Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle.

Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation. Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells via FOXO3, inhibits apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation, inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5 COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases. Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit the entry and life cycle of XBB.1.5 COVID-19 in host cells.

Investigation of the effects of catharanthine and Q10 on Nrf2 and its association with MMP-9, MRP1, and Bcl-2 and apoptosis in a model of hepatocellular carcinoma.

Since the role of Nrf2 in cancer cell survival has been highlighted, the pharmacological modulation of the Nrf2-Keap1 pathway may provide new opportunities for cancer treatment. This study purposed to use ubiquinone (Q10) as an antioxidant and catharanthine alkaloid as a cAMP inducer suppressing HepG2 cells by reducing Nrf2 level. The effects of Q10 and catharanthine on HepG2 cells in terms of viability were analyzed by MTT test. MTT results were used to determine the effective concentration of both drugs for the subsequent treatment and analysis. Subsequently, the effects of Q10 and catharanthine in a single and combined manner on oxidant/antioxidant status, apoptosis, metastasis, and drug resistance of HepG2 cells were investigated by related methods. Both Q10 and catharanthine decreased the level of oxidative stress products and increased antioxidant capacity in HepG2 cells. Nrf2 gene expression decreased by Q10, but catharanthine unexpectedly increased it. Following Nrf2 alterations, the expression levels of MMP-9 and MRP1 involved in metastasis and drug resistance were significantly and dose-dependently decreased by Q10, while catharanthine slightly increased both. However, both drugs increased caspase 3/7 activity and apoptosis rate, and the effect of Q10 on apoptosis was stronger than that of catharanthine. Most of the effects of the combination treatments were similar to those of the Q10 single treatment and indicated the dominant effect over the catharanthine component. Despite the antioxidant and apoptotic properties of both agents, Q10 was better than catharanthine in inducing apoptosis, counteracting drug resistance, and metastasis in HepG2 cells.

Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy.

Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy.

Therapeutic Potential of Resveratrol and Atorvastatin Following High-Fat Diet Uptake-Induced Nonalcoholic Fatty Liver Disease by Targeting Genes Involved in Cholesterol Metabolism and miR33.

The present study was designed to evaluate the effects of resveratrol, atorvastatin, and a combination of resveratrol and atorvastatin on expression levels of genes involved in the cholesterol metabolic pathway in the fatty liver of C57/BL6 mice. A high-fat diet was used to induce fatty liver in C57/BL6 mice treated with resveratrol, atorvastatin, or a combination of resveratrol and atorvastatin. Pathological and biochemical studies were performed. In addition, hepatic gene expressions of ATP-binding cassette transporter A1 (ABCA1), ABCG1, liver X receptor (LXR)α, scavenger receptor B1 (SR-B1), low-density lipoprotein receptor (LDLR), and miR33 were evaluated by the real-time PCR method, and the Western blot method was used to measure the ABCA1, ABCG1, and LXRα protein levels. Resveratrol and atorvastatin reduced fat accumulation in the liver of mice with fatty liver, and this effect was correlated with decreased blood glucose levels, triglyceride, cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol blood levels compared with the positive control (PC) group. In contrast to the animals of the PC group, fatty liver groups that received resveratrol and atorvastatin had a significant effect on the mRNA levels of the ABCA1, ABCG1, LXRα, SR-B1, LDLR, and miR33 genes. Moreover, resveratrol and atorvastatin administration elevated ABCA1 and ABCG1 and reduced LXRα protein expression. Obtained results showed that resveratrol and atorvastatin combination therapy can improve nonalcoholic fatty liver disease by targeting genes involved in cholesterol metabolism and miR33.

Synergetic dual antibiotics-loaded chitosan/poly (vinyl alcohol) nanofibers with sustained antibacterial delivery for treatment of XDR bacteria-infected wounds.

Resistance of bacterial pathogens to conventional antibiotics has remained a significant challenge in managing post-wound infections, especially in developing countries. Here, a nanofibrous chitosan/poly (vinyl alcohol) (CS/PVA) mat was designed for controlled delivery of three different concentrations of two antibiotics (colistin/meropenem ratio of 32/64 µg/ml (AB1), 64/128 µg/ml (AB2), and 128/256 (AB3) µg/ml) with synergistic antibacterial activity against ATCC and extensively drug-resistant (XDR) Acinetobacter baumannii clinical isolates. The scaffolds showed a uniform fibrous structure with no bead formation with a sustained release of the antibiotics for one week. The elongation at break, wettability, porosity, and average fiber diameter decreased with increased antibiotics concentrations. Young's modulus and tensile strength showed a significant increase after adding antibiotics. All the constructs showed excellent in vitro cytocompatibility for fibroblasts and biocompatibility in an animal model. The antibacterial assays confirmed the dose-dependent antibacterial activity of the CS/PVA. The scaffolds loaded with AB2 and AB3 showed biocidal properties against ATCC, while only CS/PVA/AB3 had antibacterial activity against XDR clinical isolates. This study suggests the CS/PVA/AB3 nanofibrous scaffold contained 128/256 µg/ml colistin/meropenem as an excellent antibacterial wound dressing for protection of skin wounds from XDR clinical isolates and now promises to proceed with pre-clinical investigations.

Evaluation of testicular glycogen storage, FGF21 and LDH expression and physiological parameters of sperm in hyperglycemic rats treated with hydroalcoholic extract of Securigera Securidaca seeds, and Glibenclamide.

Structural and physiological changes in sperm and semen parameters reduce fertility in diabetic patients. Securigera Securidaca (S. Securidaca) seed is a herbal medicine with hypoglycemic, antioxidant, and anti-hypertensive effects. The question now is whether this herbal medicine improves fertility in diabetic males. The study aimed to evaluate the effects of hydroalcoholic extract of S. Securidaca seeds (HESS), glibenclamide and a combination of both on fertility in hyperglycemic rats by comparing histological and some biochemical changes in testicular tissue and sperm parameters. The treatment protocol included administration of three doses of HESS and one dose of glibenclamide, as well as treatment with both in diabetic Wistar diabetic rats and comparison of the results with untrated groups. The quality of the testicular tissue as well as histometric parameters and spermatogenesis indices were evaluated during histopathological examination. Epididymal sperm analysis including sperm motility, viability, abnormalities, maturity, and chromatin structure were studied. The effect of HESS on the expression of LDH and FGF21 genes and tissue levels of glycogen, lactate, and total antioxidant capacity in testicular tissue was investigated and compared with glibenclamide. HESS improved sperm parameters in diabetic rats but showed little restorative effect on damaged testicular tissue. In this regard, glibenclamide was more effective than the highest dose of HESS and its combination with HESS enhanced its effectiveness so that histological tissue characteristics and sperm parameters were were comparable to those of healthy rats. The expression level of testicular FGF21 gene increased in diabetic rats, which intensified after treatment with HESS as well as glibenclamide. The combination of HESS and glibenclamide restored the expression level of testicular LDH gene, as well as tissue storage of glycogen, lactate and LDH activity, and serum testosterone to the levels near healthy control. S. Securidaca seeds can be considered as an effective supplement in combination with hypoglycemic drugs to prevent infertility complications in diabetes.

Effects of Securigera securidaca (L.) Degen & Dorfl seed extract combined with glibenclamide on paraoxonase1 activity, lipid profile and peroxidation, and cardiovascular risk indices in diabetic rats.

Introduction: Seeds of Securigera securidaca (L.) Degen & Dorfl are rich in flavonoids and phenolic acids which have potent biological effects. The current study was undertaken to evaluate the effects of hydroalcoholic extract of S. securidaca seeds (HESS) alone, and in combination with a standard drug, glibenclamide (GB) on paraoxonase1 (PON1) activity, lipid profile and peroxidation, and cardiovascular risk indices in streptozotocin (STZ) induced diabetic rats. Methods: Forty-eight male Wistar rats were randomly divided into eight equal groups and orally treated with various doses of HESS (100, 200, 400 mg/kg) alone and in combination with GB (5 mg/kg) for 35 consecutive days. After blood sampling, lipid profile including triglyceride (TG), cholesterol, high, low and very low-density lipoprotein-cholesterol (HDL-C, LDL-C, and VLDL-C), as well as serum PON1 activity, were assessed. Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) levels were also measured. Several indices of cardiovascular risk and the correlation between PON1 activity and these indices were calculated based on the obtained results from the lipid profile. Results: Induction of diabetes could dramatically alter all of the parameters mentioned above, and the lower dose of HESS (100 mg/kg) was not effective in restoring the parameters. However, the higher doses (200 and 400 mg/kg) alone and in combination with GB could significantly improve lipid profile, restore PON1 activity, and decrease cardiovascular risk indices, MDA, as well. However, neither HESS nor GB could significantly reduce TNF-α and hs-CRP. A significant negative correlation also was detected between PON1 activity and cardiovascular risk indices. Conclusion: conclusively, HESS can be considered as a potent antihyperlipidemic agent with remarkable cardioprotective effects and can potentiate the antidiabetic effects of GB.

A comprehensive review of COVID-19 characteristics.

In December 2019, a novel coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or (2019-nCoV) with unknown origin spread in Hubei province of China. The epidemic disease caused by SARS-CoV-2 called coronavirus disease-19 (COVID-19). The presence of COVID-19 was manifested by several symptoms, ranging from asymptomatic/mild symptoms to severe illness and death. The viral infection expanded internationally and WHO announced a Public Health Emergency of International Concern. To quickly diagnose and control such a highly infectious disease, suspicious individuals were isolated and diagnostic/treatment procedures were developed through patients' epidemiological and clinical data. Early in the COVID-19 outbreak, WHO invited hundreds of researchers from around the world to develop a rapid quality diagnosis, treatment and vaccines, but so far no specific antiviral treatment or vaccine has been approved by the FDA. At present, COVID-19 is managed by available antiviral drugs to improve the symptoms, and in severe cases, supportive care including oxygen and mechanical ventilation is used for infected patients. However, due to the worldwide spread of the virus, COVID-19 has become a serious concern in the medical community. According to the current data of WHO, the number of infected and dead cases has increased to 8,708,008 and 461,715, respectively (Dec 2019 -June 2020). Given the high mortality rate and economic damage to various communities to date, great efforts must be made to produce successful drugs and vaccines against 2019-nCoV infection. For this reason, first of all, the characteristics of the virus, its pathogenicity, and its infectious pathways must be well known. Thus, the main purpose of this review is to provide an overview of this epidemic disease based on the current evidence.