Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges.

The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-ß, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/ß-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.

Butein ameliorates chronic stress induced atherosclerosis via targeting anti-inflammatory, anti-fibrotic and BDNF pathways.

Chronic stress is a major risk factor for various diseases, including cardiovascular diseases (CVDs). Chronic stress enhances the release of pro-inflammatory cytokines like IL-1ß, IL-6, and TNF-α, making individuals susceptible to atherosclerosis which is dominant cause for CVDs. In present study, we validated a mouse model of chronic unpredictable stress (CUS), and assessed the characteristic features of atherosclerosis in thoracic aortas of CUS mice. The CUS procedure consisted of exposing groups of mice to random stressors daily for 10-weeks. The stress response was verified by presence of depressive-like behaviors and increased serum corticosterone in mice which was determined by battery of behavioural tests (SPT, EPMT, NSFT) and ELISA, respectively. Atherosclerosis parameters in CUS mice were evaluated by lipid indices estimation followed by histological assessment of plaque deposition and fibrosis in thoracic aorta. Further, we assessed the efficacy of a polyphenol, i.e. Butein in conferring protection against chronic stress-induced atherosclerosis and the possible mechanism of action. Butein (20 mg/kg x 28 days, alternatively, i.p.) was administered to CUS mice after 6-weeks of CUS exposure till the end of the protocol. Butein treatment decreased peripheral IL-1ß and enhanced peripheral as well as central BDNF levels. Histological assessment revealed decreased macrophage expression and reduced fibrosis in thoracic aorta of Butein treated mice. Further, treatment with Butein lowered lipid indices in CUS mice. Our findings thus, suggest that 10-weeks of CUS induce characteristic features of atherosclerosis in mice and Butein can offer protection in CUS-induced atherosclerosis through multiple mechanisms including anti-inflammatory, antifibrotic and anti-adipogenic actions.

ALK and ERBB2 Protein Inhibition is Involved in the Prevention of Lung Cancer Development by Vincamine.

BACKGROUND: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. OBJECTIVE: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line. METHODS: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. RESULTS: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dosedependent (0-500 µM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 µΜ. The wound-healing assay showed that vincamine treatment (150 and 300 µM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. CONCLUSION: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.