Pharmaceuticals, Volume 17, Issue 6 (June 2024) – 60 articles

Melanoma, primarily caused by solar ultraviolet (UV) radiation, can be prevented by the use of sunscreens. However, the use of synthetic sunscreens raises environmental concerns. Natural compounds with antioxidant photoprotective properties and cytotoxic effects against cancer cells can be promising for the prevention and treatment of melanoma with less environmental effect. This study focuses on Melaleuca leucadendron essential oil (EO) for photoprotection and antitumor applications. EO was hydrodistilled from M. leucadendron leaves with a 0.59% yield. Gas chromatography–mass spectrometry detected monoterpenes and sesquiterpenes. Nanoemulsions were prepared with (NE-EO) and without EO (NE-B) using the phase inversion method, showing good stability, spherical or oval morphology, and a pseudoplastic profile. Photoprotective activity assessed spectrophotometrically showed that the NE-EO was more effective than NE-B and free EO. Antioxidant activity evaluated by DPPH and ABTS methods indicated that pure and nanoemulsified EO mainly inhibited the ABTS radical, showing IC₅₀ 40.72 and 5.30 µg/mL, respectively. Cytotoxicity tests on L-929 mouse fibroblasts, NGM human melanocyte, B16-F10 melanoma, and MeWo human melanoma revealed that EO and NE-EO were more cytotoxic to melanoma cells than to non-tumor cells. The stable NE-EO demonstrates potential for melanoma prevention and treatment. Further research is required to gain a better understanding of these activities. Full article

Abstract: Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson’s disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD. Full article

The psychedelic beverage ayahuasca is originally obtained by Banisteriopsis caapi (B. caapi) (BC) and Psychotria viridis (P. viridis) (PV). However, sometimes these plant species are replaced by others that mimic the original effects, such as Mimosa hostilis (M. hostilis) (MH) and Peganum harmala (P. harmala) (PH). Its worldwide consumption and the number of studies on its potential therapeutic effects has increased. This study aimed to evaluate the anticancer properties of ayahuasca in human colorectal adenocarcinoma cells. Thus, the maximum inhibitory concentration (IC₅₀) of decoctions of MH, PH, and a mixture of these (MHPH) was determined. The activities of caspases 3 and 9 were evaluated, and the cell proliferation index was determined through immunocytochemical analysis (Ki-67). Two fluorescent probes were used to evaluate the production of oxidative stress and the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) was also evaluated. It was demonstrated that exposure to the extracts significantly induced apoptosis in Caco-2 cells, while decreasing cell proliferation. MH and MHPH samples significantly reduced oxidative stress and significantly increased glutathione peroxidase activity. No significant differences were found in SOD activity. Overall, it was demonstrated that the decoctions have a potential anticancer activity in Caco-2 cells. Full article

Antimicrobial resistance (AMR) is an increasingly concerning phenomenon that requires urgent attention because it poses a threat to human and animal health. Bacteria undergo continuous evolution, acquiring novel resistance mechanisms in addition to their intrinsic ones. Multidrug-resistant and extensively drug-resistant bacterial strains are rapidly emerging, and it is expected that bacterial AMR will claim the lives of 10 million people annually by 2050. Consequently, the urgent need for the development of new therapeutic agents with new modes of action is evident. The antibacterial prodrug approach, a strategy that includes drug repurposing and derivatization, integration of nanotechnology, and exploration of natural products, is highlighted in this review. Thus, this publication aims at compiling the most pertinent research in the field, spanning from 2021 to 2023, offering the reader a comprehensive insight into the AMR phenomenon and new strategies to overcome it. Full article

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9–11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood. Full article

The role of fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is emerging for the assessment of non-oncological diseases, such as inflammatory and infectious diseases, even if the evidence in the literature is still in its initial phases. We conducted a systematic search of Scopus, PubMed/MEDLINE, Embase, and Cochrane library databases for studies published before 31 December 2023 reporting infectious and inflammatory disease imaging with FAPI PET/CT. We included twenty-one studies for a total of 1046 patients. The most frequent disease studied was lung interstitial disease, investigated in six studies for a total of 200 patients, followed by bone and joint diseases in two studies and 185 patients, IgG4-related disease in 53 patients, and Crohn’s disease in 30 patients. Despite the heterogeneity of studies in terms of study design and technical features, FAPI PET/CT showed a high detection rate and diagnostic role. Moreover, when compared with 2-[¹⁸F]FDG PET/CT (n = 7 studies), FAPI PET/CT seems to have better diagnostic performances. The presence of chronic inflammation and tissue remodeling, typical of immune-mediated inflammatory conditions, may be the underlying mechanism of FAPI uptake. Full article

The aim of this review is to present the potential application of camphor—a bicyclic monoterpene ketone—in the prevention of skin infections. Skin diseases represent a heterogeneous group of disorders characterized by prolonged symptoms that significantly diminish the quality of life. They affect the dermis, the epidermis, and even subcutaneous tissue. They very often have a bacterial or fungal background. Therapy for dermatological skin disorders is difficult and long-term. Therefore, it is important to find a compound, preferably of natural origin, that (i) prevents the initiation of this infection and (ii) supports the skin’s repair process. Based on its documented anti-inflammatory, antibacterial, antifungal, anti-acne, anesthetic, strengthening, and warming properties, camphor can be used as a preventative measure in dermatological infectious diseases and as a component in medical and cosmetic products. This work discusses the structure and physicochemical properties of camphor, its occurrence, and methods of obtaining it from natural sources as well as through chemical synthesis. The use of camphor in industrial preparations is also presented. Additionally, after a detailed review of the literature, the metabolism of camphor, its interactions with other medicinal substances, and its antimicrobial properties against bacteria and fungi involved in skin diseases are discussed with regard to their resistance. Full article

Policosanol is a mixture of long-chain aliphatic alcohols (LCAAs) derived from various plant and insect origins that are marketed by various companies with distinct formulations and brand names. Policosanols offer several beneficial effects to treat dyslipidemia and hypertension; however, a comprehensive functionality comparison of various policosanol brands has yet to be thoroughly explored. In the present study five distinct policosanol brands from different origins and countries, Raydel-policosanol, Australia (PCO1), Solgar-policosanol, USA (PCO2), NutrioneLife-monacosanol, South Korea (PCO3), Mothernest-policosanol, Australia (PCO4), and Peter & John-policosanol, New Zealand (PCO5) were compared via dietary supplementation (1% in diet, final wt/wt) to zebrafish for six weeks to investigate their impact on survivability, blood lipid profile, and functionality of vital organs under the influence of a high-cholesterol diet (HCD, final 4%, wt/wt). The results revealed that policosanol brands (PCO1–PCO5) had a substantial preventive effect against HCD-induced zebrafish body weight elevation and hyperlipidemia by alleviating total cholesterol (TC) and triglycerides (TG) in blood. Other than PCO3, all the brands significantly reduced the HCD’s elevated low-density lipoprotein cholesterol (LDL-C). On the contrary, only PCO1 displayed a significant elevation in high-density lipoprotein cholesterol (HDL-C) level against the consumption of HCD. The divergent effect of PCO1–PCO5 against HCD-induced hepatic damage biomarkers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), was observed. PCO1, PCO2, and PCO4 efficiently curtailed the AST and ALT levels; however, PCO3 and PCO5 potentially aggravated the HCD’s elevated plasma AST and ALT levels. Consistently, the hepatic histology outcome revealed the least effectiveness of PCO3 and PCO5 against HCD-induced liver damage. On the contrary, PCO1 exhibited a substantial hepatoprotective role by curtailing HCD-induced fatty liver changes, cellular senescent, reactive oxygen species (ROS), and interleukin-6 (IL-6) production. Likewise, the histological outcome from the kidney, testis, and ovary revealed the significant curative effect of PCO1 against the HCD-induced adverse effects. PCO2–PCO5 showed diverse and unequal results, with the least effective being PCO3, followed by PCO5 towards HCD-induced kidney, testis, and ovary damage. The multivariate interpretation based on principal component analysis (PCA) and hierarchical cluster analysis (HCA) validated the superiority of PCO1 over other policosanol brands against the clinical manifestation associated with HCD. Conclusively, different brands displayed distinct impacts against HCD-induced adverse effects, signifying the importance of policosanol formulation and the presence of aliphatic alcohols on the functionality of policosanol products. Full article

Pearl oysters have been extensively utilized in pearl production; however, most pearl oyster shells are discarded as industrial waste. In a previous study, we demonstrated that the intraperitoneal administration of pearl oyster shell-derived nacre extract (NE) prevented d-galactose-induced brain and skin aging. In this study, we examined the anti-aging effects of orally administered NE in senescence-accelerated mice (SAMP8). Feeding SAMP8 mice NE prevented the development of aging-related characteristics, such as coarse and dull hair, which are commonly observed in aged mice. Additionally, the NE mitigated muscle aging in SAMP8 mice, such as a decline in grip strength. Histological analysis of skeletal muscle revealed that the NE suppressed the expression of aging markers, cyclin-dependent kinase inhibitor 2A (p16) and cyclin-dependent kinase inhibitor 1 (p21), and increased the expression of sirtuin1 and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)- α, which are involved in muscle synthesis. These findings suggest that the oral administration of NE suppresses skeletal muscle aging. Moreover, NE administration suppressed skin aging, including a decline in water content. Interestingly, oral administration of NE significantly extended the lifespan of SAMP8 mice, suggesting that its effectiveness as an anti-aging agent of various tissues including skeletal muscle, skin, and adipose tissue. Full article

Background: Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, β-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB). Methods: Human ASM cells were pre-treated with β-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of β-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration. Results: β-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, β-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2. Conclusions: In conclusion, the inhibition of RhoA activation and ROS production by β-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling. Full article

Purpose: Acute heart failure (AHF) is associated with high morbidity and mortality, and the prognosis is particularly poor in older patients. Although the application of guideline-directed medical therapy (GDMT) has shown a positive impact on prognosis, the effects are less clear in older age groups. The aim of this study was to analyze real-world data regarding GDMT and outcomes in older HF patients. Methods: This is a prospective cohort study from a secondary care hospital in central Switzerland. A total of 97 consecutive patients aged ≥60 years were enrolled between January 2019 and 2022. The main outcome parameters were prescribed GDMT at discharge, and in case of rehospitalization, GDMT at readmission, and survival in terms of all-cause mortality and HF-related hospitalizations during a 3-year follow-up period. Results: Follow-up data were available for 93/97 patients. The mean age was 77.8 ± 9.8 years, 46% being female. The mean left ventricular ejection fraction (LVEF) was 35.3 ± 13.9%, with a mean BNP level of 2204.3 ± 239 ng/L. Upon discharge, 86% received beta-blockers and 76.3% received renin–angiotensin system (RAS) inhibitors. At rehospitalization for AHF, beta-blockers use was significantly lower and decreased to 52.8% (p = 0.003), whereas RAS inhibitor use increased slightly to 88.9% (p = 0.07), and SGLT-2 inhibitors showed a significant increase from 5.4% vs. 47.2% (p = 0.04). GDMT prescription was not dependent on LVEF. Overall, 73.1% of patients received two-stage or three-stage GDMT at discharge, whereas this percentage decreased to 61% at rehospitalization (p = 0.01). Kaplan–Meier analysis for the combined outcome rehospitalization and death stratified by LV function showed significant differences between LVEF groups (aHR: 0.6 [95% CI: 0.44 to 0.8]; p = 0.0023). Conclusions: Our results indicate that first, the majority of older AHF patients from a secondary care hospital in Switzerland were not on optimal GDMT at discharge and even fewer at readmission, and second, that prognosis of the population is still poor, with almost half of the patients having been rehospitalized or died during a 3-year follow-up period under real-world conditions, without significant difference between women and men. Our findings underline the need for further improvements in the medical treatment of AHF, in particular in older patients, to improve prognosis and to reduce the burden of disease. Full article

Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10–13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10–13 might serve as selective COX-1 inhibitors. They showed IC₅₀ values ranging from 0.71 μM to 4.82 μM against COX-1 and IC₅₀ values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC₅₀ values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC₅₀ value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC₅₀ values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC₅₀ value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors. Full article

Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6–12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression. Full article

Background: Literature on the preferred anticoagulant for treating left ventricular thrombus (LVT) is lacking. Thus, our objective was to compare the efficacy of DOACs versus warfarin in treating LVT. Methods: Databases were searched for RCTs and adjusted observational studies that compared DOAC versus warfarin through March 2024. The primary efficacy outcomes of interest were LVT resolution, systemic embolism, composite of stroke, and TIA. The primary safety outcomes encompassed all-cause mortality and bleeding events. Results: Our meta-analysis including 31 studies demonstrated that DOAC use was associated with higher odds of thrombus resolution (OR: 1.08, 95% CI: 0.86–1.31, p: 0.46). A statistically significant reduction in the risk of stroke/TIA was observed in the DOAC group versus the warfarin group (OR: 0.65, 95% CI: 0.48–0.89, p: 0.007). Furthermore, statistically significant reduced risks of all-cause mortality (OR: 0.68, 95% CI: 0.47–0.98, p: 0.04) and bleeding events (OR: 0.70, 95% CI: 0.55–0.89, p: 0.004) were observed with DOAC use as compared to warfarin use. Conclusion: Compared to VKAs, DOACs are noninferior as the anticoagulant of choice for LVT treatment. However, further studies are warranted to confirm these findings. Full article

Mesenchymal stem cells (MSCs) have emerged as a promising approach for drug delivery strategies because of their unique properties. These strategies include stem cell membrane-coated nanoparticles, stem cell-derived extracellular vesicles, immunomodulatory effects, stem cell-laden scaffolds, and scaffold-free stem cell sheets. MSCs offer advantages such as low immunogenicity, homing ability, and tumor tropism, making them ideal for targeted drug delivery systems. Stem cell-derived extracellular vesicles have gained attention for their immune properties and tumor-homing abilities, presenting a potential solution for drug delivery challenges. The relationship between MSC-based drug delivery and the self-renewal and differentiation capabilities of MSCs lies in the potential of engineered MSCs to serve as effective carriers for therapeutic agents while maintaining their intrinsic properties. MSCs exhibit potent immunosuppressive functions in MSC-based drug delivery strategies. Stem cell-derived EVs have low immunogenicity and strong therapeutic potential for tissue repair and regeneration. Scaffold-free stem cell sheets represent a cutting-edge approach in regenerative medicine, offering a versatile platform for tissue engineering and regeneration across different medical specialties. MSCs have shown great potential for clinical applications in regenerative medicine because of their ability to differentiate into various cell types, secrete bioactive factors, and modulate immune responses. Researchers are exploring these innovative approaches to enhance drug delivery efficiency and effectiveness in treating various diseases. Full article

Osteoporosis is a global health challenge characterized by bone loss and microstructure deterioration, which urgently requires the development of safer and more effective treatments due to the significant adverse effects and limitations of existing drugs for long-term treatment. Traditional Chinese medicine, like Epimedium, offers fewer side effects and has been used to treat osteoporosis, yet its active compounds and pharmacological mechanisms remain unclear. In this study, 65 potential active compounds, 258 potential target proteins, and 488 pathways of Epimedium were identified through network pharmacology analysis. Further network analysis and review of the literature identified six potential active compounds and HIF-1α for subsequent experimental validation. In vitro experiments confirmed that 2″-O-RhamnosylIcariside II is the most effective compound among the six potential active compounds. It can promote osteoblast differentiation, bind with HIF-1α, and inhibit both HIF-1α gene and protein expression, as well as enhance COL1A1 protein expression under hypoxic conditions. In vivo experiments demonstrated its ability to improve bone microstructures and reduce bone loss by decreasing bone marrow adipose tissue, enhancing bone formation, and suppressing HIF-1α protein expression. This study is the first to describe the therapeutic effects of 2-O-RhamnosylIcariside II on osteoporosis, which was done, specifically, through a mechanism that targets and inhibits HIF-1α. This study provides a scientific basis for the clinical application of Epimedium and offers a new candidate drug for the treatment of osteoporosis. Additionally, it provides new evidence supporting HIF-1α as a therapeutic target for osteoporosis. Full article

The importance of natural plant materials in modern medicine is considerable, and raw materials with antiviral, antibacterial, antifungal, and anticancer properties are still sought because of microbe resistance and difficulties in anticancer therapy. This review focuses on the lemongrass Cymbopogon citratus (DC.) Stapf. and on the lemongrass oil properties and applications. Multiple applications of this plant were described in different latitudes and cultures, including cases of digestive disorders and anti-inflammatory, antipyretic, diaphoretic, stimulating, and antispasmodic conditions. Data from the literature on the composition of essential oil and extracts from C. citratus were analyzed, and the results of research on the antifungal, antibacterial, and antiviral effects were quoted. Essential oil inhibits the growth of fungi (Aspergillus niger, A. fumigatus, Candida spp.) and has an antibacterial effect (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa). It also shows antiviral activity and deters insects. Lemongrass contains active substances with potential anticancer effects. This plant has apoptosis-stimulating properties, mainly through the activity of apigenin, which is the main active flavonoid in this plant. This active substance helps inhibit cell proliferation by stopping the cell cycle and directing cancer cells toward apoptosis. Full article

Diabetes mellitus is a heterogeneous metabolic disorder that poses significant health and economic challenges across the globe. Polysaccharides, found abundantly in edible plants, hold promise for managing diabetes by reducing blood glucose levels (BGL) and insulin resistance. However, most of these polysaccharides cannot be digested or absorbed directly by the human body. Here we report the production of antidiabetic oligosaccharides from cress seed mucilage polysaccharides using yeast fermentation. The water-soluble polysaccharides extracted from cress seed mucilage were precipitated using 75% ethanol and fermented with Pichia pastoris for different time intervals. The digested saccharides were fractionated through gel permeation chromatography using a Bio Gel P-10 column. Structural analysis of the oligosaccharide fractions revealed the presence of galacturonic acid, rhamnose, glucuronic acid, glucose and arabinose. Oligosaccharide fractions exhibited the potential to inhibit α-amylase and α-glucosidase enzymes in a dose-dependent manner in vitro. The fraction DF73 exhibited strong inhibitory activity against α-amylase with IC₅₀ values of 38.2 ± 1.12 µg/mL, compared to the positive control, acarbose, having an IC₅₀ value of 29.18 ± 1.76 µg/mL. Similarly, DF72 and DF73 showed the highest inhibition of α-glucosidase, with IC₅₀ values of 9.26 ± 2.68 and 50.47 ± 5.18 µg/mL, respectively. In in vivo assays in streptozotocin (STZ)-induced diabetic mice, these oligosaccharides significantly reduced BGL and improved lipid profiles compared to the reference drug metformin. Histopathological observations of mouse livers indicated the cytoprotective effects of these sugars. Taken together, our results suggest that oligosaccharides produced through microbial digestion of polysaccharides extracted from cress seed mucilage have the potential to reduce blood glucose levels, possibly through inhibition of carbohydrate-digesting enzymes and regulation of the various signaling pathways. Full article

Despite the vast global botanical diversity, the pharmaceutical development of herbal medicinal products (HMPs) remains underexploited. Of over 370,000 described plant species, only a few hundred are utilized in HMPs. Most of these have originated from traditional use, and only a minority come from megadiverse countries. Exploiting the pharmacological synergies of the hundreds of compounds found in poorly studied plant species may unlock new therapeutic possibilities, enhance megadiverse countries’ scientific and socio-economic development, and help conserve biodiversity. However, extensive constraints in the development process of HMPs pose significant barriers to transforming this unsatisfactory socio-economic landscape. This paper proposes a roadmap to overcome these challenges, based on the technology readiness levels (TRLs) introduced by NASA to assess the maturity of technologies. It aims to assist research entities, manufacturers, and funding agencies from megadiverse countries in the discovery, development, and global market authorization of innovative HMPs that comply with regulatory standards from ANVISA, EMA, and FDA, as well as WHO and ICH guidelines. Full article

This study aimed to assess the ability of rosmarinic acid (RA) to prevent kidney stone formation in an ethylene glycol and ammonium chloride (EG/AC) model. There was an increase in diuresis in the normotensive (NTRs) and hypertensive rats (SHRs) treated with hydrochlorothiazide (HCTZ) and exposed to EG/AC, while RA restored urine volume in NTRs. The EG/AC groups exhibited lower urine pH and electrolyte imbalance; these parameters were not affected by any of the treatments. Both HCTZ+EG/AC and RA+EG/AC reduced calcium oxalate crystal formation in NTR and SHR urine. Kidney tissue analysis revealed alterations in oxidative stress and inflammation parameters in all EG/AC-receiving groups, with RA enhancing antioxidant defenses in SHRs. Additionally, crystals were found in the kidney histology of all EG/AC-exposed groups, with reduced Bowman’s capsule areas in NTRs and SHRs. The NTR VEH+EG/AC group showed intense renal damage, while the others maintained their structures, where treatments with HCTZ and RA were fundamental for kidney protection in the NTRs. Docking analysis showed that RA exhibited good binding affinity with matrix metalloproteinase-9, phosphoethanolamine cytidylyltransferase, and human glycolate oxidase enzymes. The data disclosed herein underscore the importance of further research to understand the underlying mechanisms better and validate the potential of RA for clinical use. Full article

Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and others) and cancer, seemingly disparate in their etiology and manifestation, exhibit intriguing associations in certain cellular and molecular processes. Both cancer and neurodegenerative diseases involve the deregulation of cellular processes such as apoptosis, proliferation, and DNA repair and pose a significant global health challenge. Afzelin (kaempferol 3-O-rhamnoside) is a flavonoid compound abundant in various plant sources. Afzelin exhibits a diverse range of biological activities, offering promising prospects for the treatment of diseases hallmarked by oxidative stress and deregulation of cell death pathways. Its protective potential against oxidative stress is also promising for alleviating the side effects of chemotherapy. This review explores the potential therapeutic implications of afzelin, including its capacity to mitigate oxidative stress, modulate inflammation, and promote cellular regeneration in neurodegenerative and cancer diseases. Full article

Background: We recently reported that extract prepared from the aerial part of Cichorium intybus L. (CE) possesses hepatoprotective, hypolipidemic, and hypoglycemic properties. This paper focuses on the effects of CE on the male rat reproductive system and the effects of this treatment on pregnancy and offspring development. Methods: The experimental male rats received 100 mg/kg bw/day, 500 mg/kg bw/day, and 1000 mg/kg bw/day of CE orally for 60 consecutive days. Rats that received tap water were used as controls. After treatment, we evaluated the effects of CE on the male reproductive system, fertility, and offspring development. Results: For CE-treated male rats, there was a significant increase in the (1) diameter of seminiferous tubules, (2) spermatogenic index, (3) number of total and motile spermatozoa, and (4) testosterone levels. Additionally, there was a decrease in the pre- and post-implantation death of the embryos in the CE-treated group. All pups born from CE-treated males demonstrated normal development. Conclusions: CE treatment significantly improved male reproductive functions. No adverse effects on pregnancy and offspring development were observed when males were treated with CE. Further clinical evaluation of CE should lead to the development of a safe and effective phytodrug for treating male infertility. Full article

Background: Epilepsy is defined by an excessive level of activity in the neurons and coordinated bursts of electrical activity, resulting in the occurrence of seizure episodes. The precise cause of epileptogenesis remains uncertain; nevertheless, the etiology of epilepsy may involve neuroinflammation, oxidative stress, and malfunction of the neurotransmitter system. Objective: The goal of this investigation was to assess barbaloin’s protective properties with respect to pentylenetetrazol (PTZ)-)-induced cognitive deficits in rats via antioxidative, anti-inflammatory, and neurotransmitter-modulating effects. Methods: Wistar rats were subjected to PTZ [40 mg/kg (i.p.)], which induced cognitive decline. Behavior assessment using a kindling score, open-field test (OFT), novel object recognition test (NORT), and assays for superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), malondialdehyde (MDA), acetylcholinesterase (AChE), caspase-3, nitric oxide (NO), interleukins-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6, nuclear factor kappa-B (NF-κB), Bcl-2 and Bax, and neurotransmitter levels [GABA, DA, NE, and serotonin (5-HT)] were performed. Results: The treatment of rats with barbaloin resulted in behavior improvement and significant changes in the levels of GSH, SOD, CAT, MDA, AChE, NO, IL-6, IL-1β, TNF-α, NF-κB, caspase-3, Bcl-2, and Bax compared to the PTZ control group. Barbaloin treatment resulted in notable changes in neurotransmitter levels (GABA, NE, 5-HT, DA) compared to the PTZ group. Conclusions: The ongoing study has gathered evidence indicating that the injection of barbaloin has resulted in significant improvements in cognitive performance in rats. This is achieved by inhibiting oxidative stress, enhancing the activity of natural antioxidant enzymes, reducing cytokine levels, and increasing the levels of neurotransmitters in the brain. These results were detected in comparison to a PTZ control and can be attributed to the potent anti-inflammatory and antioxidant capabilities of barbaloin, which could be linked to its neuroprotective properties. Barbaloin may potentially increase cognitive decline and boost neuronal survival by altering the expression of Bax, caspase-3, Bcl-2. Full article

Novel potassium-competitive acid blockers (P-CABs) have emerged as effective acid-suppressive drugs in recent years, replacing proton pump inhibitors (PPIs). We aim to compare the efficacy and safety of P-CABs versus PPIs in the treatment of peptic ulcers with or without Helicobacter pylori (H. pylori) infection. We searched in PubMed, Embase, WOS, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases (all years up to January 2024). Efficacy and safety outcomes were evaluated using odds ratio (OR) and 95% confidence intervals (CI). The Surface Under the Cumulative Ranking (SUCRA) probabilities were used to rank each intervention. Among 14,056 studies screened, 56 studies involving 9792 participants were analyzed. Vonoprazan demonstrated the best efficacy in ulcer healing rate and H. pylori eradication rate (SUCRA = 86.4% and 90.7%, respectively). Keverprazan ranked second in ulcer healing rates (SUCRA = 76.0%) and was more effective in pain remission rates (SUCRA = 91.7%). The risk of adverse events was low for keverprazan (SUCRA = 11.8%) and tegoprazan (SUCRA = 12.9%), and moderate risk for vonoprazan (SUCRA = 44.3%) was demonstrated. Compared to lansoprazole, vonoprazan exhibited a higher risk of drug-related adverse events (OR: 2.15; 95% CI: 1.60–2.89) and serious adverse events (OR: 2.22; 95% CI: 1.11–4.42). Subgroup analysis on patients with H. pylori-positive peptic ulcers showed that vonoprazan was at the top of the SUCRA rankings, followed by keverprazan. Vonoprazan showed superior performance in peptic ulcers, especially for patients with H. pylori-positive peptic ulcers. However, the risk of adverse events associated with vonoprazan should be noted. Keverprazan has also shown good therapeutic outcomes and has performed better in terms of safety. Full article

Statins function beyond regulating cholesterol and, when administered systemically, can promote wound healing. However, studies have yet to explore the topical use of statins for wound healing. The present study demonstrated the topical administration of SIM and aimed to formulate, evaluate, and optimize Simvastatin (SIM)-encapsulated liposome gel carrier systems to facilitate successful topical wound healing. Liposomes containing SIM were formulated and optimized via a response surface methodology (RSM) using the thin-film hydration method. The effects of formulation variables, including the 1,2-dioleoyloxy-3-trimethylammoniumpropan (DOTAP) concentration, Span 80 concentration, and cholesterol concentration, on zeta potential (mV), entrapment efficacy (%), and particle size (nm) were studied. The optimized liposome formulation (F-07) exhibited a zeta potential value of 16.56 ± 2.51 mV, revealing robust stability and a high SIM encapsulation efficiency of 95.6 ± 4.2%, whereas its particle size of 190.3 ± 3.3 nm confirmed its stability and structural integrity. The optimized liposome gel demonstrated pseudoplastic flow behavior. This property is advantageous in topical drug delivery systems because of its ease of application, improved spreadability, and enhanced penetration, demonstrating prolonged SIM release. The assessment of the wound healing efficacy of the optimized liposomal gel formulation demonstrated a substantial decrease in wound size in mice on the sixteenth day post-wounding. These findings suggest that the use of liposomal gels is a potential drug delivery strategy for incorporating SIM, thereby augmenting its effectiveness in promoting wound healing. Full article

Mebendazole (MBZ) is a benzimidazole carbamate anthelmintic used worldwide for the treatment and prevention of parasitic disorders in animals and humans. A large number of in vivo and in vitro studies have demonstrated that MBZ also has anticancer activity in multiple types of cancers. After oral administration, the phenylketone moiety of MBZ is rapidly reduced to the hydroxyl group to form the chiral hydroxy metabolite (MBZ-OH). To the best of our knowledge, there is no information in the literature on the stereochemical course of transformation and the anthelmintic and antitumor activity of individual enantiomers of MBZ-OH. In the present study, we describe in detail the direct HPLC resolution of MBZ-OH on a 100 mm × 4.6 mm Chirapak IG-3 column packed with 3 μm silica particles containing amylose (3-chloro-5-methylphenylcarbamate) as a selector. At 25 °C and using pure methanol as the mobile phase, the enantioseparation and resolution factors were 2.38 and 6.13, respectively. These conditions were scaled up at a semi-preparative scale using a 250 mm × 10 mm Chiralpak IG column to isolate multi-milligram amounts of both enantiomeric forms of the chiral metabolite. The chiroptical properties of the collected enantiomers were determined and, through a theoretical study, were related to the more stable conformations of MBZ-OH. The first and second eluted enantiomers were dextrorotatory and levorotatory, respectively, in dimethylformamide solution. Finally, by recording the retention factors of the enantiomers as the water content in the water–acetonitrile mobile phases was progressively varied, U-shaped retention maps were generated, indicating a dual and competitive hydrophilic interaction liquid chromatography and reversed-phase liquid chromatography retention mechanism on the Chirapak IG-3 chiral stationary phase. Full article

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter regulating numerous physiological functions, and its dysregulation is a crucial component of the pathological processes of schizophrenia, depression, migraines, and obesity. 5-HT interacts with 14 different receptors, of which 5-HT_1A-1FRs, 5-HT_2A-CRs, and 5-HT_4-7Rs are G protein-coupled receptors (GPCRs), while 5-HT₃R is a ligand-gated ion channel. Over the years, selective orthosteric ligands have been identified for almost all serotonin receptors, yielding several clinically relevant drugs. However, the high degree of homology between 5-HTRs and other GPCRs means that orthosteric ligands can have severe side effects. Thus, there has recently been increased interest in developing safer ligands of GPCRs, which bind to less conserved, more specific sites, distinct from that of the receptor’s natural ligand. The present review describes the identification of allosteric ligands of serotonin receptors, which are largely natural compounds (oleamide, cannabidiol, THC, and aporphine alkaloids), complemented by synthetic modulators developed in large part for the 5-HT_2C receptor. The latter are positive allosteric modulators sought after for their potential as drugs preferable over the orthosteric agonists as antiobesity agents for their potentially safer profile. When available, details on the interactions between the ligand and allosteric binding site will be provided. An outlook on future research in the field will also be provided. Full article

Recently, there has been great interest in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, and lupane-type triterpenes are phytochemicals that exert significant activity against diseases like cancer. Lung cancer is the leading cause of cancer-related death worldwide. Although chemotherapy is the treatment of choice for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects and chemoresistance. Herein, we investigated six pentacyclic triterpenes, oleanolic acid, ursolic acid, asiatic acid, betulinic acid, betulin, and lupeol, on NSCLC A549 cells. These triterpenes have several structural variations that can influence the activation/inactivation of key cellular pathways. From our results, we determined that most of these triterpenes induced apoptosis, S-phase and G2/M-phase cycle arrest, the downregulation of ribonucleotide reductase (RR), reactive oxygen species, and caspase 3 activation. For chemoresistance markers, we found that most triterpenes downregulated the expression of MAPK/PI3K, STAT3, and PDL1. In contrast, UrA and AsA also induced DNA damage and autophagy. Then, we theoretically determined other possible molecular targets of these triterpenes using the online database ChEMBL. The results showed that even slight structural changes in these triterpenes can influence the cellular response. This study opens up promising perspectives for further research on the pharmaceutical role of phytochemical triterpenoids. Full article

Background: Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy. Methods: We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV. Results: A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m² vs. 29.11 ± 4.09 kg/m²; p < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; p < 0.001). In the logistic regression, BMI (kg/m²) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m²); CI 75% 0.864–0.946). Conclusions: We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy. Full article

There are a wide variety of phytochemicals collectively known as polyphenols. Their structural diversity results in a broad range of characteristics and biological effects. Polyphenols can be found in a variety of foods and drinks, including fruits, cereals, tea, and coffee. Studies both in vitro and in vivo, as well as clinical trials, have shown that they possess potent antioxidant activities, numerous therapeutic effects, and health advantages. Dietary polyphenols have demonstrated the potential to prevent many health problems, including obesity, atherosclerosis, high blood sugar, diabetes, hypertension, cancer, and neurological diseases. In this paper, the protective effects of polyphenols and the mechanisms behind them are investigated in detail, citing the most recent available literature. This review aims to provide a comprehensive overview of the current knowledge on the role of polyphenols in preventing and managing chronic diseases. The cited publications are derived from in vitro, in vivo, and human-based studies and clinical trials. A more complete understanding of these naturally occurring metabolites will pave the way for the development of novel polyphenol-rich diet and drug development programs. This, in turn, provides further evidence of their health benefits. Full article