Current molecular pharmacology最新文献

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.

Background: Curcumin has been isolated from the rhizomes of Curcuma longa. Over the years, it has shown outstanding therapeutic potential in various human disorders, including cancers.

Objective: The aim is to study curcumin's effects on the apoptosis signaling pathway in the head and neck squamous cell carcinoma (HNSCC) cell line HN5.

Methods: The cytotoxicity of curcumin on HN5 cells were assessed. In addition, HN5 cells were also treated with curcumin to evaluate its effect on the caspase-8, -9, Bcl-2, Bax, and Stat3 gene expressions.

Results: The results exhibited that cell viability reduced following curcumin treatment in a concentration- dependent manner. Curcumin treatment caused decreased expression of Bcl2, with simultaneous upregulation of the Bax/Bcl2 ratio. Curcumin increased caspase-9 expression, did not affect caspase-8, and decreased Stat3 expression. The induction of the mitochondria-dependent apoptosis pathway of curcumin happened by modulating the expression of Bcl2 and Bax genes, resulting in the caspase-9 activation. Furthermore, curcumin decreased the expression of the Stat3 in HN-5 cells.

Conclusions: In conclusion, curcumin showed marked anticancer effects in the HN-5 cell line by modulating Stat-3; Bax/Bcl-2 expression in vitro.

In recent years, attention has increasingly focused on herbal medicines and their bioactive components attributed to their multi-target pharmacological activity and low side effects. Oridonin is a natural diterpenoid extracted from the traditional Chinese herb and is one of the main active components of Rabdosia rubescens. Modern pharmacological studies have shown that oridonin has anti-tumor, anti-bacterial, anti-inflammatory, anti-oxidant, cardiovascular protective, immunomodulatory, and other effects. Based on the published literature in recent years, we outline the pharmacological activities of oridonin, aiming to provide a theoretical basis for the design and development of new oridonin-based drugs, as well as to facilitate the process of oridonin for clinical use.

Effective and better-tolerated agents for the treatment of most of psychiatric disorders are one of the main challenges. Recently, anti-inflammatory, antioxidants and neuroprotective agents as adjuvant therapy have been shown to be able to play a role against the degenerative mechanisms commonly related to psychiatric conditions. Berberine, a biologically active alkaloid derived from various plants, represents many pharmacological impacts, such as antimicrobial, antidiabetic, anticancer, antioxidant and anti-inflammatory activities. This compound also protects neurons and improves the survival, growth and action of nerve cells due to its high potential for crossing the blood-brain barrier. Ample evidence reported that berberine had been associated with CNS-related disorders, including Alzheimer's, cerebral ischemia, mental depression, schizophrenia and anxiety. Thus, in this review, we aimed to indicate the effectiveness of berberine on mental disorders.

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.

Type-2 diabetes mellitus is a prime factor for the development of Diabetic Nephropathy (DN) that affects the vital organ namely the kidneys, and further alters the functions of the nephron system. DN is nowadays becoming a challenge for scientists towards the world because of its high pervasiveness and complexity of medication. Various risk factors are involved in the initiation of pathogenic DN, which are associated with different pathways against drug activity. Due to this DN becomes an unpredictable query to the researchers. SIRT1 is a silent information regulator factor 2 related enzyme 1 (SIRT1) is nicotinamide adenine dinucleotide (NAD+) dependent deacetylase that functions as an intracellular regulator of transcriptional activity. An activated version of SIRT-1 improves the metabolic diseased conditions associated with other molecular pathways. SIRT1 attenuates diabetic nephropathy in in vitro and in vivo experimental models of diabetes containing Podocytes, Mesangial cells, and Renal proximal tubular cells. SIRT1 shows nephroprotective effects in DN in part through deacetylation of transcription factors i.e., imply in the disease like p53, PTP1B, FOXO, RelA, NF- kβ, STAT-3, and PGC-1α/ PPARγ. It has been shown that some natural products like resveratrol and synthetic compounds are activating the SIRT1, this further involved the cascade pathways to prevent the DN. This review will help regarding the effectiveness of SIRT1as target in the prevention and treatment of DN.

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.

Objective: This study aimed to explore the influence of the irreversible EGFR inhibitor CL-387785 on invasion, metastasis, and radiation sensitization of non-small cell lung cancer cells.

Methods: The proliferation inhibitory rate at different time points was detected by MTT assay. The apoptosis of H1975 cells treated with CL-387785 was detected using flow cytometry. The invasion and migration of H1975 cells treated with CL-387785 were determined by Transwell assay and wound healing assay. The survival fraction (SF) of H1975 cells cultured with CL- 387785 under X-ray (0, 2, 4, 6, 8, and 10 Gy) was detected by cloning formation experiment, and the sensitization ratio (SER) was calculated by clicking the multi-target model to fit the cell survival curve.

Results: CL-387785 restrained H1975 cell proliferation in a concentration- and time-dependent manner. CL-387785 promoted H1975 cell apoptosis and reduced cell migration distance and the number of transmembrane cells. The SF treated by different concentrations of CL-387785 (10, 25, 50, and 100 nM) was all below 0 nM. The radiation SER of CL-387785 (10, 25, 50 and 100 nM) were 1.17, 1.39, 2.88, and 3.64, respectively.

Conclusion: The invasion and metastasis of H1975 cells were restrained by irreversible EGFR inhibitor CL-387785. CL-387785 also exhibited the effect of radiotherapy sensitization.