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Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression ( p  < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex ( p  < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

As peptide-based therapies gain recognition for their potential anti-cancer activity, cyclic peptides like Sansalvamide A, a marine-derived cyclic depsipeptide, have emerged as a potential anti-cancer agent due to their potent activity against various cancer types in preclinical studies. This review offers a comprehensive overview of Sansalvamide A, including its sources, structure-activity relationship, and semi-synthetic derivatives. The review also aims to outline the mechanisms through which Sansalvamide A and its analogs exert their anti-proliferative effects and to discuss the need for enhancements in pharmacokinetic profiles for better clinical utility. An extensive literature search was conducted, focusing on studies that detailed the anti-cancer activity of Sansalvamide A, its pharmacokinetics, and mechanistic pathways. Data from both in vitro and in vivo studies were collated and analyzed. Sansalvamide A and its analogs demonstrated significant anti-cancer activity across various cancer models, mediated through Hsp 90 inhibition, Topoisomerase inhibition, and G0/G1 cell cycle arrest. However, their pharmacokinetic properties were identified as a significant limitation, requiring improvement for effective clinical translation. Despite its notable anti-cancer effects, the utility of Sansalvamide A is currently limited by its pharmacokinetic characteristics. Therefore, while Sansalvamide A exhibits promise as an anti-cancer agent, there is a compelling need for further clinical and toxicological studies and optimization of its pharmacokinetic profile to fully exploit its therapeutic potential alongside modern cancer therapies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer remains one of the predominant causes of mortality globally, accounting for over 10 million deaths each year. Despite advancements in medical treatments, the challenge of resistance and treatment failure persists, necessitating innovative approaches. Traditional cancer treatments include surgery, chemotherapy, radiation therapy, and pharmaceutical therapy. In recent years, significant attention has been directed towards plant-derived compounds as potential chemotherapeutic agents and preventive measures against cancer. Vincristine, a distinguished alkaloid derived from plant secondary metabolites, has shown considerable efficacy in cancer treatment. As a member of the antimitotic class of compounds, vincristine disrupts the cell cycle by causing aberrations in microtubule function, thereby inhibiting cell division and proliferation. This mechanism of action positions vincristine as a potent agent against various malignancies. Its role in combination therapy is crucial, as it is often administered in low doses alongside other chemotherapeutic agents to enhance its efficacy and reduce the risk of resistance. In the realm of medicinal chemistry, understanding vincristine's molecular mechanism is paramount. Detailed investigations into its interaction with cellular components can provide insights into its antineoplastic properties. This review aimed to elucidate vincristine's mechanism of action and structure-activity relationship, and summarize current in vitro and in vivo studies evaluating its efficacy. Moreover, it discusses innovative strategies, including nanotechnology-based delivery systems, designed to optimize vincristine formulations. These advanced delivery systems aim to improve bioavailability, target specificity, and minimize systemic toxicity. This comprehensive analysis underscores the critical role of vincristine in contemporary cancer treatment and highlights future directions for research and development in this field., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Insulin resistance, induced by high fructose consumption, affects cognitive function negatively. Nifedipine may be suggested for neurological disorders. This study aimed to assess the effect of nifedipine with either a normal diet (ND) or a ketogenic diet (KD) in cognitive dysfunction. Male Wistar rats received 10% fructose in drinking water for 8 weeks to induce insulin resistance. Rats received nifedipine (5.2 mg/kg/day; p.o.) later with ND or KD for an additional five weeks. One and two-way ANOVAs were used in analyzing the data. Reversion to the ND improved insulin resistance and lipid profile, besides brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 beta (GSK3β), and insulin-degrading enzyme (IDE) levels. Rats fed KD alone and those that received nifedipine with KD did not show similar improvement in the previously mentioned parameters as the ND group. However, nifedipine-ND rats showed improvement in cognitive behavior and insulin resistance. Treatment with nifedipine-KD ameliorated GSK3β, amyloid β (Aβ), and tau protein levels. As the nifedipine-KD combination succeeded in diminishing the accumulated Aβ and tau protein, KD may be used for a while due to its side effects, then nifedipine treatment could be continued with an ND. This conclusion is based on the finding that this combination mitigated insulin resistance with the associated improved behavior.

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid 2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into five groups as control, vehicle, and LFND (2.5, 5, and 10 mg/kg). We investigated cardiac enzymes, histopathology, and the mRNA expression of Nrf2, NF-κB, BAX, and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5- to 0.34-fold decrease in Nrf2 and 2.6- to 4.61-fold increases in NF-κB genes) and increased (1.76- and 2.625-fold) serum creatine kinase (CK) and 1.38- and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear, and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration and highlights, for the first time, dysregulation in Nrf2/NF-κB signaling.

Anthocyanins are colored polyphenolic compounds that belong to the flavonoids family and are largely present in many vegetables and fruits. They have been used in traditional medicine in many cultures for a long time. The most common and abundant anthocyanins are those presenting an O-glycosylation at C-3 (C ring) of the flavonoid skeleton to form -O-β-glucoside derivatives. The present comprehensive review summarized recent data on the anticancer properties of cyanidings along with natural sources, phytochemical data, traditional medical applications, molecular mechanisms and recent nanostrategies to increase the bioavailability and anticancer effects of cyanidins. For this analysis, in vitro, in vivo and clinical studies published up to the year 2022 were sourced from scientific databases and search engines such as PubMed/Medline, Google scholar, Web of Science, Scopus, Wiley and TRIP database. Cyanidins' antitumor properties are exerted during different stages of carcinogenesis and are based on a wide variety of biological activities. The data gathered and discussed in this review allows for affirming that cyanidins have relevant anticancer activity in vitro, in vivo and clinical studies. Future research should focus on studies that bring new data on improving the bioavailability of anthocyanins and on conducting detailed translational pharmacological studies to accurately establish the effective anticancer dose in humans as well as the correct route of administration., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study aimed to formulate a pharmaceutical dosage form containing omeprazole (OMP) and curcumin (CURC) to treat experimental peptic ulcers. OMP and CURC were preliminarily complexed with hydroxypropyl-β-cyclodextrin for enhancing their solubilization. After that, the combined complex (CURC/OMP) was loaded to alginate beads to sustain their release and then coated with chitosan. Finally, we tested the anti-ulcerogenic impact of the best formula versus free OMP or OMP-only-loaded beads. The formulated spherical beads' diameter ranged from a minimum value of 1.5 ± 0.08 mm to 2.6 ± 0.24 mm; the swelling results ranged from 400.00 ± 8.5% to 800.00 ± 6.2%. The entrapment efficiency was in a range from 60.85 ± 1.01% to 87.44 ± 1.88%. The optimized formula (F8) showed a maximum EE% (87.44 ± 1.88%), swelling (800.00 ± 6.2%), and diameter in the range of 2.60 ± 0.24, with a desirability of 0.941. In the first hour following the administration of the free drug complex, 95% of OMP and 98% of CURC were released. This is unacceptable for medications that require a delayed release in the stomach. The initial drug release from hydrogel beads was 23.19% for CURC and 17.19% for OMP after 2 h and 73.09% for CURC and 58.26% for OMP after 12 h; however, after 24 h, 87.81% of CURC and 81.67% of OMP had been released. The OMP/CURC beads showed a more stable particle size (0.52 ± 0.01 mm) after 6 weeks. In conclusion, the OMP/CURC hydrogel beads give stronger anti-ulcer effectiveness compared to free OMP, CURC-only beads, and OMP-only-loaded beads, indicating a prospective application for managing peptic ulcers.

Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is most valuable for exploring novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs, including etoposide, sorafenib, cisplatin, and triclosan, against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Although World Health Organization-approved emergency vaccines are available in many countries, the mortality rate from COVID-19 remains high due to the fourth or fifth wave and the delta variant of the coronavirus. Thus, an effective mechanistic investigation in treating this disease is urgently needed. In this work, we extracted phytochemicals from two mangrove plants, Pistacia integerrima and Pandanus odorifer , assessing their potential actions against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. The antioxidant activities of Pistacia integerrima leaves and fruits were 142.10 and 97.13 µg/mL, respectively, whereas Pandanus odorifer leaves and fruits were 112.50 and 292.71 µg/mL, respectively. Furthermore, leaf extracts from both plants had lower cytotoxicity against Artemia salina than fruit extracts. Gas chromatography-mass spectrometry analysis revealed a total of 145 potential phytochemicals from these extracts. Three phytochemicals, 28-demethyl-beta-amyrone, 24-Noroleana-3,12-diene, and stigmasterol, displayed binding free energy values of - 8.3, -7.5, and - 8.1 Kcal/mol, respectively, in complexes with the spike protein of SARS-CoV-2. The root-mean-square deviation, solvent-accessible surface area, radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation. Thus, wet-lab validations are necessary to support these findings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Plumeria rubra (L.) is a traditional folkloric medicinal herb used to treat cardiovascular disorders. The present investigation was methodically planned to investigate the pharmacological foundations for the therapeutic effectiveness of P. rubra in cardiovascular illnesses and its underlying mechanisms. Ex vivo vaso-relaxant effects of crude leaf extract of P. rubra were observed in rabbit aorta ring preparations. Hypotensive effects were measured using pressure and force transducers connected to the Power Lab data acquisition system. Furthermore, P. rubra displayed cardioprotective properties in rabbits when they were exposed to adrenaline-induced myocardial infarction. In comparison to the intoxicated group, the myocardial infarction model showed decreased troponin levels, CK-MB, LDH, ALT, ALP, AST, and CRP, as well as necrosis, apoptosis, oedema, and inflammatory cell enrollment. P. rubra has revealed good antioxidant properties and prolonged the noradrenaline intoxicated platelet adhesion. Its anticoagulant, vasorelaxant, and cardioprotective effects in both in vivo and ex vivo investigations are enabled by blocking L-type calcium channels, lowering adrenaline, induced oxidative stress, and tissue tear, justifying its therapeutic utility in cardiovascular disorders.

Boerhavia diffusa is a great tropical plant and is widely used for various traditional purposes. In the present study, we examined the influence of solvents (dichloromethane, ethyl acetate, methanol and infusion (water)) on chemical composition and biological capabilities of B. diffusa . An UHPLC-HRMS method was used to determine the chemical characterization. The biological ability was examined for antioxidant, enzyme inhibitory and anti-cancer effects. To evaluate antioxidant effects, different chemical methods (ABTS, DPPH, CUPRAC, FRAP, metal chelating and phosphomolybdenum) were applied. With regard to enzyme inhibitory properties, cholinesterases, amylase, glucosidase and tyrosinase were used. The MDA-MB-231 breast cancer cell line was chosen to determine anticancer activity. Based on the UHPLC-HRMS analysis, 37 specialized metabolites were dereplicated and identified in the studied extracts. Results revealed the presence of 15 hydroxybenzoic, hydroxycinnamic, acylquinic acids, and their glycosides, one rotenoid, seven flavonoids, 12 fatty acids and two other glycosides. Among the tested extracts, the methanol extract showed a stronger antioxidant ability compared with other extracts. The methanol extract also showed the best inhibitory effects on tyrosinase and glucosidase. In the anti-cancer evaluation, the methanol extract showed stronger anticancer effects compared with water extract. In summary, our observations can contribute to the establishment of B. diffusa as a potential candidate for functional applications in the preparation.

Parmotremaperlatum is traditionally used in different areas of Pakistan to treat gastrointestinal, respiratory, and vascular diseases. This study evaluates the underlying mechanisms for traditional uses of P. perlatum in diarrhea, asthma, and hypertension. In vitro pharmacological studies were conducted using isolated jejunum, trachea, and aortic preparations, while the cytotoxic study was conducted in mice. Crude extract of P. perlatum (Pp.Cr), comprising appreciable quantities of alkaloids and flavonoids, relaxed spontaneously contracting jejunum preparation, K + (80 mM)-induced, and carbachol (1 µM)-induced jejunum contractions in a concentration-dependent manner similar to dicyclomine and dantrolene. Pp.Cr showed a rightward parallel shift of concentration-response curves (CRCs) of Cch after a non-parallel shift similarto dicyclomine and shifted CRCs of Ca +2 to rightward much likeverapamil and dantrolene, demonstrating the coexistence of antimuscarinic and Ca +2 antagonistic mechanism. Furthermore, Pp.Cr, dicyclomine, and dantrolene relaxed K + (80 mM)-induced and Cch (1 µM)-induced tracheal contractions and shifted rightward CRCs of Cch similar to dicyclomine, signifying the dual blockade. Additionally, Pp.Cr also relaxed the K + (80 mM)-induced and phenylephrine (1 µM)-induced aortic contraction, similarly to verapamil and dantrolene, suggesting Ca +2 channel antagonism. Here, we explored for the first time thespasmolytic and bronchodilator effects of Pp.Crand whether they maybe due to the dual blockade of Ca +2 channels and muscarinic receptors, while the vasodilator effect might be owing to Ca +2 antagonism. Our results provide the pharmacological evidence that P. perlatum could be a new potential therapeutic option to treat gastrointestinal, respiratory, and vascular diseases. Hence, there is a need for further research to explore bioactive constituent of P. perlatum as well as further investigation by suitable experimental models are required to further confirm the importance and usefulness of P. perlatum in diarrhea, asthma, and hypertension treatment.