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.

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.