Current Drug Targets - Volume 24, Issue 7, 2023

Proteostasis is crucial for the maintenance and proper operation of cells. Under typical circumstances, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are used to clean out undesired, damaged, misfolded, or aggregated proteins. Any dysregulation in the above-mentioned pathways leads to neurodegeneration. One of the most renowned neurodegenerative disorders is AD. This condition is more prevalent in senior people and is frequently linked to dementia, progressive memory loss, and cognitive function decline, which further contributes to cholinergic neuron degradation and synaptic plasticity loss. Extracellular accumulation of amyloid beta plaques and the intraneuronal deposition of misfolded neurofibrillary tangles are two prime pathological reasons for AD. At present, there is no treatment for AD. All that remains available is the symptomatic treatment of this disease. Autophagy is the major mechanism by which the cells degrade the protein aggregates. Deposited immature autophagic vacuoles (AVs) in AD brains suggest interruption of a person's normal autophagy process. This review has briefly covered various forms and mechanisms of autophagy. Furthermore, the discussion in the article is supported by different ways and mechanisms via which autophagy can be stimulated in a beneficial way and can emerge as a novel target in the treatment of various metabolic CNS related disorders. In the current review article, the mTOR-dependent ones are PI3K/Akt/TSC/mTOR, AMPK/TSC/mTOR, and Rag/mTOR pathways and mTOR-independent ones which include Ca2+/calpain, inositol-dependent, cAMP/EPAC/PLC, and JNK1/Beclin-1/PI3K pathways have been discussed in details. The article sheds light on drugs which are validated with details in tabular form from recent updates in clinical trials.

To date, the incidence and mortality of chronic liver diseases such as cirrhosis and hepatocellular carcinoma due to the continued progression of hepatic fibrosis are increasing annually. Unfortunately, although a large number of studies have exhibited that some drugs have great potential for anti-fibrosis in animal and clinical trials, no specific anti-fibrosis drugs have been developed, and there is no better treatment for advanced cirrhosis than liver transplantation. It is a prevailing viewpoint that hepatic stellate cells (HSCs), as the mainstay of extracellular matrix secretion, are of great concern in the development of hepatic fibrosis. Therefore, targeting HSCs becomes extremely important to confront hepatic fibrosis. As previous studies described, inhibition of HSC activation and proliferation, induction of HSC death, and restoration of HSC quiescence are effective in reversing hepatic fibrosis. This review focuses on the current status of research on the treatment of hepatic fibrosis by inducing HSC death and elucidates the HSC death modes in detail and the crosstalk between them.

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint inhibitors have been on the front line of clinical revolution in which, the targeted PD-L1 therapy has obtained some success in patients with solid tumors. A large number of clinical trials revealed that both monotherapy and combination therapy of PD-L1 antibody significantly suppress some tumor growth and promote the survival of patients. At present, anti-PD-L1 treatment has been used as a portion of standard treatment for lung cancer, breast cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. Although much evidence has demonstrated that PD-L1 antibody is safe in most patients, there are still some adverse reactions, such as pneumonitis, hepatitis, colitis, neurologic events and myocarditis. In this review, the clinical information, including the efficacy and safety of durvalumab in solid tumors, was enumerated and summarized at this stage to grasp the current application of targeted PD-L1 therapy and provide guidance for clinical application.

Background: Fermentation of lactose in milk by bacteria and yeasts naturally present in kefir grains produces a beverage that has been suggested to have cardiovascular benefits. This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effects of this kefir beverage on cardiometabolic risk factors. Methods: Literature search utilised PubMed, Scopus, ISI Web of Science, and Google Scholar for articles published from inception until June 2021. Cardiometabolic risk indices extracted included insulin and insulin resistance (HOMA_IR), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood sugar (FBS), haemoglobin A1c (HbA1c) and body weight (BW). In total, six RCTs (314 subjects) were selected for the meta-analysis. Inverse-variance weighted mean difference (WMD) with a 95% confidence interval (CI) was calculated for the mean changes in TC, TG, HDL-C, LDL-C, FBS, HbA1c and BW compared to baseline. A random effects model was used to estimate the pooled WMD. Results: Kefir intake significantly reduced fasting insulin (WMD: -3.69 micro-IU/mL,95% CI: -6.30 to -1.07, p = 0.006, I² = 0.0%) and HOMA-IR (WMD: -2.56, 95% CI: -3.82 to -1.30, p<0.001, I² = 19.4%). No effect on TC (p = 0.088), TG (p = 0.824), HDL-C (p = 0.491), LDL-C (p = 0.910), FBS (p = 0.267), HbA1c (p = 0.339) or body weight (p = 0.439) were found for kefir treatment. Conclusion: Kefir has a beneficial effect in decreasing insulin resistance; however, no effect was seen on BW, FBS, HbA1C, and lipid profile.

Introduction: Salmonellosis, which is typically distinguished by an immediate onset of fever, abdominal pain, diarrhea, nausea, and vomiting, is a bacterial infection caused by Salmonella. The rising incidence of antibiotic resistance in Salmonella Typhimurium is a major worldwide problem, and a better knowledge of the distribution of antibiotic resistance patterns in Salmonella Typhimurium is critical for selecting the best antibiotic for infection treatment. In this work, the efficiency of bacteriophage therapy of vegetative cells and biofilms of S. Typhimurium was investigated. Methods: Based on their host ranges, five Bacteriophages were chosen for therapy against 22 Salmonella isolates collected from various sources. PSCs1, PSDs1, PSCs2, PSSr1, and PSMc1 phages were found to exhibit potent anti-S. Typhimurium properties. In a 96-well microplate, the efficacy of bacteriophage therapy (10⁵-10¹¹ PFU/mL) against S. Typhimurium biofilm formers was first tested. A bacteriophage treatment (10⁹ PFU/mL) was subsequently applied in the laboratory for 24 hours to minimize Salmonella adhering to the surfaces of gallstones and teeth. In 96-well microplate experiments, bacteriophage treatment inhibited biofilm development and reduced biofilm by up to 63.6% (P ≤ 0.05). Result: When compared to controls, bacteriophages (PSCs1, PSDs1, PSCs2, PSSr1, PSMc1) demonstrated a rapid drop in the populations of S. Typhimurium biofilms generated on the surfaces of gallstones and teeth where the structure of the Salmonella bacteria in the biofilm was broken and holes were created. Conclusion: Clearly, this study indicated that phages might be employed to eliminate S. Typhimurium biofilms on gallstone and tooth surfaces.