Search Results (2,872)

TGR5 has emerged as a promising therapeutic target for obesity and metabolic disorders due to its regulatory roles in energy expenditure, glucose homeostasis, thermogenesis, and gut hormone secretion. This review summarizes the structural mechanisms of TGR5 activation, focusing on orthosteric and allosteric ligand interactions, toggle switch dynamics, and G protein coupling based on cryo-EM and docking-based models. A wide range of bioactive natural compounds including oleanolic acid, curcumin, betulinic acid, ursolic acid, quinovic acid, obacunone, nomilin, and 5β-scymnol are examined for their ability to modulate TGR5 signaling and elicit favorable metabolic effects. Molecular docking simulations using CB-Dock2 and PDB ID 7BW0 revealed key interactions within the orthosteric pocket, supporting their mechanistic potential as TGR5 agonists. Emerging strategies in TGR5-directed drug development are also discussed, including gut-restricted agonism to minimize gallbladder-related side effects, biased and allosteric modulation to fine-tune signaling specificity, and AI-guided optimization of natural product scaffolds. These integrated insights provide a structural and pharmacological framework for the rational design of safe and effective TGR5-targeted therapeutics. Full article

Background/Objectives: Cancer progression is characterized by the suppression of apoptosis, activation of metastatic processes, and dysregulation of cell proliferation. The proper functioning of these mechanisms relies on critical signaling pathways, including Phosphoinositide 3-kinase/Protein kinase B/mammalian Target of Rapamycin (PI3K/Akt/mTOR), Mitogen-Activated Protein Kinase (MAPK), and Signal Transducer and Activator of Transcription 3 (STAT3). Although curcumin and resveratrol exhibit anticancer properties and affect these pathways, their pharmacokinetic limitations, including poor bioavailability and low solubility, restrict their clinical application. The aim of our study was to evaluate the synergistic anticancer potential of curcumin and resveratrol through hybrid molecules rationally designed from these compounds to mitigate their pharmacokinetic limitations. Furthermore, we analyzed the multi-target anticancer effects of these hybrids on the AKT serine/threonine kinase 1 (AKT1), MAPK, and STAT3 pathways using in silico molecular modeling approaches. Methods: Three hybrid molecules, including a long-chain (ELRC-LC) and a short-chain (ELRC-SC) hybrid, an ester-linked hybrid, and an ether-linked hybrid (EtLRC), were designed using the Avogadro software (v1.2.0), and their geometry optimization was carried out using Density Functional Theory (DFT). The electronic properties of the structures were characterized through Frontier Molecular Orbital (FMO), Molecular Electrostatic Potential (MEP), and Fourier Transform Infrared (FTIR) analyses. The binding energies of the hybrid molecules, curcumin, resveratrol, their analogs, and the reference inhibitor were calculated against the AKT1, MAPK, and STAT3 receptors using molecular docking. The stabilities of the best-fitting complexes were evaluated through 100 ns molecular dynamics (MD) simulations, and their binding free energies were estimated using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Results: DFT analyses demonstrated stable electronic characteristics for the hybrids. Molecular docking analyses revealed that the hybrids exhibited stronger binding compared to curcumin and resveratrol. The binding energy of −11.4 kcal/mol obtained for the ELRC-LC hybrid against AKT1 was particularly remarkable. Analysis of 100 ns MD simulations confirmed the conformational stability of the hybrids. Conclusions: Hybrid molecules have been shown to exert multi-target mechanisms of action on the AKT1, MAPK, and STAT3 pathways, and to represent potential anticancer candidates capable of overcoming pharmacokinetic limitations. Our in silico-based study provides data that will guide future in vitro and in vivo studies. These rationally designed hybrid molecules, owing to their receptor affinity, may serve as de novo hybrid inhibitors. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ_1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC₅₀ = 6.67 μM, and 36.68% inhibition of Aβ_1–42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD. Full article

Protein-based emulsion gels and bigels serve as ideal delivery systems owing to their distinctive structural properties, high encapsulation efficiency, and adjustable digestive behavior. However, limited research has examined the differences between emulsion gels and bigels as polyphenol delivery systems. In this study, oil-in-water (O/W)-type emulsion gels formulated with soy protein isolate (SPI) and κ-carrageenan (κ-CG) were fabricated using a cold-set gelation method, and then the bigels were prepared through further oil gelation by the addition of glycerol monostearate (GMS). Both SPI-κ-CG emulsion gels and bigels were mainly stabilized by electrostatic and hydrophobic interactions, exhibiting high gel strength, varying from 940 g to 1304 g, and high water holding capacity (~84%). Both the SPI-κ-CG emulsion gels and bigels demonstrated high curcumin encapsulation efficiency, reaching 98~99%. Stability testing revealed that bigels prepared with 15% and 20% GMS exhibited the highest curcumin retention ratios, with a value of around 78% after storage for 21 days at 25 °C, suggesting that denser network structures more effectively prevent the degradation of the encapsulated compound. During the in vitro simulated gastric digestion, higher GMS content significantly delayed curcumin release by over 7%. Increasing GMS concentration from 0% to 20% elevated lipolysis by over 8% and concurrently improved the release of curcumin by more than 18% during the in vitro simulated intestinal digestion. This study provides comparative insights into polyphenol delivery performance between emulsion gels and bigels, offering valuable guidance for developing functional foods based on gel delivery systems. Full article

Natural products, such as turmeric rhizome meal (TRM), may hold the key to a sustainable solution to antimicrobial resistance rise and antibiotic prohibition in food-producing animals. This study evaluated the effects of dietary TRM at 0 (CON), 0.3 (TRM3), 0.6 (TRM6), and 0.9 g/kg (TRM9) on growth, nutrient digestibility, immunity, gut function, nutrient transport biomarkers, microbiome, and meat quality in 280 one-day-old male Ross 308 chicks over a 42-day feeding trial. Birds fed TRM indicated higher body weight gain and lower feed conversion ratio (p < 0.05). The TRM groups promoted higher (p = 0.001) serum immunoglobulin Y, immunoglobulin M, and interleukin-10 compared to the CON. Birds fed CON had higher interleukin-2 (p = 0.025), interleukin-6 (p = 0.027), and TNF-α (p = 0.008) levels compared to the TRM groups. Lactobacillus counts in jejunal villi and crypts were higher in the TRM groups than in the CON (p < 0.05). Dietary TRM increased electrogenic glucose and lysine transport, accompanied by up-regulation of claudin-5, zonula occludens 1, and mucin-2 expression (p < 0.05). In breast muscle, TRM fortification reduced malondialdehyde levels (p < 0.05) while increasing long-chain polyunsaturated fatty acids (p < 0.05). Thus, TRM is a potent, residue-free phytobiotic alternative to conventional antibiotic growth promoters in poultry systems. Full article

Biocompatible nanofibrous dressings integrating bioactive compounds with antioxidative and antimicrobial properties offer a promising solution for effective wound healing. In the presented study, we developed a novel dual-delivery system by combining forcespun nanofibres with poly(3-hydroxybutyrate) (PHB)-liposomes to enhance bioavailability and enable targeted release of bioactive agents (eugenol, thymol, curcumin, ampicillin, streptomycin, gentamicin). These agents exhibited notable antioxidant activity (2.27–2.33 mmol TE/g) and synergistic or partially synergistic antimicrobial effects against E. coli, M. luteus, S. epidermidis, and P. aeruginosa ( Fractional Inhibitory Concentration index 0.09–0.73). The most potent combinations, particularly thymol, eugenol, and ampicillin, were encapsulated in the nanofibre–liposomal matrix. The successful preparation of a new combined delivery system was confirmed by structural analysis using Electron and Fluorescence Microscopy. The dual-composite materials retained the antimicrobial properties of the individual compounds upon release, with the highest increases of ~73.56% against S. epidermidis. Cell viability and in vitro immunology assays using the human keratinocyte cell line (HaCaT) showed a slight decrease in viability and immune response stimulation, while not impairing wound re-epithelisation. These findings highlight the potential of firstly reported novel carrier utilising both PHB-nanofibres and PHB-liposomes, exhibiting simultaneous antioxidant and antimicrobial activity as promising candidates for the treatment of infected wounds under oxidative stress. Full article

The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration. Full article

Curcumin (CUR) is a bioactive compound with well-documented therapeutic potential in diverse pathological conditions, encompassing intestinal disorders—most notably colonic cancer—as well as extra-intestinal malignancies such as hepatic, breast, and renal tumors. However, the therapeutic efficacy of CUR is severely constrained by its poor aqueous solubility, chemical instability, and consequent low systemic bioavailability. Nano-scaled carriers (nanocurcumin) enhance CUR solubility and membrane permeability through their reduced dimensions and/or specific interactions with membrane constituents. Nevertheless, conventional nanocurcumin formulations, such as unmodified liposomes, nanocapsules, nanogels, and nanofibers, continue to accumulate substantially in non-target tissues because of their lack of disease-specific tropism. This review focuses on the most recent advances in active targeting strategies for nanocurcumin, specifically receptor-mediated cellular targeting for extra-intestinal pathologies and colon-specific ligand-directed delivery for intestinal disorders. Current methodologies for validating the efficacy of engineered nanocurcumin formulations are critically reviewed, and the prevailing limitations alongside prospective future applications of nanocurcumin are delineated and discussed. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) exhibits pronounced biological heterogeneity, aggressive behavior, and a high risk of recurrence and metastasis. The conventional treatments for TNBC have notable limitations: surgical resection may leave residual tumor cells; chemotherapy (CT) frequently induces systemic toxicity and drug resistance; and radiotherapy damages surrounding organs and compromises the patients’ immune function. Methods: Herein, we designed a carrier-free nanodrug delivery system composed of self-assembled Curcumin nanoparticles (NPs) coated with a tannic acid (TA)/Fe(III) network (denoted as CUR@TA-Fe(III) NPs). We systematically evaluated the in vitro cytotoxicity and photothermal–ferroptosis synergistic therapeutic efficacy of CUR@TA-Fe(III) NPs in 4T1 breast cancer cells, as well as the in vivo antitumor activity using 4T1 tumor-bearing mouse models. Results: CUR@TA-Fe(III) NPs had high drug loading efficiency (LE) of 27.99%, good dispersion stability, and photothermal properties. Curcumin could inhibit the growth of 4T1 cancer cells, while TA-Fe(III) efficiently converted light energy into heat upon exposure to near-infrared (NIR) light, leading to direct thermal ablation of 4T1 cells. Additionally, TA-Fe(III) could supply Fe(II) via TA, increase intracellular Fe(II) content, and generate reactive oxygen species (ROS) through the Fenton reaction, in turn inducing lipid peroxidation (LPO), a decrease in mitochondrial membrane potential (MMP), and glutathione depletion, eventually triggering ferroptosis. Conclusions: This treatment strategy, which integrates CT, PTT, and ferroptosis, is expected to overcome the limitations of traditional single-treatment methods and provide a more effective method for the treatment of TNBC. Full article

Curcumin is a diarylheptanoid polyphenol compound derived from the plant species Curcuma longa. For thousands of years, it has been used as a dietary supplement, food coloring agent, and natural antibiotic in many Asian countries. Recent studies have also investigated its potential therapeutic role in a variety of inflammatory diseases, including osteoarthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, irritable bowel syndrome, sepsis, atopic dermatitis, and psoriasis. Although individual studies have reported beneficial effects, a comprehensive discussion on findings across these conditions has been lacking. This review systematically evaluates the therapeutic potential of curcumin in inflammatory diseases. Literature was sourced through a PubMed search using relevant terms such as curcumin, treatment, and the names of each targeted disease over the past two decades. We discussed the key findings on how curcumin administration was associated with improvements in disease markers, symptom relief, or progression delay. Despite promising research outcomes, the current evidence underscores the need for more robust, large-scale studies to confirm these effects and guide the clinical applications of curcumin in managing inflammatory disorders. Full article

Irritable Bowel Syndrome (IBS) is a complex and multifactorial gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel habits, impacting quality of life. Therapy is mainly based on relieving symptoms with specific drugs, whereas herbal and complementary remedies have gained attention in recent years. This review examines the current knowledge on herbal remedies in IBS management. Several herbal treatments, particularly peppermint oil and Iberogast, have demonstrated efficacy in randomized controlled trials. Preclinical studies have revealed promising anti-inflammatory and antispasmodic effects for herbs, e.g., curcumin, fennel oil, and cannabis derivatives. However, many studies suffer from some limitations, e.g., small sample sizes, short study durations, or methodological weaknesses. There is a lack of large-scale, long-term randomized controlled trials for most herbal remedies, and heterogeneity in study designs makes direct comparisons challenging. Moreover, limited evidence exists regarding herb–drug interactions and long-term safety profiles. Despite these limitations, certain herbal remedies may offer a valuable complementary approach for some IBS patients when used under medical supervision. Future research should focus on larger, well-designed clinical trials to establish efficacy, optimal dosing, and long-term safety, as well as elucidate specific mechanisms of action and identify patient subgroups that may benefit most from specific herbal treatments. Full article

Background/Objectives: Curcumin (Cur) has various biological properties, including anti-microbial, antioxidant, anticancer, anti-diabetic, anticarcinogenic, antitumor, and anti-inflammatory activities. However, using Cur in functional food products is challenging because of its low solubility in an aqueous environment, rapid degradation, and low bioavailability. Nanostructure delivery systems provide a high surface area to volume ratio and sustainable release properties. Methods: Coconut protein nanoparticles (CPNPs) have been fabricated through heat treatment at 85 °C and pH 2 for 5 h. The formation of CPNP-Cur was used to improve Cur solubility, followed by antioxidant activity at neutral pH in an aqueous solution. Results: The maximum efficiency and loading capacity of Cur in CPNP were 96.6% and 19.32 µg/mg protein, respectively. Scanning electron microscopy indicated the spherical and organized shape of CPNP with a small size of 80 nm. The fluorescence quenching of CPNP-Cur confirmed the potential of Cur to bind to the tryptophane and tyrosine residues in CPNP. The structural properties of CPNP and CPNP-Cur were investigated using FTIR and X-ray diffraction. The antioxidant activity of samples, measured with the ABTS radical scavenging method, demonstrated that the antioxidant capacity of the aqueous solution of Cur was significantly enhanced through the encapsulation into CPNP. The steady release of Cur was observed in the simulated gastrointestinal tract, and the percentage of the cumulative release increased up to 29.2% after 4 h. Conclusions: Our findings suggest that CPNP was a suitable nanocarrier for Cur due to improved antioxidant activity and controlled release behavior. These results are valuable for the development of coconut protein nanoparticles to use as a novel nano-delivery system of bioactive components. Full article

Liver steatosis, the hallmark component of metabolic dysfunction-associated steatotic liver disease (MASLD), is particularly common among individuals with type 2 diabetes mellitus (T2DM). Shared mechanisms such as insulin resistance, oxidative stress, and chronic inflammation contribute to the coexistence of these conditions and accelerate disease progression, emphasizing the need for effective therapeutic strategies. In this 12-month, randomized, double-blind, placebo-controlled trial, 227 obese individuals with T2DM were assigned to receive either 1500 mg of curcumin daily or placebo. Curcumin significantly reduced liver fat content, liver stiffness, and glycated hemoglobin (HbA1c) compared with placebo (all p < 0.001). Improvements were also noted in inflammatory mediators, including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) (all p < 0.001), reflecting curcumin’s anti-inflammatory effects. Antioxidant benefits were evident, as total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase (SOD) increased, while malondialdehyde levels decreased (all p < 0.001). Systematic safety assessments, including liver and kidney function tests, revealed no clinically significant abnormalities. Mild gastrointestinal discomfort was the most common non-serious adverse event. Overall, these findings support curcumin as a safe and effective adjunctive therapy for improving liver steatosis in obese patients with T2DM. Full article

Helicobacter pylori is the main etiological factor of gastritis, peptic ulcers, and gastric cancer. This bacterium’s antibiotic resistance has led to a lower eradication rate; therefore, new drugs with anti-H. pylori activity are needed. Curcumin exhibits multiple biological activities, but it has low stability and poor bioavailability. To overcome these disadvantages, different metal complexes have been synthesized. The objective of this study was to determine the in vitro anti-H. pylori activity of diacetylcurcumin (DAC), DAC₂-Cu, DAC₂-Zn, DAC₂-Mn, and DAC₂-Mg by obtaining the minimum inhibitory concentration of bacterial growth, and to investigate some mechanisms by which they could affect the bacteria (urease and DNA gyrase activities). Moreover, their gastroprotective potential was assayed in an ethanol-induced gastric ulcer model in mice. The results showed that DAC₂-Cu and DAC₂-Zn have good anti-H. pylori activity, exhibit specific activity against this bacterium, inhibit the urease activity, and provide 70% gastroprotection at a dose of 200 mg/kg of body weight. In a subacute toxicity study in mice, DAC₂-Cu and DAC₂-Zn did not cause death or any deleterious symptoms, nor did they have a significant effect on serum and urine biochemical parameters compared to control mice. These compounds are promising candidates for use in H. pylori eradication schemes. Full article