Current molecular pharmacology最新文献

Objective: Diabetic nephropathy is an unavoidable complication of chronic uncontrolled diabetes mellitus. The pathogenesis of diabetic nephropathy is multifactorial, and the development of an effective therapy remains to be elucidated. The aim of the present study was to assess the role of NOX2 and Nrf2 in the protective mechanism of thymoquinone (THQ) against streptozotocin (STZ)-induced diabetic nephropathy.

Methods: Rats were injected with STZ (55 mg/kg) to induce diabetes. The diabetic rats were orally treated with THQ (10 mg/kg/day) for eight weeks.

Results: STZ-treated rats exhibit an elevation of serum creatinine, serum urea, and creatinine clearance. The renal abnormalities were associated with increased NADPH oxidase isoform, NOX2 protein expression, and activity, along with elevated malondialdehyde (MDA). In addition, the tumor necrotic factor-alpha (TNF-α) level and nitric oxide (NO) bioavailability, as well as the transforming growth factor-beta (TGF)-β, were markedly increased. On the other hand, the nuclear factor-E2-related factor (Nrf2) protein expression was significantly reduced in diabetic rats compared to the control. However, treatment with THQ significantly reversed these alterations with subsequent ameliorating renal dysfunction and pathological abnormalities.

Conclusion: The present study demonstrates that THQ could protect against STZ-induced diabetic nephropathy by modulating the Nrf2/NOX2 signaling pathway.

Osteoporosis is becoming more prevalent in the ageing society, however, its treatment is still a problem for both society and individuals. Traditional Chinese Medicine (TCM) has a long history in treating osteoporosis and is receiving increasing attention. Multiple formulas of TCM showed satisfactory effects in treating osteoporosis in both animal models and clinical patients. However, because TCM usually consists of multiple plant and/or animal products, it is difficult to clarify the mechanism of TCM according to the requirements of Western medicine regarding purity, efficacy, dosage, and safety. With increasing researchers have started to investigate the TCM using modern scientific tools such as bioinformatics and network pharmaceutics in osteoporosis and the addition of TCM in the latest version of International Statistical Classification of Diseases and Related Health Problems (ICD-11 version, 2019) by WHO, TCM is showing large potential in treating osteoporosis although there is still a long way. The review aimed to summarize recent advancements of TCM treating osteoporosis.

Background: Myristicin is a type of natural compound showing anti-proliferative, anti-microbial, and anti-inflammatory effects. However, its role in gastric cancer treatment remains unknown.

Objective: In this study, the effect of myristicin on gastric cancer as well as its underlying mechanism was investigated.

Methods: Human gastric cancer cells were exposed to various concentrations of myristicin (0, 7.8125, 15.625, and 31.25 μM) for 48 h. Then CCK-8, fluorescence-activated cell sorting, and Hoechst staining were performed to evaluate the cell proliferation and apoptosis. The levels of proteins associated with cell cycle, apoptosis, endoplasmic reticulum (ER) stress, and EGFR/ERK signaling pathway were detected by western blot. JC-1 staining was conducted to determine the mitochondrial membrane potential. On the other hand, the effect of myristicin on gastric cancer growth and apoptosis was also determined in vivo.

Results: Myristicin retarded proliferation and induced ER stress and apoptosis in gastric cancer cells, with decreased expression of cyclins, increased Bax expression, activated caspases, and enhanced cytochrome C release and mitochondrial ROS. Furthermore, the EGFR/ERK signaling pathway was restrained by myristicin. In addition, EGFR over-expression abolished the inhibitory function of myristicin on proliferation, apoptosis, and ER stress. Also, myristicin inhibited the growth of gastric cancer cells as well as the EGFR/ERK signaling pathway in vivo.

Conclusion: Myristicin exerts an anti-cancer effect on gastric cancer cells by restraining the EGFR/ ERK signaling pathway. It may have the potential to be applied as a novel drug in gastric cancer treatment.

Background and objective: This investigation explores the neuroprotective effect of PIASA, a newly designed peptide, VCSVY, in in-silico and in opposition to rotenone stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in an SH-SY5Y cellular model.

Methods: Docking and visualization of the PIASA and rotenone were progressed against mitochondrial respiratory complex I (MCI). The in-silico analysis showed PIASA to have interaction with the binding sites of rotenone, which may reduce the rotenone interaction and its toxicity too. The SH-SY5Y cells were segregated into four experimental groups: Group I: untreated control cells; Group II: rotenone-only (100 nM) treated cells; Group III: PIASA (5 μM) + rotenone (100 nM) treated cells; and Group IV: PIASA-only (5 μM) treated cells.

Results: We evaluated the cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), apoptosis (dual staining technique), nuclear morphological changes (Hoechst staining technique), the expressions of BAX, Bcl-2, cyt c, pro-caspase 3, and caspase 3, -6, -8, -9, and cleaved caspase 3 by western blot analysis. In SH-SY5Y cells, we further observed the cytotoxicity, oxidative stress and mitochondrial dysfunction in rotenone-only treated cells, whereas pretreatment of PIASA attenuated the rotenone-mediated toxicity. Moreover, rotenone toxicity is caused by complex I inhibition, which leads to mitochondrial dysfunction, increased BAX expression, while downregulating the Bcl-2 expression and cyt c release, and then finally, caspases activation. PIASA pretreatment prevented the cytotoxic effects via the normalization of apoptotic marker expressions influenced by rotenone. In addition, pre-clinical studies are acceptable in rodents to make use of PIASA as a revitalizing remedial agent, especially for PD in the future.

Conclusion: Collectively, our results propose that PIASA mitigated rotenone-stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in rotenone-induced SH-SY5Y cells.

Cancers with a high capability for angiogenesis are frequently regarded as being difficult to treat. Anti-angiogenesis drugs are considered the primary therapy for these types of cancers. Due to intrinsic or acquired anti-angiogenesis resistance, therapies result in moderate clinical consequences, despite some hopeful findings. The importance of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding (lncRNAs), and circular RNAs (circRNAs) in drug resistance mechanisms in cancer treatment has been discovered in the previous decade. Anti-angiogenic drug resistance can be influenced by ncRNA dysregulation. Hence, ncRNAs are potential drug resistance targets for new anti-angiogenic drugs in the inhibition of angiogenesis in tumors. Furthermore, some ncRNAs can be employed as biomarkers for anti-angiogenic drug responses and can be used to monitor cancer non-invasively. Combination treatment approaches, combined with routine anti-angiogenesis and some drugs that target the ncRNAs causing resistance, can be potential ways to overcome anti-angiogenesis resistance. For the first time, we explain the mechanisms of anti-angiogenic drug resistance and the related miRNAs and lncRNAs and their signaling pathways in commonly used antiangiogenic drugs implicated in this review article. These ncRNAs could be suggestions for targeting and reducing anti-angiogenic drugs in the future.

Aims and objective: This study aimed to unveil the specific function of lncRNA BBOX1 antisense RNA 1 (BBOX1-AS1) in ESCC cells and the underlying regulatory mechanism.

Background: Esophageal squamous cell carcinoma (ESCC) is a deadly disease. Molecular mechanisms essential to ESCC development and progression require in-depth investigation. Long noncoding RNAs (lncRNAs) have been suggested as crucial effectors in modulating tumor growth.

Methods: RT-qPCR and western blot examined the expression of genes and proteins of concern, respectively. Colony formation and EdU assays assessed the changes in cell proliferation. Sphere formation assay also detected the stemness of ESCC cells. Bioinformatics prediction, along with mechanistic assays (FISH, Subcellular fractionation, RNA pull-down, RIP, and luciferase reporter), was conducted to explore the gene interactions and regulatory relationship.

Results: BBOX1-AS1 was observed to be aberrantly up-regulated in ESCC tissues and cell lines. BBOX1-AS1 depletion exerted suppressive impacts on ESCC cell proliferation and stemness, while BBOX1-AS1 overexpression led to the opposite consequences. Moreover, BBOX1-AS1 was verified to activate Hedgehog signaling pathway via up-regulating PTCH1, and BBOX1-AS1 could sponge miR-506-5p to up-regulate EIF5A, thus stabilizing PTCH1 mRNA. Rescue experiments indicated that BBOX1-AS1 could affect ESCC cell proliferation and stemness via modulation on PTCH1.

Conclusion: To conclude, BBOX1-AS1 activates Hedgehog signaling pathway to facilitate the proliferation and stemness of ESCC cells via miR-506-5p/EIF5A/PTCH1 axis.

Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin-Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and Sci- ELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs that lower blood glucose levels while decreasing blood pressure, volume loss, and weight loss. SGLT2 inhibitors were studied to determine their effectiveness in treating cardiovascular disease and their side effects. Study outcomes related to cardiovascular and metabolic outcomes were examined in patients on SGLT2 inhibitors by searching PubMed, Embase, Cochrane, and SCOPUS. Articles related to clinical trials, reviews, and meta-analyses were considered. A review of SGLT2 inhibitors' mechanisms of action in preventing cardiovascular (CVS) disease progression was described. We then reviewed the possible effects of SGLT2 inhibitors on CVS dysfunction development, composition, and stability. In the following, we discussed the impact of SGLT2 inhibitors on CVD events, such as ischemic strokes and myocardial infarctions, and their role in treating congestive heart failure and cardiovascular mortality.

Background: Diabetic retinopathy (DR) is a slow eye disease that affects the retina due to a long-standing uncontrolled diabetes mellitus. Hyperglycemia-induced oxidative stress can lead to neuronal damage leading to DR.

Objective: The aim of the current investigation is to assess the protective effects of thymoquinone (TQ) as a potential compound for the treatment and/or prevention of neurovascular complications of diabetes, including DR.

Methods: Diabetes was induced in rats by the administration of streptozotocin (55 mg/kg intraperitoneally, i.p.). Subsequently, diabetic rats were treated with either TQ (2 mg/kg i.p.) or vehicle on alternate days for three weeks. A healthy control group was also run in parallel. At the end of the treatment period, animals were euthanized, and the retinas were collected and analyzed for the expression levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), nerve growth factor receptor (NGFR), and caspase-3 using Western blotting techniques in the retina of diabetic rats and compared with the normal control rats. In addition, dichlorofluorescein (DCF) levels in the retina were assessed as a marker of reactive oxygen species (ROS), and blood-retinal barrier breakdown (BRB) was examined for vascular permeability. The systemic effects of TQ treatments on glycemic control, kidney and liver functions were also assessed in all groups.

Results: Diabetic animals treated with TQ showed improvements in the liver and kidney functions compared with control diabetic rats. Normalization in the levels of neuroprotective factors, including BDNF, TH, and NGFR, was observed in the retina of diabetic rats treated with TQ. In addition, TQ ameliorated the levels of apoptosis regulatory protein caspase-3 in the retina of diabetic rats and reduced disruption of the blood-retinal barrier, possibly through a reduction in reactive oxygen species (ROS) generation.

Conclusion: These findings suggest that TQ harbors a significant potential to limit the neurodegeneration and retinal damage that can be provoked by hyperglycemia in vivo.