels of the thermogenesis markers UCP1 and PRDM16, according to molecular studies. According to the study, supplementing with curcumin during pregnancy and lactation may promote thermogenesis and improve metabolic outcomes in children fed an obesogenic diet [45].

A similar investigation [46] aimed to evaluate the inhibitory capacity of curcumin against two pathogenic gram-positive bacteria, Streptococcus mutans and Streptococcus pyogenes, in comparison to the antibiotic ciprofloxacin, by utilizing the well diffusion method. Minimum Inhibitory Concentration (MIC) assays demonstrated that curcumin effectively hindered the growth of both Streptococcus mutans and Streptococcus pyogenes. Curcumin produced inhibition zones of 9.7 mm and 10.2 mm against S. mutans and S. pyogenes, respectively. While these zones were smaller compared to those produced by Ciprofloxacin (15.52 mm and 13.4 mm for S. mutans and S. pyogenes, correspondingly), they provide evidence for curcumin’s potent antibacterial properties. The observed antimicrobial activity of curcumin against these bacteria suggested its potential application in controlling dental biofilms and preventing dental caries [46].

Namgyal et al. [47] explored the potential neuroprotective effects of curcumin against cadmium-induced neurotoxicity. Using Swiss Albino mice previously exposed to cadmium, the study evaluates the impacts of various concentrations of curcumin (20, 40, 80 and 160 mg/kg) on behavior, biochemical parameters, hippocampal proteins (brain-derived neurotrophic factor (BDNF), cyclic amp–response element binding protein (CREB), doublecortin (DCX), Synapsin II and histological alterations. The findings reveal that cadmium (Cd) exposure elicits behavioral deficits, oxidative stress, diminished levels of hippocampal neurogenesis-associated proteins and neuronal degeneration in the CA3 region and cortex. Nonetheless, treatment with differing concentrations of curcumin effectively mitigates these effects, with the highest dosage (160 mg/kg body weight) exhibiting pronounced efficacy. This finding suggests that curcumin counteracts Cd-induced neurotoxicity and fosters neurogenesis, potentially offering therapeutic advantages against heavy metal-triggered neuronal harm [47]. Below is a summary of several significant and recent pharmacological uses, which are included in Table 2.

2.3. Curcumin in Wound Healing

Curcumin also has considerable potential in the area of wound healing. Curcumin, well known for its anti-inflammatory, antioxidant and antibacterial qualities, provides a variety of benefits to aid the complex process of tissue healing. It helps to create the ideal environment for healing by reducing inflammatory reactions, eliminating damaging free radicals and preventing microbial developments. Its capacity to increase angiogenesis and stimulate collagen production further emphasizes its function in promoting vascularization and tissue regeneration [48].

In this section, the research regarding curcumin in wound healing will be discussed. An in vivo study investigated a curcumin nano-formulation as a wound healing treatment in rats. While wound closure was not significantly faster than in the control treatment, the curcumin formulation appeared to improve other healing aspects. Specifically, the curcumin nano-formulation may reduce inflammation as effectively as the control medication, while both treatments exhibited similar progress in blood vessel formation and skin cell growth. Importantly, the curcumin formulation significantly increased collagen production compared to the control. These observations pointed to the curcumin nano-formulation’s potential as a wound healing agent by suggesting that it may improve wound repair via lowering inflammation, encouraging angiogenesis, fibroblast proliferation and collagen formation [49]. Also, Cao et al. [50] explored how curcumin helps diabetic foot ulcers (DFU) heal. By delving into cells and rats with DFU, researchers discovered the miR-152-3p molecule that is high in DFU and the FBN1 one that is correspondingly low. Curcumin promoted angiogenesis, proliferation, migration and inhibition of fibroblast apoptosis, all of which sped up the wound healing process [50].

Table 2. Indicative studies of curcumin in the pharmaceutical industry.

Aim of the Study	Study Design	Results	Reference
This study sought to validate curcumin’s potential for cardio-protection against myocardial ischemia/reperfusion damage (in vivo and in vitro)	The study employed a systematic review and meta-analysis methodology to assess both preclinical (animal model) and clinical evidence. Eight databases were used, and 24 studies involving animals, totaling 503 animals, and 4 studies involving humans, totaling 435 patients, were included.	Curcumin reduced myocardial infarction size, improved cardiac function and showed beneficial effects on markers of myocardial injury and inflammation in animals. Research on animals suggests that curcumin may have cardioprotective benefits in cases of acute myocardial infraction, primarily via antioxidative, anti-inflammatory, anti-apoptotic and anti-fibrosis properties. Curcumin’s effectiveness is mostly demonstrated by lowering the frequency of myocardial infraction and MACE, and it may require a longer course of treatment and a higher dose to protect the myocardium.	[35]
Evaluation of the efficacy of curcumin in preventing myocardial ischemia/reperfusion (I/R) injury in animal models, through a comprehensive meta-analysis of preclinical studies (in vivo)	Designing a meta-analysis and systematic review. Up until January 2023, studies were gathered from the following databases: Wan-Fang, CNKI, Embase, Wan-Med, Web of Science and VIP. Methodological quality evaluated with the RoB tool from SYRCLE. To handle substantial heterogeneity, sensitivity and subgroup analyses were carried out. A funnel plot is used to analyze publication bias.	Curcumin treatment significantly decreased the size of the myocardial infarction. Better heart function and reduced expression of biomarkers for myocardial injury. Significant drops in serum inflammatory cytokine levels and the heart apoptosis index, suggesting anti-inflammatory and anti-apoptotic qualities. Subgroup analysis exposed differences in dosage, species, animal type, administration technique and treatment duration.	[36]
Investigation of the efficacy of curcumin in mitigating hypoxia/reoxygenation (H/R) injury in cardiomyocytes (in vitro).	The research focused on morphological alterations, cell viability, oxidative stress and apoptosis in H9c2 cardiomyocytes in order to investigate the protective effects of Cur.	Notable alterations in cell shape and lower viability were seen by the researchers under H/R conditions. Additionally, there was an increase in apoptosis, a rise in malondialdehyde (MDA) and lactate dehydrogenase (LDH), and a drop in superoxide dismutase (SOD) activity. Curcumin treatment effectively mitigated these effects by increasing SOD activity, decreasing ROS and apoptosis, and elevating LDH and MDA levels. Curcumin decreased the amount of stress that H/R produced in the endoplasmic reticulum (ER) and inhibited the mitogen-activated protein kinase (MAPK) signaling cascade, which comprises p38, JNK, and ERK1/2.	[37]
Investigation of the potential of curcumin as a therapeutic agent for mitigating neurological and cognitive impairments caused by global cerebral ischemia (GCI) (in vivo and in vitro).	Forty-six male Sprague Dawley rats participated in the study, and they were divided into four groups at random: sham (n = 14), control (n = 14), curcumin 50 mg/kg (n = 14) and curcumin 100 mg/kg (n = 14). The treatment periods for each group were further split into short-term (7 days) and long-term (28 days). At different post-operative days, neurological evaluations such as the traction test, passive avoidance task and Neurological Severity Score (NSS) were carried out. In addition, on days 7 and 28 following GCI, the Voronoi tessellation and the new object recognition test were performed.	Compared to the control and lower dosage (50 mg/kg) groups, curcumin at a dose of 100 mg/kg significantly improved neurological scores and decreased memory impairments. Step-through latency times and the novelty preference index significantly improved in the high-dose curcumin group, suggesting improved memory function. Additionally, a 100-mg/kg dose of curcumin preserved neuronal aggregation in the CA1 area at a level similar to that of normal rats. In summary, the study shows that curcumin, especially at larger dosages and when taken over an extended period of time, can significantly improve memory and neurological impairments that result from GCI and restore neuronal distribution in the CA1 area.	[38]
This study aimed to confirm that co-administration of curcumin alleviated doxorubicin-induced cardiotoxicity via its antioxidant, antiapoptotic and anti-inflammatory properties (in vivo and in vitro).	The study design included both in vivo (animal model) and in vitro (cell cultures) components. Systematic reviews and meta-analysis framework, were held. Participants in this framework comprised patients, cells, or animals that had adverse cardiac effects generated by doxorubicin (in vivo), as well as control groups and cardiac cells that were harmed by the drug (in vitro).	The findings suggested that curcumin co-administration mitigated doxorubicin-induced cardiotoxicity through mechanisms involving antioxidant, antiapoptotic and anti-inflammatory effects. The chemotherapy drug doxorubicin caused biochemical and histological alterations in the heart’s cells and tissue, which resulted in adverse cardiac consequences. Curcumin co-treatment reduces the cardiotoxicity produced by doxorubicin by acting through many major pathways, including anti-inflammatory, anti-apoptotic and antioxidant ones.	[39]
Moderate-intensity aerobic exercise and curcumin supplementation individually administered would be able to demonstrate cardioprotective effects against myocardial injury induced by I/R, as proved in this clinical trial (in vivo and in vitro).	The study design primarily involved in vivo experimentation, as it utilized male Wistar rats as the experimental model. A total of 50 male Wistar rats, aged between six and eight weeks, were randomized into one of five groups (n = 10): (1) sedentary control, (2) sedentary I/R, (3) exercise (15–45 min at 12–24 m/min) with I/R, (4) curcumin (50 mg/kg/day) + I/R and (5) both exercise and I/R. The workout was a motor-driven horizontal treadmill familiarization and training session that consisted of ten minutes of jogging at a speed of ten meters per minute. The treadmill running program started at 12 m/min for 15 min/day on week 1 and gradually rose to 24 m/min for 45 min/day until week 7, when it stayed constant. The rats were then made to run five sessions each week for ten weeks. These rats were kept in clean, well-ventilated rooms with normal water and food in rodent cages with conventional temperature ranges of 21–24 °C and humidity levels of 40–50%. The size of infracts, the expression of the amyloid precursor protein gene, the enzymes β-secretase-1, presenilin-1 and -2, and neprilysin, a marker of β-amyloid precursor peptide breakdown in the rat left ventricle, were all studied.	Both exercise and curcumin supplementation independently exerted cardioprotective effects against I/R–induced injury. In the myocardium of both the exercise- and curcumin-treated rats, there was an increase in the gene expression of neprilysin and a decrease in the mRNA expression of amyloid precursor protein, β-secretase-1, presenilin-1 and -2, and infarct size. There were no more advantages shown with concurrent treatments (exercise combined with curcumin). In the rat heart, moderate aerobic exercise (15–45 min at 12–24 m/min, five times a week) and 50 mg/kg of curcumin supplementation reduced the size of I/R-induced infarcts, improved the expression of processing enzymes and the amyloid precursor protein (APP) genes, and increased the mRNA expression of neprilysin.	[40]
Co-administration of curcumin capsules with glyburide may have positive effects on lipid levels and enhance glycemic control in individuals with type-2 diabetes mellitus, as this study shows (in vivo and in vitro).	An open, randomized control trial was held in this study over 11 days on eight type-2 diabetes mellitus patients on glyburide therapy. Blood samples were taken from the patients on the first day of the trial at different intervals, spanning from 0.5 to 24 h, after 5 mg of glyburide was administered (in vitro study). On the eleventh day of the trial, a blood sample was taken again following ten days of curcumin treatment for the participants.	The results indicated that glyburide and curcumin capsules together improve glucose control in diabetic individuals. Glyburide concentrations altered at the second hour, maximum concentration was unchanged and glucose levels decreased. AUMC increased and no patient experienced hypoglycemia. LDL, VLDL and HDL increased, while patients who received glyburide and curcumin pills together experienced improved glycemic control.	[41]
Curcumin mediated the enhancement of thermogenesis and the reduction of obesity in mice, as evaluated in this clinical trial (in vivo)	The study design involved in vivo experiments conducted on HFD-fed mice. HFD-fed wild-type, uncoupling protein 1 (Ucp–1) knockout and G-protein-coupled membrane receptor5 (TGR5) knockout mice were treated with curcumin of a 100 mg/kg dose. 16S ribosomal DNA sequencing analysis, fecal microbiota transplantation (FTM) and endogenous GM depletion were held.	Curcumin treatment significantly reduced BW gain and enhanced cold tolerance in HFD-fed mice, indicating increased adaptive thermogenesis. Compared to control mice, mice treated with curcumin and fed a high-fat diet had reduced body weight gain and increased cold tolerance as a result of increased adaptive thermogenesis. Curcumin reorganized the GM in HFD-fed mice, according to the 16S ribosomal DNA sequencing study, and FTM and GM depletion showed that the GM mediated the improved impact of curcumin on Ucp-1 dependent thermogenesis. Curcumin increased the fractions of DCA and LCA in BA metabolism. By influencing the activity of BA metabolism, the GM eventually mediates the effects of curcumin on augmenting Ucp-1 thermogenesis and mitigating HFD-induced obesity.	[42]
Examination of the impact of curcumin (CUR) supplementation on white adipose tissue (WAT) browning and thermogenesis in rats subjected to early postnatal overfeeding (in vivo and in vitro).	The experimental design involved adjusting litter sizes to three (small litters, SL) or ten (normal litters, NL) to simulate early overfeeding or standard feeding conditions from postnatal day 3. From postnatal week 3, SL rats were given a standard diet, or a diet supplemented with 1% (SL1% CUR) or 2% (SL2% CUR) CUR for ten weeks. Various parameters were assessed at postnatal week 13 to evaluate the effects of CUR supplementation.	SL rats receiving 1% or 2% CUR supplementation exhibited lower body weight, reduced WAT gain and an increased lean mass ratio compared to SL rats that did not receive CUR. CUR supplementation also normalized glucose tolerance and blood lipid levels. The SL2% CUR group showed significant increases in heat generation, with higher expression levels of uncoupling protein 1 (UCP1) and other browning-related genes in subcutaneous adipose tissue (SAT). The SL1% CUR group did not show these effects. Additionally, 2% CUR supplementation led to elevated serum norepinephrine levels and increased mRNA expression of β3-adrenergic receptors in SAT. Overall, CUR supplementation mitigated body fat gain and metabolic disturbances in postnatally overfed rats, with more pronounced effects at the higher dose of 2%.	[43]
The aim of this study is to explore the impact of curcumin (CUR) supplementation on rats subjected to early postnatal overfeeding, a condition that increases the risk of obesity and metabolic diseases (in vivo).	Male rats were divided into normal litters (NL) and small litters (SL), with the SL group being overfed. After weaning, SL rats received a normal diet or a diet supplemented with 2% CUR starting at different developmental stages: weaning (W3), puberty (W6), or end of puberty (W8), for 10 weeks.	SL rats had higher body weight, glucose intolerance and hyperlipidemia compared to NL rats, especially after puberty. CUR supplementation starting at weaning (SL-CURW13) or early puberty (SL-CURW16) significantly reduced body weight gain, adipose tissue weight and improved glucose tolerance and serum lipid levels, with the SL-CURW13 group showing the most pronounced benefits. However, starting CUR supplementation at the end of puberty (SL-CURW18) did not produce significant improvements compared to untreated SL rats. The study suggests that prepuberty is a critical window for CUR intervention to effectively mitigate obesity and metabolic disorders caused by early-life overnutrition.	[44]
This study aimed to investigate the long-term effects of maternal obesity and dietary habits during pregnancy and lactation on the metabolic health of offspring, focusing on the potential benefits of curcumin supplementation (in vivo and in vitro).	In this study, 24 male mice were divided into three groups: control group (SD) (offspring of dams fed a standard diet), hyperglycemic group (HGD) (offspring of dams fed a hyperglycemic, high-sugar, diet) and curcumin group (CUR) (offspring of dams fed a hyperglycemic diet and supplemented with curcumin during pregnancy and lactation). All offspring were subsequently fed a hyper-glycemic diet for 12 weeks. Various parameters, including body weight, food consumption and biochemical markers, were assessed. Additionally, the study measured the expression of thermogenesis-related genes in the in-terscapular brown adipose tissue and inguinal white adipose tissue.	Offspring from the CUR group experienced less weight gain and reduced food consumption compared to those from the HGD group. Biochemical analyses indicated that the CUR group had lower levels of total cholesterol, glucose and insulin, alongside improved glucose tolerance and insulin sensitivity. Molecular assessments showed elevated mRNA expression of uncoupling protein 1 (UCP1) and PR domain containing 16 (PRDM16) in both brown and white adipose tissues, suggesting enhanced thermogenesis. Overall, curcumin supplementation during the pregnancy-lactation period in obese mice led to significant improvements in the metabolic health of their offspring, despite continued exposure to a high-sugar diet.	[45]
This study evaluated the potential of curcumin towards inhibiting the growth of two pathogenic Gram-positive bacteria commonly found in the oral cavity: Streptococcus mutans and Streptococcus pyogenes (in vitro).	This in vitro clinical trial involved growing bacteria in a controlled setting. Using the well diffusion technique, the questions of whether curcumin inhibited the growth of Streptococcus mutans and Streptococcus pyogenes more than the antibiotic ciprofloxacin was explored. MIC tests were also held.	The findings revealed that curcumin demonstrably inhibited the growth of both S. mutans and S. pyogenes. MICs revealed that ciprofloxacin’s inhibition zone was found to be 15.52 to 13.4 m, accordingly, while curcumin’s inhibition zone was found to be 9.7 and 10.2 mm for Streptococcus mutans and Streptococcus pyogenes growth, respectively. As an alternative treatment approach, curcumin has a therapeutic impact against pathogenic gram-positive bacteria, which may be helpful for regulating dental biofilms and the development of dental caries.	[46]
Curcumin administration may counteract the neurotoxic effects induced by Cd exposure in mice, as this study’s main aim proved (in vivo).	A total of 56 young Swiss Albino mice were used in this in vivo experiment, were housed in a propylene cage at an ambient temperature of 22 ± 2 °C and were given a plenty of food and tap water, and over the 60 days of the experiment they were kept in a regular cycle of light and shade. The animals were split into eight groups of seven mice each, and both CD and curcumin were given orally. Open field test analysis, novel object recognition tests, Morris’s water maze test, tissue sample collection, oxidative stress level and hippocampus protein estimation, morphometrical and histopathological analysis, as well as statistical analysis were held.	This study provided compelling evidence for curcumin’s ability to mitigate Cd-induced neurotoxicity and to promote neurogenesis in mice. Curcumin appeared to exert its neuroprotective effects by reducing oxidative stress and enhancing the expression of key neurogenic proteins in the hippocampus. Downregulation of hippocampus proteins, such as BDNF, Synapsin II, DCX, and CREB ones, and increased lipid peroxidation and decreased antioxidant enzyme activity, were indicators of behavioral impairment in mice treated with Cd. Different concentrations of curcumin (20, 40, 80 and 160 mg/kg) were used to treat the dose-dependent behavioral impairment caused by mercury exposure; 160 mg/kg proved to be the most efficacious dosage. Curcumin restored Cd–induced neurotoxicity and memory impairment, without any lingering side effects.	[47]

Table 2. Indicative studies of curcumin in the pharmaceutical industry.

Aim of the Study	Study Design	Results	Reference
This study sought to validate curcumin’s potential for cardio-protection against myocardial ischemia/reperfusion damage (in vivo and in vitro)	The study employed a systematic review and meta-analysis methodology to assess both preclinical (animal model) and clinical evidence. Eight databases were used, and 24 studies involving animals, totaling 503 animals, and 4 studies involving humans, totaling 435 patients, were included.	Curcumin reduced myocardial infarction size, improved cardiac function and showed beneficial effects on markers of myocardial injury and inflammation in animals. Research on animals suggests that curcumin may have cardioprotective benefits in cases of acute myocardial infraction, primarily via antioxidative, anti-inflammatory, anti-apoptotic and anti-fibrosis properties. Curcumin’s effectiveness is mostly demonstrated by lowering the frequency of myocardial infraction and MACE, and it may require a longer course of treatment and a higher dose to protect the myocardium.	[35]
Evaluation of the efficacy of curcumin in preventing myocardial ischemia/reperfusion (I/R) injury in animal models, through a comprehensive meta-analysis of preclinical studies (in vivo)	Designing a meta-analysis and systematic review. Up until January 2023, studies were gathered from the following databases: Wan-Fang, CNKI, Embase, Wan-Med, Web of Science and VIP. Methodological quality evaluated with the RoB tool from SYRCLE. To handle substantial heterogeneity, sensitivity and subgroup analyses were carried out. A funnel plot is used to analyze publication bias.	Curcumin treatment significantly decreased the size of the myocardial infarction. Better heart function and reduced expression of biomarkers for myocardial injury. Significant drops in serum inflammatory cytokine levels and the heart apoptosis index, suggesting anti-inflammatory and anti-apoptotic qualities. Subgroup analysis exposed differences in dosage, species, animal type, administration technique and treatment duration.	[36]
Investigation of the efficacy of curcumin in mitigating hypoxia/reoxygenation (H/R) injury in cardiomyocytes (in vitro).	The research focused on morphological alterations, cell viability, oxidative stress and apoptosis in H9c2 cardiomyocytes in order to investigate the protective effects of Cur.	Notable alterations in cell shape and lower viability were seen by the researchers under H/R conditions. Additionally, there was an increase in apoptosis, a rise in malondialdehyde (MDA) and lactate dehydrogenase (LDH), and a drop in superoxide dismutase (SOD) activity. Curcumin treatment effectively mitigated these effects by increasing SOD activity, decreasing ROS and apoptosis, and elevating LDH and MDA levels. Curcumin decreased the amount of stress that H/R produced in the endoplasmic reticulum (ER) and inhibited the mitogen-activated protein kinase (MAPK) signaling cascade, which comprises p38, JNK, and ERK1/2.	[37]
Investigation of the potential of curcumin as a therapeutic agent for mitigating neurological and cognitive impairments caused by global cerebral ischemia (GCI) (in vivo and in vitro).	Forty-six male Sprague Dawley rats participated in the study, and they were divided into four groups at random: sham (n = 14), control (n = 14), curcumin 50 mg/kg (n = 14) and curcumin 100 mg/kg (n = 14). The treatment periods for each group were further split into short-term (7 days) and long-term (28 days). At different post-operative days, neurological evaluations such as the traction test, passive avoidance task and Neurological Severity Score (NSS) were carried out. In addition, on days 7 and 28 following GCI, the Voronoi tessellation and the new object recognition test were performed.	Compared to the control and lower dosage (50 mg/kg) groups, curcumin at a dose of 100 mg/kg significantly improved neurological scores and decreased memory impairments. Step-through latency times and the novelty preference index significantly improved in the high-dose curcumin group, suggesting improved memory function. Additionally, a 100-mg/kg dose of curcumin preserved neuronal aggregation in the CA1 area at a level similar to that of normal rats. In summary, the study shows that curcumin, especially at larger dosages and when taken over an extended period of time, can significantly improve memory and neurological impairments that result from GCI and restore neuronal distribution in the CA1 area.	[38]
This study aimed to confirm that co-administration of curcumin alleviated doxorubicin-induced cardiotoxicity via its antioxidant, antiapoptotic and anti-inflammatory properties (in vivo and in vitro).	The study design included both in vivo (animal model) and in vitro (cell cultures) components. Systematic reviews and meta-analysis framework, were held. Participants in this framework comprised patients, cells, or animals that had adverse cardiac effects generated by doxorubicin (in vivo), as well as control groups and cardiac cells that were harmed by the drug (in vitro).	The findings suggested that curcumin co-administration mitigated doxorubicin-induced cardiotoxicity through mechanisms involving antioxidant, antiapoptotic and anti-inflammatory effects. The chemotherapy drug doxorubicin caused biochemical and histological alterations in the heart’s cells and tissue, which resulted in adverse cardiac consequences. Curcumin co-treatment reduces the cardiotoxicity produced by doxorubicin by acting through many major pathways, including anti-inflammatory, anti-apoptotic and antioxidant ones.	[39]
Moderate-intensity aerobic exercise and curcumin supplementation individually administered would be able to demonstrate cardioprotective effects against myocardial injury induced by I/R, as proved in this clinical trial (in vivo and in vitro).	The study design primarily involved in vivo experimentation, as it utilized male Wistar rats as the experimental model. A total of 50 male Wistar rats, aged between six and eight weeks, were randomized into one of five groups (n = 10): (1) sedentary control, (2) sedentary I/R, (3) exercise (15–45 min at 12–24 m/min) with I/R, (4) curcumin (50 mg/kg/day) + I/R and (5) both exercise and I/R. The workout was a motor-driven horizontal treadmill familiarization and training session that consisted of ten minutes of jogging at a speed of ten meters per minute. The treadmill running program started at 12 m/min for 15 min/day on week 1 and gradually rose to 24 m/min for 45 min/day until week 7, when it stayed constant. The rats were then made to run five sessions each week for ten weeks. These rats were kept in clean, well-ventilated rooms with normal water and food in rodent cages with conventional temperature ranges of 21–24 °C and humidity levels of 40–50%. The size of infracts, the expression of the amyloid precursor protein gene, the enzymes β-secretase-1, presenilin-1 and -2, and neprilysin, a marker of β-amyloid precursor peptide breakdown in the rat left ventricle, were all studied.	Both exercise and curcumin supplementation independently exerted cardioprotective effects against I/R–induced injury. In the myocardium of both the exercise- and curcumin-treated rats, there was an increase in the gene expression of neprilysin and a decrease in the mRNA expression of amyloid precursor protein, β-secretase-1, presenilin-1 and -2, and infarct size. There were no more advantages shown with concurrent treatments (exercise combined with curcumin). In the rat heart, moderate aerobic exercise (15–45 min at 12–24 m/min, five times a week) and 50 mg/kg of curcumin supplementation reduced the size of I/R-induced infarcts, improved the expression of processing enzymes and the amyloid precursor protein (APP) genes, and increased the mRNA expression of neprilysin.	[40]
Co-administration of curcumin capsules with glyburide may have positive effects on lipid levels and enhance glycemic control in individuals with type-2 diabetes mellitus, as this study shows (in vivo and in vitro).	An open, randomized control trial was held in this study over 11 days on eight type-2 diabetes mellitus patients on glyburide therapy. Blood samples were taken from the patients on the first day of the trial at different intervals, spanning from 0.5 to 24 h, after 5 mg of glyburide was administered (in vitro study). On the eleventh day of the trial, a blood sample was taken again following ten days of curcumin treatment for the participants.	The results indicated that glyburide and curcumin capsules together improve glucose control in diabetic individuals. Glyburide concentrations altered at the second hour, maximum concentration was unchanged and glucose levels decreased. AUMC increased and no patient experienced hypoglycemia. LDL, VLDL and HDL increased, while patients who received glyburide and curcumin pills together experienced improved glycemic control.	[41]
Curcumin mediated the enhancement of thermogenesis and the reduction of obesity in mice, as evaluated in this clinical trial (in vivo)	The study design involved in vivo experiments conducted on HFD-fed mice. HFD-fed wild-type, uncoupling protein 1 (Ucp–1) knockout and G-protein-coupled membrane receptor5 (TGR5) knockout mice were treated with curcumin of a 100 mg/kg dose. 16S ribosomal DNA sequencing analysis, fecal microbiota transplantation (FTM) and endogenous GM depletion were held.	Curcumin treatment significantly reduced BW gain and enhanced cold tolerance in HFD-fed mice, indicating increased adaptive thermogenesis. Compared to control mice, mice treated with curcumin and fed a high-fat diet had reduced body weight gain and increased cold tolerance as a result of increased adaptive thermogenesis. Curcumin reorganized the GM in HFD-fed mice, according to the 16S ribosomal DNA sequencing study, and FTM and GM depletion showed that the GM mediated the improved impact of curcumin on Ucp-1 dependent thermogenesis. Curcumin increased the fractions of DCA and LCA in BA metabolism. By influencing the activity of BA metabolism, the GM eventually mediates the effects of curcumin on augmenting Ucp-1 thermogenesis and mitigating HFD-induced obesity.	[42]
Examination of the impact of curcumin (CUR) supplementation on white adipose tissue (WAT) browning and thermogenesis in rats subjected to early postnatal overfeeding (in vivo and in vitro).	The experimental design involved adjusting litter sizes to three (small litters, SL) or ten (normal litters, NL) to simulate early overfeeding or standard feeding conditions from postnatal day 3. From postnatal week 3, SL rats were given a standard diet, or a diet supplemented with 1% (SL1% CUR) or 2% (SL2% CUR) CUR for ten weeks. Various parameters were assessed at postnatal week 13 to evaluate the effects of CUR supplementation.	SL rats receiving 1% or 2% CUR supplementation exhibited lower body weight, reduced WAT gain and an increased lean mass ratio compared to SL rats that did not receive CUR. CUR supplementation also normalized glucose tolerance and blood lipid levels. The SL2% CUR group showed significant increases in heat generation, with higher expression levels of uncoupling protein 1 (UCP1) and other browning-related genes in subcutaneous adipose tissue (SAT). The SL1% CUR group did not show these effects. Additionally, 2% CUR supplementation led to elevated serum norepinephrine levels and increased mRNA expression of β3-adrenergic receptors in SAT. Overall, CUR supplementation mitigated body fat gain and metabolic disturbances in postnatally overfed rats, with more pronounced effects at the higher dose of 2%.	[43]
The aim of this study is to explore the impact of curcumin (CUR) supplementation on rats subjected to early postnatal overfeeding, a condition that increases the risk of obesity and metabolic diseases (in vivo).	Male rats were divided into normal litters (NL) and small litters (SL), with the SL group being overfed. After weaning, SL rats received a normal diet or a diet supplemented with 2% CUR starting at different developmental stages: weaning (W3), puberty (W6), or end of puberty (W8), for 10 weeks.	SL rats had higher body weight, glucose intolerance and hyperlipidemia compared to NL rats, especially after puberty. CUR supplementation starting at weaning (SL-CURW13) or early puberty (SL-CURW16) significantly reduced body weight gain, adipose tissue weight and improved glucose tolerance and serum lipid levels, with the SL-CURW13 group showing the most pronounced benefits. However, starting CUR supplementation at the end of puberty (SL-CURW18) did not produce significant improvements compared to untreated SL rats. The study suggests that prepuberty is a critical window for CUR intervention to effectively mitigate obesity and metabolic disorders caused by early-life overnutrition.	[44]
This study aimed to investigate the long-term effects of maternal obesity and dietary habits during pregnancy and lactation on the metabolic health of offspring, focusing on the potential benefits of curcumin supplementation (in vivo and in vitro).	In this study, 24 male mice were divided into three groups: control group (SD) (offspring of dams fed a standard diet), hyperglycemic group (HGD) (offspring of dams fed a hyperglycemic, high-sugar, diet) and curcumin group (CUR) (offspring of dams fed a hyperglycemic diet and supplemented with curcumin during pregnancy and lactation). All offspring were subsequently fed a hyper-glycemic diet for 12 weeks. Various parameters, including body weight, food consumption and biochemical markers, were assessed. Additionally, the study measured the expression of thermogenesis-related genes in the in-terscapular brown adipose tissue and inguinal white adipose tissue.	Offspring from the CUR group experienced less weight gain and reduced food consumption compared to those from the HGD group. Biochemical analyses indicated that the CUR group had lower levels of total cholesterol, glucose and insulin, alongside improved glucose tolerance and insulin sensitivity. Molecular assessments showed elevated mRNA expression of uncoupling protein 1 (UCP1) and PR domain containing 16 (PRDM16) in both brown and white adipose tissues, suggesting enhanced thermogenesis. Overall, curcumin supplementation during the pregnancy-lactation period in obese mice led to significant improvements in the metabolic health of their offspring, despite continued exposure to a high-sugar diet.	[45]
This study evaluated the potential of curcumin towards inhibiting the growth of two pathogenic Gram-positive bacteria commonly found in the oral cavity: Streptococcus mutans and Streptococcus pyogenes (in vitro).	This in vitro clinical trial involved growing bacteria in a controlled setting. Using the well diffusion technique, the questions of whether curcumin inhibited the growth of Streptococcus mutans and Streptococcus pyogenes more than the antibiotic ciprofloxacin was explored. MIC tests were also held.	The findings revealed that curcumin demonstrably inhibited the growth of both S. mutans and S. pyogenes. MICs revealed that ciprofloxacin’s inhibition zone was found to be 15.52 to 13.4 m, accordingly, while curcumin’s inhibition zone was found to be 9.7 and 10.2 mm for Streptococcus mutans and Streptococcus pyogenes growth, respectively. As an alternative treatment approach, curcumin has a therapeutic impact against pathogenic gram-positive bacteria, which may be helpful for regulating dental biofilms and the development of dental caries.	[46]
Curcumin administration may counteract the neurotoxic effects induced by Cd exposure in mice, as this study’s main aim proved (in vivo).	A total of 56 young Swiss Albino mice were used in this in vivo experiment, were housed in a propylene cage at an ambient temperature of 22 ± 2 °C and were given a plenty of food and tap water, and over the 60 days of the experiment they were kept in a regular cycle of light and shade. The animals were split into eight groups of seven mice each, and both CD and curcumin were given orally. Open field test analysis, novel object recognition tests, Morris’s water maze test, tissue sample collection, oxidative stress level and hippocampus protein estimation, morphometrical and histopathological analysis, as well as statistical analysis were held.	This study provided compelling evidence for curcumin’s ability to mitigate Cd-induced neurotoxicity and to promote neurogenesis in mice. Curcumin appeared to exert its neuroprotective effects by reducing oxidative stress and enhancing the expression of key neurogenic proteins in the hippocampus. Downregulation of hippocampus proteins, such as BDNF, Synapsin II, DCX, and CREB ones, and increased lipid peroxidation and decreased antioxidant enzyme activity, were indicators of behavioral impairment in mice treated with Cd. Different concentrations of curcumin (20, 40, 80 and 160 mg/kg) were used to treat the dose-dependent behavioral impairment caused by mercury exposure; 160 mg/kg proved to be the most efficacious dosage. Curcumin restored Cd–induced neurotoxicity and memory impairment, without any lingering side effects.	[47]

The study was conducted on the effectiveness of curcumin on healing burns in rats, and in which 70 female Sprague Dawley rats were randomly assigned to five groups, each receiving different treatments, including various concentrations of curcumin, silver sulfadiazine ointment, or a control substance. The animals were inspected and the burn wounds were evaluated histologically and visually throughout the course of 7, 14 and 21 days. Findings indicated that curcumin, especially at a concentration of 2%, contributed to reduced inflammation, smaller burn wound sizes and improved re-epithelialization compared to other treatments. Histological examination showed well-organized epidermal layers and aligned fibroblasts in the curcumin-treated groups, particularly in the 2% concentration group. Such results suggested that curcumin could be a promising and affordable option for treating burn wounds [51]. Another clinical trial also examined how topical curcumin affects burn wound healing in rats. In this study, Wistar-albino rats were divided into groups based on the time after the burn (4th, 8th, or 12th day), with each group further divided into subgroups, receiving either burn alone or burn plus curcumin treatment. Both microscopic inception and biochemical analysis revealed that these rats exhibited quicker wound healing, which was defined by decreased inflammation, enhanced collagen deposition, blood vessel creation, granulation tissue formation, skin cell regeneration, as well as upregulation of a cell proliferation marker. Overall, the study strongly suggested that topical curcumin application could accelerate burn wound healing in the tested rats [52].

Ranjbar-Mohammadi et al. [53] examined a special wound dressing made of tiny fibers (polycaprolactone/gum tragacanth/curcumin (PCL/GT/Cur) nanofibers), which were loaded with curcumin for diabetic rats. These dressings fought bacteria and were tested in two forms: plain and with added cells. After 15 days, wounds treated with the curcumin nanofibers healed much faster and showed better tissue formation, compared to untreated wounds. This included more collagen deposition, thicker regenerated skin and even signs of sweat glands and hair follicles. Analysis confirmed that the dressing increased blood vessel growth, granulation tissue and the number of healing cells, while also reducing the unhealed wound area. As a whole, the study suggested these curcumin-loaded nanofibers have great promise as a treatment for diabetic wounds [53]. In another similar study, a nanohybrid scaffold containing curcumin-loaded chitosan nanoparticles (CUR-CSNPs) for diabetic wound healing was developed. In vitro tests showed the scaffold’s favorable characteristics, including small particle size, good stability and biocompatibility with fibroblast cells. Moreover, the scaffold exhibited sustained curcumin release. In vivo experiments using diabetic rats, demonstrated improved wound healing outcomes, with faster wound closure, reduced inflammation and enhanced fibroblast activity and collagen deposition compared to control groups [54].

Vinay et al. [55] set out to determine whether topical use of curcumin might be used to accelerate skin wound healing in rats with diabetes. Experimental rats, rendered diabetic via streptozotocin (STZ) induction, were subjected to open excision skin wounds and subsequently categorized into three groups: control, gel-treated and curcumin-treated. Over a 19-day period, Pluronic F-127 gel (25%) and curcumin (0.3%) within Pluronic gel were applied topically once daily to the respective groups. Results demonstrated that the curcumin application resulted in accelerated wound contraction and decreased expression levels of inflammatory cytokines/enzymes, including TNF–α, IL–1β and matrix metalloproteinase–9 (MMP–9). Additionally, curcumin administration elevated levels of the anti-inflammatory cytokine IL-10 and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Histopathological examination revealed enhanced granulation tissue characterized by notable fibroblast proliferation and collagen deposition, as well as thickened regenerated epithelial layers in curcumin-treated wounds. These findings underscored curcumin’s potential as a novel therapeutic modality for managing impaired wound healing in diabetic conditions, owing to its anti-inflammatory and antioxidant attributes [55].

Pandya et al. [56] investigated whether a gel made from Curcuma longa (turmeric) could help with healing and pain after tooth extraction. Over a three-month period, 21 patients that underwent bilateral extractions were enrolled in a split-mouth randomized controlled trial. In comparison to the control group, they discovered that the Curcuma longa (turmeric) gel group recovered more quickly and experienced less discomfort on day 7. Researchers advised dentists to use this gel as a therapy, particularly in cases of difficult tooth extraction [56]. A summary of some notable and current applications for wound healing is shown below; these are also included in Table 3.

2.4. Curcumin in the Cosmetic Industry

Curcumin has long been used in the cosmetics sector due to its anti-inflammatory and antioxidant characteristics. Curcumin has shown great potential for a wide range of cosmetic goods intended for the skin, face and hair because of its beneficial benefits against UV radiation, aging, inflammation and hair loss, and for lip and nail care [27].

The skin is in serious danger from ultraviolent B (UVB) radiation, which may lead to skin cancer in addition to sunburn, redness and early aging. In research by Li et al. [57], hairless mice and human keratino-cytes (HaCaT) were used to test curcumin’s photoprotective properties against UVB-induced acute damage. Results showed that the topical application of curcumin effectively reduced UVB-induced inflammation, collagen damage and lipid peroxidation in mice, while also promoting the accumulation of Nrf2 in the skin. Additionally, curcumin treatment in HaCaT cells reduced the UVB-induced release of lactate dehydrogenase, the generation of reactive oxygen species and DNA damage, while enhancing the expression of detoxifying enzymes and DNA repair activity [57]. Ahmed et al. [58] compared the effectiveness of nano-curcumin and a chemical sunscreen composed of phenylbenzimidazole-5-sulfonic acid (PBSA) for protecting rat skin from ultraviolet (UV) radiation damage. Rats were exposed to UV radiation, with some being treated with nano-curcumin, some with PBSA and some being fully untreated. Untreated skin displayed notable damage under the microscope, while skin treated with nano-curcumin appeared mostly normal. Interestingly, nano-curcumin was able to provide better protection than the conventional sunscreen PBSA [58].

The aging process in humans is a highly detailed biochemical and physiological mechanism influenced by a complex interplay of genetic and environmental variables, as aging triggers significant body changes. The most frequent and crucial ones are alterations in the immune response linked to distinct phases of cell differentiation and the occurrence of inflammaging, which is recognized as low-grade, subclinical inflammation indicated by increased levels of proinflammatory factors. Asada et al. [59,60] investigated whether a hot water extract of Curcuma longa (WEC) could improve skin health. They conducted cell studies where the extract was applied to skin cells exposed to ultraviolet B (UVB) light. The extract calmed inflammation and increased the production of hyaluronan, a molecule crucial for keeping the skin hydrated. To confirm these findings, they ran a clinical trial where participants received daily supplements containing the extract, with or without additional turmeric extract, or a placebo for eight weeks. Results showed that the extract alone markedly improved facial skin hydration compared to the placebo [59,60]. Studies on the cosmetic uses of curcumin have been widely conducted, and some of the most recent ones are included in

Table 4. Indicative studies of curcumin in the cosmetic field.

Aim of the Study	Study Design	Results	Reference
This clinical experiment demonstrated that curcumin had photoprotective properties against UVB-induced acute photodamage in both hairless mice and HaCaT cells (in vivo and in vitro).	Randomized controlled in vivo and in vitro laboratory study was conducted. Curcumin’s ability to prevent UVB-induced acute photodamage in hairless mice and immortalized HaCaT cells was assessed.	Curcumin application reduced inflammation, collagen damage, lipid peroxidation and promoted Nrf2 accumulation in mice. In particular, curcumin prevented lipid peroxidation, collagen accretion disorder and acute UVB-induced inflammatory cells in the skin of bare, hairless mice. In HaCaT cells, curcumin attenuated lactate dehydrogenase (LDH) release, ROS production, DNA damage and enhanced DNA repair.	[57]
Nano-curcumin formulations have photoprotective effects on skin histopathology, as confirmed in this study (in vivo).	An in vivo, comparative study design, which was conducted on a rat skin model, is evaluated. The obtained results were compared to a commercial sunscreen agent, namely PBSA. Size distribution was used to produce and characterize the nanocurcumin. A histological analysis of the skin was used to assess the photoprotective potential.	The absence of histopathological alterations in skin treated with nano-curcumin suggested that it can shield the skin from UV-induced damage. By eliminating any negative effects, nano-curcumin provided a secure substitute for PBSA.	[58]
A hot water extract of Curcuma longa (WEC) had beneficial effects on skin health by reducing the inflammation and promoting hydration, which was the main aim of this clinical trial case (in vivo and in vitro).	Two-pronged approach combining in vitro (cell-based) and in vivo (human) studies was held. Levels of pro-inflammatory cytokines in UVB-irradiated keratinocytes with or without WEC. The effects of WEC on hyaluronan production in keratinocytes were also determined. Eight-week intervention groups consisting of daily WEC intakes with or without curcumin or a placebo were allocated to 47 healthy volunteers. Following UVB irradiation, the water content, trans-epidermal water loss in the face and minimum erythematous dosage on the back were assessed every four weeks.	The hot water extract of Curcuma longa reduced inflammation in skin cells and increased the production of hyaluronan from non-stimulated keratinocytes. Also, it significantly inhibited the increase in UVB–TNF–α and IL—1β at the mRNA- and protein-associated levels. The WEC group saw considerably higher baseline increases in the face’s water content at weeks four and eight. Significant differences in trans-epidermal water loss and minimal erythema dose among the group were not observed. Also, participants who received the WEC showed a significant increase in facial skin hydration.	[60]

.

Table 3. Indicative studies of curcumin in wound healing procedures.

Aim of the Study	Study Design	Results	Reference
Researchers looked at how individuals with DFU’s metabolic condition and wound healing responded to curcumin use (in vitro and in vivo).	A randomized double-blind placebo-controlled clinical trial was conducted. In this experiment, 60 patients with grade 3 DFU were divided into two equal groups at random and given either a placebo or 80 mg of nanocurcumin daily for a period of 12 weeks. Measurements were made of serum insulin levels and insulin resistance.	The study showed that while the markers of ulcer size were unaffected, the use of nano-curcumin in patients with DFU significantly improved their glycemic control, reduced total and LDL cholesterol, and increased total antioxidant capacity and total GSH levels, as opposed again to the placebo group. Curcumin intake significantly decreased fasting plasma glucose, insulin and insulin resistance, while it increased insulin sensitivity compared to the placebo group. However, there was no discernible increase in wound healing, and ulcer size markers remained unchanged.	[49]
The investigation of curcumin’s mechanism in DFU wound healing was evaluated in this clinical trial (in vitro and in vivo)	Animal and cell culture models (DFU rat model and fibroblasts cultured in high-glucose environment) were utilized. Twenty pairs of healthy people and DFU patients had their elbows harvested for venous blood collection. Fifty male Sprague Dawley rats, 4–6 weeks of age, were fed in restricted circumstances (22 ± 2 °C, 45% humidity, 12-h light/dark cycle), with fully sterilized feed. Following four to five days of accommodating feeding, the rats were randomized into five groups and given a high-fat diet together with intraperitoneal injections of STZ (50 mg/kg) for five days in order to develop diabetes. The same quantity of sodium citrate buffer and a regular diet were provided to the control group. Following a seven-day period, rats exhibiting elevated blood glucose levels (>250 mg/dL) were designated as diabetic models. They underwent isoflurane anesthesia, and rectangular wounds were utilized to produce the DFU rat model. For 12 days, the rats in the curcumin treatment group received 300 mg/kg/day of curcumin intraperitoneally, while the rats received an injection of the lentivirus carrying miR-152-3p mimic, also known as OE-FBN1. The injuries on the rats’ right feet were seen and documented while they were receiving treatment. Isolation and culture of fibroblasts, construction and transfection of the cell model, RT– qPCR, Western blot analysis, cell viability, apoptosis by flow cytometry, transwell detection of cell migration, scratch test, immunohistochemistry, hematoxylin–eosin (HE) staining, dual–luciferase reporter assay, MDA and SOD detection, as well as statistical analysis, were conducted in this trial.	In DFU rats, curcumin decreased fibroblast apoptosis, enhanced angiogenesis, migration and proliferation, and hastened wound healing. Curcumin more specifically may cause fibroblasts to infiltrate into the wound site and accelerate wound healing. Curcumin was beneficial for DFU as well, as it alleviated the damage of fibroblasts, attenuated vascular calcification and encouraged the production of miR-218-5p, shielding the PC12 cells from inflammatory reactions brought on by high glucose. In summary, curcumin activated the cascade of fibrillin 1/transforming growth factor β (FBN1/TGF-β), hence it also promoted fibroblast proliferation and mitigation, a hypothesis confirmed by each test conducted.	[50]
An assessment of curcumin’s ability to cure burn burns in rats was the primary study aim (in vivo experimental procedure)	An animal study using Sprague-Dawley rats was held. Seventy female Sprague Dawley rats were randomly divided into five equal groups (A–E), housed one per cage and maintained under controlled environmental conditions (21 ± 2 °C, 65–70% relative humidity and a balanced diet with free access to food and water at all times). Each animal in groups A, B and C received 0.1, 0.5 and 2% curcumin, respectively, while D group administered silver sulfadiazine ointment and E group were considered the control group and treated with Eucerin. Using a hot plate of the same size, around 20% of the total body surface area (TBSA) and temperature, a conventional 3 degree burn wound was created. The rats’ skin was cleaned with a povidone-iodine solution, washed with sterile water and their back hairs were shaved before they were given an intramuscular injection of xylocaine (1.1 mg/kg) and ketamine (15 mg/kg) to induce sedation. Every 24 h, all wounds were inspected, decaying tissue was removed, photos were taken and some animals were then slaughtered.	After 14 days, the burn wounds’ dimensions and level of inflammation decreased as a result of the administration of curcumin. Curcumin, particularly in 2% concentration, was shown to be a suitable substitute for healing burn wounds. In groups A–C, re-epithelialization was more noticeable and distinct; in this group, the epidermis showed well-structured layers devoid of crusting, spindle-shaped fibrocytes arranged in a fascicular pattern and eosinophilic collagen matrix parallel to the epithelial surface. Because curcumin treatment increased the expression of proliferating cell nuclear antigen in skin tissues, curcumin was a natural pharmacological for controlling severe burn pain and promoting wound healing models of rats. Curcumin-treated groups showed greater myofibroblast, fibroblast and macrophage re-epithelialization and enhanced migration. Curcumin’s antioxidant and anti-inflammatory properties are primarily attributed to its diferuloyl–methane structure, which also inhibits NF-κB pathways, quenches free radicals and reduces inflammation by regulating a variety of transcription and growth factors, inflammatory cytokines, protein kinases and several enzymes. Curcumin is safe to use, even at high doses.	[51]
An analysis of the impact of topical curcumin therapy on rat burn wound healing was also further analyzed in this study (in vivo and in vitro).	An animal study using Wistar albino rats was conducted. A total of thirty-six healthy Wistar albino rats were used, fed a normal diet of chow and tap water at will, and kept in an automated temperature-controlled windowless animal quarter and housing conditions (22 ± 2 °C, 50–55% relative humidity, and 14 h light/10 h dark cycle). These rats were divided into three groups at random: group A was assigned on the fourth day following burn, group B on the eighth day, and group C on the twelfth day. Each group had two subgroups: a control group (consisting of six rats) and an experimental group (consisting of six rats plus curcumin). Following anesthesia, the dorsum was shaved and aluminum branding irons heated in a water bath to 100 °C for 30 min were used to create a second-degree burn wound with a surface diameter of 2.5 cm on their back. The irons were applied without pressure for 30 s. After that, all of the animals were given physiological saline solution (10 mL/kg, subcutaneously) to revive them, and the experimental burn + curcumin group had 200 μL of the drug topically once a day for 12 days, at a dose of 100 mg/kg BW. Histopathological evaluation, immunohistochemical staining, hydroxyproline analysis and statistical analysis were conducted.	The wounds healed significantly more quickly after curcumin treatment. In a rat model of full-thickness injuries, curcumin improved the rates of inflammatory cells, collagen deposition, angiogenesis, granulation tissue development and epithelialization. Curcumin enhanced wound healing in biopsy wounds, which showed an increase in neutrophils, macrophages and fibroblasts, as well as faster wound contraction from myofibroblasts. Curcumin also enhanced the expression of fibronectin and collagen, as well as neovascularization, re–epithelialization and cell regeneration. Moreover, treatment with curcumin inhibited the hydrogen peroxide-induced oxidative damage in human keratinocytes and fibroblasts, thus inducing potent anti-inflammatory, antioxidant, immunomodulatory and anticancer activity	[52]
A study was done to evaluate the potential of electrospun PCL/GT nanofibers loaded with curcumin for wound healing in diabetic rats (in vivo and in vitro assay).	An animal study using a diabetic rat model was held. Twelve adult male Sprague Dawley rats were used, kept separately in plastic cages for adaptation 1 week prior to study and maintained under controlled environmental conditions (22 ± 2 °C, 50–60% relative humidity). To induce diabetes mellitus-like symptoms in the animals, single intraperitoneal injections of 50 mg/kg ketamine + 5 mg/kg xylazine and intraperitoneal injections of 100 mL (60 mg/kg) of STZ were used. Blood glucose levels were then measured after 3–4 days, and acellular scaffolds were applied to the test wounds. Three time windows were chosen for the animal sacrifices on days 5, 10 and 15, during which each animal had four circular excisional wounds and was once again sedated, Pictures were taken by a digital camera on days 5, 10 and 15. The electrospinning process, curcumin release from electrospun nanofibers, antibacterial properties, cell-seeded scaffolds, histology, in vivo assay and statistical analysis were conducted in this trial.	By promoting fibroblast proliferation, collagen deposition, a fully regenerated epithelial layer, the creation of sweet glands and hair follicles, and quick wound healing, the nanofibers of GT/PCL/Cur were deemed significant wound healing enhancers. Curcumin accelerated wound healing because of the scaffolds’ nanofibrous structure, which mimics the extracellular matrix (ECM) in nature, the high biological properties of GT, the curcumin release that lasts for 20 days and high physical and mechanical properties of PCL, which improve scaffold stability in the face of blood and fibrin. When compared to control scaffolds, histochemical study results demonstrated that scaffold stem cells had much greater healing performance, followed by acellular scaffolds. In comparison to control samples, PCL/GT/Curcumin nanofibers lowered blood glucose levels.	[53]
The hypothesis that nanohybrid scaffold of curcumin-loaded chitosan-derived nanoparticles or CUR-CSNPs would enhance diabetic wound healing was analyzed further (in vivo and in vitro) as the aim of the study.	In vitro experiments with diabetic rat fibroblasts and in vivo experiments using diabetic rats with induced wounds, alongside comparison groups and statistical analysis, were the primary aspects of this study. A total of 8 mg of curcumin was taken and dissolved in 10 mL of absolute ethanol for 800 μg/mL of curcumin solution, where a 0.5% chitosan solution was prepared by 2% acetic acid and after standard procedures the nanoparticles were then formed spontaneously. Scaffolds were prepared by the freeze-drying method by the standard procedures as well. Necessary characterization was conducted by matrix morphology assessment via SEM, thermal characterization, swelling behavior analysis, in vitro biodegradation, cell viability and morphology assessment, in vitro drug release, and in vivo wound healing through diabetes induction, wound creation, collection of tissue, histopathological and statistical analysis.	The curcumin-loaded chitosan nanohybrid scaffold exhibited enhanced cytocompatibility and biological activity in vitro by promoting cell proliferation, adhesion and migration. Moreover, in vivo experiments revealed accelerated wound closure, improved epithelialization and increased collagen deposition in diabetic rats treated with this scaffold. The porous morphology of nanohybrid scaffold enhanced great biodegradability and biocompatibility properties, as well as sustained delivery of curcumin to control inflammation and related complications. In STZ-induced diabetic rats, topical administration of a nanohybrid scaffold sped up cutaneous wound healing by reducing inflammation at the wound site.	[54]
Curcumin’s ability to facilitate cutaneous wound healing in diabetic rats by reducing inflammation, oxidative stress and promoting tissue regeneration was investigated extensively in this study (in vivo).	This study employed a randomized controlled trial design with diabetic rats. Healthy adult male Wistar rats (170–200 g) were kept in standard polycarbonate cages with unlimited access to food and water. They were also kept on a 12:12 h light/dark cycle in a climate-controlled environment. A single intraperitoneal injection of STZ (60 mg/kg) in citrate buffer solution (0.1 M, pH = 4.5) was given for the development of diabetes after 10 days of acclimatization. Prior to the induction of diabetes, fasting blood glucose levels were measured using a glucometer. Animals with blood glucose levels > 300 mg/dL were observed for seven days following the two-day STZ injection, and rats that continuously had increased blood glucose levels were chosen. A 2 × 2 cm (about 400 mm2) open excision-type wound was made on the rats’ back (thoraco-lumber area) while they were sedated with pentobarbitone sodium at a dosage of 40 mg/kg. The lesion was either covered or dressed. In this investigation, three groups consisting of twenty diabetic rats each were used. The groups were as follows: (1) Control: sterile normal saline was applied on the wounds once daily for 19 days, (2) Pluronic F-127 (PF-127) gel-treated: 400 μL of PF-127 gel (25) was applied topically once per day for 19 days, and (3) Curcumin-treated: 400 μL of curcumin (0.3%) in PF-127 gel (25%) was applied topically on wounds once per day for 19 days. Diabetes induction, excision wound model analysis, wound contraction measurements, tissue collection, real time RT–PCR and ELISA assessments, histopathological determination, picrosirius red staining for collagen and statistical analysis were performed.	When curcumin was applied topically to rats’ wound sites, levels of anti-inflammatory cytokines like IL-10 and antioxidant enzymes like SOD, CAT and GPx increased, and inflammatory cytokines and enzymes like TNF-α, IL-1β, and MMP-9 decreased. This resulted in an acceleration of wound healing with marked collagen synthesis and full epithelial layer regeneration. Curcumin, a new therapeutic agent for the therapy of impaired wound healing in diabetics, demonstrated quicker and better wound healing in diabetic rats due to its anti-inflammatory and antioxidant properties. In the group treated with curcumin, MMP-9 expression was greatly balanced during the various stages of recovery. The hematoxylin–eosin staining revealed much superior granulation tissue with marked fibroblast proliferation formation in the wounds of the curcumin-treated group and regeneration of the epithelial layer, while increased collagen fraction in the curcumin-treated wounds is probably due to decreased TNF–α levels and increased fibroblast proliferation. Curcumin’s application was found to cause faster wound closure, earlier epidermis re-epithelialization and much higher collagen content, as the re-epithelialization aids the wound closure by altering the keratinocytes’ migratory, proliferative phenotype, which is compromised by diabetes, from a sedentary phenotype.	[55]
Topical application of Curcuma longa (turmeric) gel was discovered to improve healing of wounds and lessen postoperative pain after dental extraction in this in vivo and in vitro clinical trial.	A randomized controlled experiment with a split mouth was carried out. Twenty-one patients in all had bilateral extractions. Curcuma longa (turmeric) gel was applied to one extraction socket randomly allocated to the test group, while a placebo was administered to the contralateral socket serving as the control group. On the third and seventh days following extraction, pain and wound healing were assessed using established measures. SPSS software was used to perform descriptive statistics, paired and unpaired t-tests used, and statistical significance was set at p < 0.05. At p < 0.05, statistical significance was established.	The study found that the group treated with topical Curcuma longa (turmeric) gel exhibited significantly higher mean healing scores on the third and seventh days post-extraction compared to the control group, with significantly lower mean pain scores observed in the Curcuma longa (turmeric) gel group on the seventh day. Additionally, neither participating group experienced any incidences of dry sockets. As a post-extraction medication, topical Curcuma longa (turmeric) gel had beneficial results in improving wound healing and lowering pain.	[56]

Table 3. Indicative studies of curcumin in wound healing procedures.

Aim of the Study	Study Design	Results	Reference
Researchers looked at how individuals with DFU’s metabolic condition and wound healing responded to curcumin use (in vitro and in vivo).	A randomized double-blind placebo-controlled clinical trial was conducted. In this experiment, 60 patients with grade 3 DFU were divided into two equal groups at random and given either a placebo or 80 mg of nanocurcumin daily for a period of 12 weeks. Measurements were made of serum insulin levels and insulin resistance.	The study showed that while the markers of ulcer size were unaffected, the use of nano-curcumin in patients with DFU significantly improved their glycemic control, reduced total and LDL cholesterol, and increased total antioxidant capacity and total GSH levels, as opposed again to the placebo group. Curcumin intake significantly decreased fasting plasma glucose, insulin and insulin resistance, while it increased insulin sensitivity compared to the placebo group. However, there was no discernible increase in wound healing, and ulcer size markers remained unchanged.	[49]
The investigation of curcumin’s mechanism in DFU wound healing was evaluated in this clinical trial (in vitro and in vivo)	Animal and cell culture models (DFU rat model and fibroblasts cultured in high-glucose environment) were utilized. Twenty pairs of healthy people and DFU patients had their elbows harvested for venous blood collection. Fifty male Sprague Dawley rats, 4–6 weeks of age, were fed in restricted circumstances (22 ± 2 °C, 45% humidity, 12-h light/dark cycle), with fully sterilized feed. Following four to five days of accommodating feeding, the rats were randomized into five groups and given a high-fat diet together with intraperitoneal injections of STZ (50 mg/kg) for five days in order to develop diabetes. The same quantity of sodium citrate buffer and a regular diet were provided to the control group. Following a seven-day period, rats exhibiting elevated blood glucose levels (>250 mg/dL) were designated as diabetic models. They underwent isoflurane anesthesia, and rectangular wounds were utilized to produce the DFU rat model. For 12 days, the rats in the curcumin treatment group received 300 mg/kg/day of curcumin intraperitoneally, while the rats received an injection of the lentivirus carrying miR-152-3p mimic, also known as OE-FBN1. The injuries on the rats’ right feet were seen and documented while they were receiving treatment. Isolation and culture of fibroblasts, construction and transfection of the cell model, RT– qPCR, Western blot analysis, cell viability, apoptosis by flow cytometry, transwell detection of cell migration, scratch test, immunohistochemistry, hematoxylin–eosin (HE) staining, dual–luciferase reporter assay, MDA and SOD detection, as well as statistical analysis, were conducted in this trial.	In DFU rats, curcumin decreased fibroblast apoptosis, enhanced angiogenesis, migration and proliferation, and hastened wound healing. Curcumin more specifically may cause fibroblasts to infiltrate into the wound site and accelerate wound healing. Curcumin was beneficial for DFU as well, as it alleviated the damage of fibroblasts, attenuated vascular calcification and encouraged the production of miR-218-5p, shielding the PC12 cells from inflammatory reactions brought on by high glucose. In summary, curcumin activated the cascade of fibrillin 1/transforming growth factor β (FBN1/TGF-β), hence it also promoted fibroblast proliferation and mitigation, a hypothesis confirmed by each test conducted.	[50]
An assessment of curcumin’s ability to cure burn burns in rats was the primary study aim (in vivo experimental procedure)	An animal study using Sprague-Dawley rats was held. Seventy female Sprague Dawley rats were randomly divided into five equal groups (A–E), housed one per cage and maintained under controlled environmental conditions (21 ± 2 °C, 65–70% relative humidity and a balanced diet with free access to food and water at all times). Each animal in groups A, B and C received 0.1, 0.5 and 2% curcumin, respectively, while D group administered silver sulfadiazine ointment and E group were considered the control group and treated with Eucerin. Using a hot plate of the same size, around 20% of the total body surface area (TBSA) and temperature, a conventional 3 degree burn wound was created. The rats’ skin was cleaned with a povidone-iodine solution, washed with sterile water and their back hairs were shaved before they were given an intramuscular injection of xylocaine (1.1 mg/kg) and ketamine (15 mg/kg) to induce sedation. Every 24 h, all wounds were inspected, decaying tissue was removed, photos were taken and some animals were then slaughtered.	After 14 days, the burn wounds’ dimensions and level of inflammation decreased as a result of the administration of curcumin. Curcumin, particularly in 2% concentration, was shown to be a suitable substitute for healing burn wounds. In groups A–C, re-epithelialization was more noticeable and distinct; in this group, the epidermis showed well-structured layers devoid of crusting, spindle-shaped fibrocytes arranged in a fascicular pattern and eosinophilic collagen matrix parallel to the epithelial surface. Because curcumin treatment increased the expression of proliferating cell nuclear antigen in skin tissues, curcumin was a natural pharmacological for controlling severe burn pain and promoting wound healing models of rats. Curcumin-treated groups showed greater myofibroblast, fibroblast and macrophage re-epithelialization and enhanced migration. Curcumin’s antioxidant and anti-inflammatory properties are primarily attributed to its diferuloyl–methane structure, which also inhibits NF-κB pathways, quenches free radicals and reduces inflammation by regulating a variety of transcription and growth factors, inflammatory cytokines, protein kinases and several enzymes. Curcumin is safe to use, even at high doses.	[51]
An analysis of the impact of topical curcumin therapy on rat burn wound healing was also further analyzed in this study (in vivo and in vitro).	An animal study using Wistar albino rats was conducted. A total of thirty-six healthy Wistar albino rats were used, fed a normal diet of chow and tap water at will, and kept in an automated temperature-controlled windowless animal quarter and housing conditions (22 ± 2 °C, 50–55% relative humidity, and 14 h light/10 h dark cycle). These rats were divided into three groups at random: group A was assigned on the fourth day following burn, group B on the eighth day, and group C on the twelfth day. Each group had two subgroups: a control group (consisting of six rats) and an experimental group (consisting of six rats plus curcumin). Following anesthesia, the dorsum was shaved and aluminum branding irons heated in a water bath to 100 °C for 30 min were used to create a second-degree burn wound with a surface diameter of 2.5 cm on their back. The irons were applied without pressure for 30 s. After that, all of the animals were given physiological saline solution (10 mL/kg, subcutaneously) to revive them, and the experimental burn + curcumin group had 200 μL of the drug topically once a day for 12 days, at a dose of 100 mg/kg BW. Histopathological evaluation, immunohistochemical staining, hydroxyproline analysis and statistical analysis were conducted.	The wounds healed significantly more quickly after curcumin treatment. In a rat model of full-thickness injuries, curcumin improved the rates of inflammatory cells, collagen deposition, angiogenesis, granulation tissue development and epithelialization. Curcumin enhanced wound healing in biopsy wounds, which showed an increase in neutrophils, macrophages and fibroblasts, as well as faster wound contraction from myofibroblasts. Curcumin also enhanced the expression of fibronectin and collagen, as well as neovascularization, re–epithelialization and cell regeneration. Moreover, treatment with curcumin inhibited the hydrogen peroxide-induced oxidative damage in human keratinocytes and fibroblasts, thus inducing potent anti-inflammatory, antioxidant, immunomodulatory and anticancer activity	[52]
A study was done to evaluate the potential of electrospun PCL/GT nanofibers loaded with curcumin for wound healing in diabetic rats (in vivo and in vitro assay).	An animal study using a diabetic rat model was held. Twelve adult male Sprague Dawley rats were used, kept separately in plastic cages for adaptation 1 week prior to study and maintained under controlled environmental conditions (22 ± 2 °C, 50–60% relative humidity). To induce diabetes mellitus-like symptoms in the animals, single intraperitoneal injections of 50 mg/kg ketamine + 5 mg/kg xylazine and intraperitoneal injections of 100 mL (60 mg/kg) of STZ were used. Blood glucose levels were then measured after 3–4 days, and acellular scaffolds were applied to the test wounds. Three time windows were chosen for the animal sacrifices on days 5, 10 and 15, during which each animal had four circular excisional wounds and was once again sedated, Pictures were taken by a digital camera on days 5, 10 and 15. The electrospinning process, curcumin release from electrospun nanofibers, antibacterial properties, cell-seeded scaffolds, histology, in vivo assay and statistical analysis were conducted in this trial.	By promoting fibroblast proliferation, collagen deposition, a fully regenerated epithelial layer, the creation of sweet glands and hair follicles, and quick wound healing, the nanofibers of GT/PCL/Cur were deemed significant wound healing enhancers. Curcumin accelerated wound healing because of the scaffolds’ nanofibrous structure, which mimics the extracellular matrix (ECM) in nature, the high biological properties of GT, the curcumin release that lasts for 20 days and high physical and mechanical properties of PCL, which improve scaffold stability in the face of blood and fibrin. When compared to control scaffolds, histochemical study results demonstrated that scaffold stem cells had much greater healing performance, followed by acellular scaffolds. In comparison to control samples, PCL/GT/Curcumin nanofibers lowered blood glucose levels.	[53]
The hypothesis that nanohybrid scaffold of curcumin-loaded chitosan-derived nanoparticles or CUR-CSNPs would enhance diabetic wound healing was analyzed further (in vivo and in vitro) as the aim of the study.	In vitro experiments with diabetic rat fibroblasts and in vivo experiments using diabetic rats with induced wounds, alongside comparison groups and statistical analysis, were the primary aspects of this study. A total of 8 mg of curcumin was taken and dissolved in 10 mL of absolute ethanol for 800 μg/mL of curcumin solution, where a 0.5% chitosan solution was prepared by 2% acetic acid and after standard procedures the nanoparticles were then formed spontaneously. Scaffolds were prepared by the freeze-drying method by the standard procedures as well. Necessary characterization was conducted by matrix morphology assessment via SEM, thermal characterization, swelling behavior analysis, in vitro biodegradation, cell viability and morphology assessment, in vitro drug release, and in vivo wound healing through diabetes induction, wound creation, collection of tissue, histopathological and statistical analysis.	The curcumin-loaded chitosan nanohybrid scaffold exhibited enhanced cytocompatibility and biological activity in vitro by promoting cell proliferation, adhesion and migration. Moreover, in vivo experiments revealed accelerated wound closure, improved epithelialization and increased collagen deposition in diabetic rats treated with this scaffold. The porous morphology of nanohybrid scaffold enhanced great biodegradability and biocompatibility properties, as well as sustained delivery of curcumin to control inflammation and related complications. In STZ-induced diabetic rats, topical administration of a nanohybrid scaffold sped up cutaneous wound healing by reducing inflammation at the wound site.	[54]
Curcumin’s ability to facilitate cutaneous wound healing in diabetic rats by reducing inflammation, oxidative stress and promoting tissue regeneration was investigated extensively in this study (in vivo).	This study employed a randomized controlled trial design with diabetic rats. Healthy adult male Wistar rats (170–200 g) were kept in standard polycarbonate cages with unlimited access to food and water. They were also kept on a 12:12 h light/dark cycle in a climate-controlled environment. A single intraperitoneal injection of STZ (60 mg/kg) in citrate buffer solution (0.1 M, pH = 4.5) was given for the development of diabetes after 10 days of acclimatization. Prior to the induction of diabetes, fasting blood glucose levels were measured using a glucometer. Animals with blood glucose levels > 300 mg/dL were observed for seven days following the two-day STZ injection, and rats that continuously had increased blood glucose levels were chosen. A 2 × 2 cm (about 400 mm2) open excision-type wound was made on the rats’ back (thoraco-lumber area) while they were sedated with pentobarbitone sodium at a dosage of 40 mg/kg. The lesion was either covered or dressed. In this investigation, three groups consisting of twenty diabetic rats each were used. The groups were as follows: (1) Control: sterile normal saline was applied on the wounds once daily for 19 days, (2) Pluronic F-127 (PF-127) gel-treated: 400 μL of PF-127 gel (25) was applied topically once per day for 19 days, and (3) Curcumin-treated: 400 μL of curcumin (0.3%) in PF-127 gel (25%) was applied topically on wounds once per day for 19 days. Diabetes induction, excision wound model analysis, wound contraction measurements, tissue collection, real time RT–PCR and ELISA assessments, histopathological determination, picrosirius red staining for collagen and statistical analysis were performed.	When curcumin was applied topically to rats’ wound sites, levels of anti-inflammatory cytokines like IL-10 and antioxidant enzymes like SOD, CAT and GPx increased, and inflammatory cytokines and enzymes like TNF-α, IL-1β, and MMP-9 decreased. This resulted in an acceleration of wound healing with marked collagen synthesis and full epithelial layer regeneration. Curcumin, a new therapeutic agent for the therapy of impaired wound healing in diabetics, demonstrated quicker and better wound healing in diabetic rats due to its anti-inflammatory and antioxidant properties. In the group treated with curcumin, MMP-9 expression was greatly balanced during the various stages of recovery. The hematoxylin–eosin staining revealed much superior granulation tissue with marked fibroblast proliferation formation in the wounds of the curcumin-treated group and regeneration of the epithelial layer, while increased collagen fraction in the curcumin-treated wounds is probably due to decreased TNF–α levels and increased fibroblast proliferation. Curcumin’s application was found to cause faster wound closure, earlier epidermis re-epithelialization and much higher collagen content, as the re-epithelialization aids the wound closure by altering the keratinocytes’ migratory, proliferative phenotype, which is compromised by diabetes, from a sedentary phenotype.	[55]
Topical application of Curcuma longa (turmeric) gel was discovered to improve healing of wounds and lessen postoperative pain after dental extraction in this in vivo and in vitro clinical trial.	A randomized controlled experiment with a split mouth was carried out. Twenty-one patients in all had bilateral extractions. Curcuma longa (turmeric) gel was applied to one extraction socket randomly allocated to the test group, while a placebo was administered to the contralateral socket serving as the control group. On the third and seventh days following extraction, pain and wound healing were assessed using established measures. SPSS software was used to perform descriptive statistics, paired and unpaired t-tests used, and statistical significance was set at p < 0.05. At p < 0.05, statistical significance was established.	The study found that the group treated with topical Curcuma longa (turmeric) gel exhibited significantly higher mean healing scores on the third and seventh days post-extraction compared to the control group, with significantly lower mean pain scores observed in the Curcuma longa (turmeric) gel group on the seventh day. Additionally, neither participating group experienced any incidences of dry sockets. As a post-extraction medication, topical Curcuma longa (turmeric) gel had beneficial results in improving wound healing and lowering pain.	[56]

3. Curcumin’s Antioxidant, Anti-Inflammatory and Anticancer Potential

Curcumin has been exploited for centuries due to its non-toxic, antioxidant, analgesic, anti-septic, anti-inflammatory and anticancer profile. Several in vitro and in vivo studies have pointed out curcumin’s vast potential towards cancer’s treatment as a newly emerged therapeutic enhancer of currently available treatment protocols.

3.1. Curcumin’s Antioxidant and Pro-Oxidant Profile

As a lipophilic, water-insoluble polyphenol, curcumin displays a great antioxidant as it is highly protective against ROS and pro-oxidant in character, due to the fact that when induced by light, it is able to initiate the photogeneration of singlet oxygen [61,62] to mobilize endogenous copper ions in order to kill malignant cancer cells, and, thus, results in anticancer, anti-tumor, anti-thrombosis and apoptosis-inducing effects [63,64].

Curcumin has been reportedly able to inhibit both lipid peroxidation and free-radical scavenging. Using oxidized linoleate as a fatty acid radical, curcumin acts as a chain–breaking factor at the 3′ position, and via an intramolecular Diels–Alder reaction and neutralization of the lipid radicals, hence it functions as a lipid peroxidation inhibitor with confirmed efficacy. Moreover, as a free-radical scavenger of various oxygen species generated by differentiated macrophages like superoxide anions, hydrogen peroxide and nitrite radicals, it has been implicated in downregulating iNOS activity by inhibiting macrophages to generate nitric oxide (NO) that reacts with superoxide radicals so as to form the cell-toxic peroxynitrite and by reducing the oxidative stress-responsive ROS formation. As a consequence, many neuroinflammatory diseases related to oxidative stress like Alzheimer’s or Parkinson’s disease and other similar disorders could be efficiently confronted though curcumin’s activity [65,66,67].

3.2. Curcumin’s Anti-Inflammatory Profile

In general, curcumin has been found to be implicated in several anti-inflammatory manifestations, as an effective suppressor of many inflammation-related pathways including the NF-κΒ pathway, which is a transcription regulative factor implicated in inflammation, cellular proliferation and cell survival [62,65,68].

The NF-κΒ pathway is involved in the regulation of pro-inflammatory genes (IL–6, Il–8, TNF–α, iNOS, COX-2, Bcl-2, MMP-9, PAF, etc.) and cellular responses to inflammation-associated stimuli (cytokines, UV radiation, free radicals, hypoxia, several infectious antigens, etc.). The activation of such a potentially malignant pathway is highly related to angiogenesis, cancerous cells’ proliferation, tumor promotion and metastatic procedures’ induction [65,69,70,71]. Curcumin, specifically, may place an inhibitory effect on NF-κΒ pathway’s activation, as it has been reported to block the inhibitor kappa B kinase (IκΚ)-mediated phosphorylation of the inhibitor of NF-κΒ (IκΒ), as well as the NF-κΒ inhibitor’s (IκΒα) degradation, which both result in NF-κΒ’s inability to enter the nucleus and to initiate transcription. All aforementioned pro-inflammatory cytokines, chemokines and enzymes’ production is inhibited by treatment with curcumin or curcuminoid derivatives [65,70,71].

However, curcumin’s suppressive activity is also released upon other inflammatory pathways, including the ARA pathway which is responsible for generating reactive lipid products like prostaglandins, leukotrienes, prostacyclins and thromboxanes [65,72,73]. Curcumin is able to reduce ARA’s metabolism by mainly downregulating lipoxygenase’s (LOX) and COX-2′s activity, by limiting prostaglandin E_2’s biosynthesis by directly inhibiting the corresponding enzyme’s action and by reducing oxidative stress factor’s transcription. The anti-inflammatory profile of curcumin has been thoroughly examined in many complications and diseases, such as Alzheimer’s disease [74], cardiovascular diseases [75,76], diabetes [77], inflammatory bowel disease (IBD) [78], renal diseases [79,80], asthma [81], etc.

3.3. Curcumin’s Anticancer Properties

The following of diets rich in curcumin in several Asian countries has been considered as the main reason why several human carcinomas, including melanoma, colon, ovarian, pancreatic, breast, intestinal, prostate, head and neck carcinomas, occur less frequently among these populations. Not only because it inhibits pro-inflammatory transcription factors, signaling proteins and oncogenes, but also because it targets many carcinogenesis stages like DNA mutations initiation, tumorigenesis–angiogenesis, tumor growth, and proliferation and metastasis, does curcumin hold great promise as a chemotherapeutic, cell-growth regulatory agent, for a plethora of cancer-related manifestations [82,83,84,85,86,87,88,89]. As a potent suppressor of carcinogenesis, curcumin, in addition to its antioxidant activity, affects Phase I and Phase II enzymes building the cytochrome p450 enzymatic system, which participate in the oxidation and detoxification of toxic substances [65]. Curcumin inhibits the Phase I enzymes (p450 isoforms and reductase) that are triggered by toxins and produce DNA damaging carcinogenic and mutagenic metabolites, while, on the other hand, it stimulates Phase II enzymes (glutathione S–transferase, glutathione peroxidase and glutathione reductase) that are implicated in the detoxification of harmful metabolites [65].

As previously mentioned, curcumin inhibits NF-κΒ pathway’s activation. The AP-1 pathway, similar to the NF-κΒ pathway, is also activated by pro-inflammatory/inflammation-associated stimuli and is involved through its c-Jun domain in cyclin D1 and p53 expression, p16′s expression downregulation and tumorigenic phenotype induction. Treatment with curcumin reportedly suppressed the c-Jun mRNA of the AP-1 pathway in vivo [90].

Cellular growth and proliferation is a highly regulated procedure summarized in a cell cycle; if the cell cycle is deregulated, the uncontrollable proliferation of normal cells occurs and, thus, tumorigenesis is initiated. Cell cycle’s control is monitored by cyclin-dependent kinases (CDKs) and the tumor suppressor gene p53, while various points of the cycle are regulated by cyclin/CDK complexes (cyclin D (D1)/CDK4,6, cyclin E/CDK2, cyclin A/CDK2 and cyclin B/CDK2). CDK inhibitors including the INK-4 and Cip/Kip families are highly affected by curcumin’s existence. Curcumin has been shown to upregulate Cip/Kip’s family of CDK inhibitors, and, hence, to inhibit cyclin D1′s association with CDK4,6, while decreasing Rb’s phosphorylation, IL-6’s and IL-8′s expression, and suppressing E₂F-regulated genes’ transcription. Furthermore, it has been demonstrated to suppress cyclin D1, to initiate mitochondrial apoptosis via increased Bax expression and to upregulate p53, Fas, FADD, caspace–8 and caspase–3′s expression [65,91,92,93].

Autophagy is considered a Type II programmed cell death, where cells break down their own components, are able to dispose of old damaged organelles and proteins, upregulate lysosomal proteases, phosphatases and lipases, and recycle endogenous biosynthetic substrates like amino acids [65]. Curcumin partakes in autophagic cell death in cancer-associated diseases like malignant glioma cells, where it inhibits ROS production and oxidative stress induction, as well as inducing G2/M cell cycle arrest and non-apoptotic autophagic death by inhibiting the Akt/mTOR/p70S6 and ERK1,2 inflammatory pathways, as observed by in vivo tumor volume reduction [94,95,96].

At this point, it is important to elucidate curcumin’s effects on angiogenesis and metastasis procedures, as they are vicious cell cycle processes where the rapid proliferation and mitigation of malignant cancerous cells takes place. Curcumin treatment has been associated with the decreased expression of MMP-9, reduced levels of the angiogenic COX-2 and vascular endothelial growth factor (VEGF) biomarkers, and minimized levels of the intercellular adhesion molecule 1 (ICAM1), Bcl-2 and chemokine receptor 4 (CXCR4). Conversely, it increases the expression of anti-metastatic proteins like the tissue inhibitor metalloproteinase 2 (TIMP-2) and E–cadherin, and, thus, its anti-tumorigenic profile was confirmed in a plethora of clinical trials upon several cancer types. Furthermore, curcumin inhibits tumor epithelial–mesenchymal transition by downregulating the Wnt, NF-κΒ, STAT3 and HIF-1α pathways, while upregulating NKD2′s expression in cancer cells and modulation microRNA expression [65,97,98]. All of curcumin’s aforementioned antioxidant, anti-inflammatory and anticancer properties are depicted in Figure 4.

4. Limitations and Potential Side Effects

Curcumin has attracted substantial attention as a bioactive component in various functional products, such as functional foods, dietary supplements, nutraceuticals and cosmetics. It has demonstrated a broad range of beneficial effects towards human pathological conditions and vast pharmacological activity including anti-inflammatory, antioxidant, antitumor and immune-regulating properties. Curcumin has also shown therapeutic promise in managing neurodegenerative, cardiovascular and cerebrovascular diseases [8]. A relatively low dose of the complex may promote many health benefits for people with undiagnosed health conditions. Curcumin also helps with the management of oxidative stress and inflammation-associated complications, such as metabolic syndrome, arthritis, anxiety, hyper-lipidemia and skin aging. It may also help reduce exercise-induced inflammation and muscle soreness, improving recovery and performance in active individuals. The majority of these advantages are really ascribed to its anti-inflammatory and antioxidant properties [8].

However, despite curcumin’s potential in managing several health conditions, it still faces significant challenges in clinical use. For example, one major issue is its extremely poor water solubility, low absorption in the small intestine and rapid elimination by the liver, leading to its poor bioavailability. Curcumin’s low bioavailability notably limits its clinical applications. Therefore, consuming curcumin alone often does not produce the expected health benefits, while there are many components able to increase its bioavailability. For instance, it has been demonstrated that combining piperine, a significant bioactive component of black pepper, with curcumin increases the resultant bioavailability by 2000%. Other methods involve forming curcumin complexes with metal ions, like Zn²⁺, Cu²⁺, Mg²⁺ and Se²⁺, or carriers like liposomes, polysaccharides, proteins (e.g., serum albumin), cyclodextrins and nanoparticles, all of which enhance curcumin’s solubility and pharmacological effectiveness [11,15].

The search term “curcumin” on the website “National Institutes of Health Clinical trial.gov” revealed hundreds of clinical studies, though only a few had published results available. While curcumin research remains active, compared to its pre-clinical study, its clinical study is insufficient and suffers from limitations such as small sample sizes, focus on specific diseases (mainly cancers like breast, colorecta or prostate cancer, etc.), variations in dosage and administration, and excessive study endpoints (e.g., survival, safety, tolerance). Consequently, curcumin still has significant hurdles to overcome before being widely applied in clinical practice [8].

Curcumin is generally considered safe, with long-established guidelines from organizations including the Joint United Nations and World Health Organization Expert Committee on Food Additives (JECFA), the European Union Food Science Committee (SCF) and the European Food Safety Authority (EFSA) reports, which set the Allowable Daily Intake (ADI) value of curcumin at 0–3 mg/kg body weight. While curcumin’s safety and effectiveness have been demonstrated in several clinical trials including healthy participants, excessive dosages may cause unintended adverse effects. For instance, consuming too much turmeric may raise oxalate levels in urine, which increases the chance of kidney stones developing in those who are vulnerable. Even though curcumin-induced iron failure may improve the anticancer effects, high dosages of curcumin should be administered cautiously in patients with subclinical iron shortage, chronic anemia and consumptive anemia produced by heavy burdens of malignant tumors. While cases of curcumin-induced liver damage are scarce, those that do exist highlight the significance of curcumin supplementation as a risk factor for drug-induced liver toxicity. Abnormal cardiac conductions influence the pharmacokinetic parameters when curcumin interacts with drugs like tamoxifen, edoxifen and cyclophosphamide, while allergic reactions to curcumin administration and several other risks have also been reported. Reportedly, curcumin may also not be appropriate for those who have a high risk of cancer [8].

A rather recent clinical trial warned the scientific community that several dietary supplements may seriously damage the liver if excessively used. Herbal and dietary supplements (HDSs), including turmeric, as well as green tea, black cohosh, Garcinia cambogia, yeast rice and ashwagandha, when administrated as dietary supplements, may induce liver damage at an excessive dose. Overconsumption of such botanical sources has led to severe hepatotoxicity and hepatocellular damage, while possibly being fatal, leading to urgent liver transplantation or even death, as scientists claimed. Study data from 2017–2021 on nearly 9700 adult patients were obtained from the National Health and Nutrition Examination Survey (NHANES), while baseline weighted characteristics of HDS users and users of the six preferred potentially hepatotoxic botanicals were compared to those of non-HDS users, using a multi-variable analysis for the risk factors associated with HDS use. Surprisingly, among the participants enrolled in this NHANES cohort, a high prevalence of these herbs’ (HDS users) rates were recorded (57.6%), while the most popular goods, notably among older customers with higher educational attainment and a higher likelihood of having arthritis, had botanicals that contained turmeric. In this survey study, as a conclusion, an estimated 15.6 million US adults had consumed at least one of the six listed botanicals with liver liability, with the purpose of improving their health and/or relieving arthritis-derived pain within the past 30 days. The estimated number of patients who used non-steroidal anti-inflammatory medicines (such as simvastatin) and a widely prescribed hypolipidemic medication, where a high risk of unfavorable interactions between HDSs and prescription medication was noted, was comparable to these results. Physicians should be aware of the serious consequences of overindulging in these highly unregulated consumables because of the lack of regulatory monitoring over the production and testing of botanical goods [99].

5. Conclusions and Perspectives

Considering all of the aforementioned points, we may conclude that curcumin exhibits great promise as a medicinal tool. Because curcumin affects a wide range of molecular targets, clinical research on people, both in vivo and in vitro, has demonstrated encouraging results for the prevention and treatment of various disorders. This polyphenolic molecule’s anti-inflammatory, antioxidant, antinociception, antibacterial and anticancer effects have been shown to account for the majority of its beneficial effects. Thus, curcumin, the primary bioactive component of turmeric, has demonstrated a broad variety of uses in the culinary, cosmetic and pharmaceutical industries.

However, as with any natural compound, curcumin is not a panacea, as difficulties such as its poor bioavailability, rapid metabolism, instability and possible toxicity when overconsumed limit its use. These challenges underline the need for further research and development, in order to resolve all existing disadvantages and to fully elucidate curcumin’s great potential. Overcoming these obstacles could unlock the full therapeutic potential of curcumin, ensuring that its benefits are consistently exploited in clinical settings.