Molecular and Cellular Biochemistry最新文献

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

BCR::ABL1 inhibitors, the treatment of choice for the majority of patients with chronic myeloid leukaemia (CML), can cause vascular side effects that vary between agents. The exact underlying mechanisms are still poorly understood, but the vascular endothelium has been proposed as a site of origin. The present study investigates the effects of three BCR::ABL1 inhibitors, ponatinib, nilotinib and imatinib, on angiogenesis and signalling in human endothelial cells in response to vascular endothelial growth factor (VEGF). The experiments were performed in endothelial cells isolated from human umbilical veins. After exposure to imatinib, ponatinib and nilotinib, the angiogenic capacity of endothelial cells was assessed in spheroid assays. VEGF-induced signalling pathways were examined in Western blotting experiments using different specific antibodies. RNAi technology was used to downregulate proteins of interest. Intracellular cGMP levels were measured by ELISA. Imatinib had no effect on endothelial function. Ponatinib inhibited VEGF-induced sprouting, while nilotinib increased spontaneous and VEGF-stimulated angiogenesis. These effects did not involve wild-type ABL1 or ABL2, as siRNA-mediated knockdown of these kinases did not affect angiogenesis and VEGF signalling. Consistent with their effects on sprouting, ponatinib and nilotinib affected angiogenic pathways in opposite directions. While ponatinib inhibited VEGF-induced signalling and cGMP formation, nilotinib activated angiogenic signalling, in particular phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2). The latter occurred in an epidermal growth factor receptor (EGFR)-dependent manner possibly via suppressing Fyn-related kinase (FRK), a negative regulator of EGFR signalling. Both, pharmacological inhibition of Erk1/2 or EGFR suppressed nilotinib-induced angiogenic sprouting. These results support the notion that the vascular endothelium is a site of action of BCR::ABL1 inhibitors from which side effects may arise, and that the different vascular toxicity profiles of BCR::ABL1 inhibitors may be due to their different actions at the molecular level. In addition, the as yet unknown pro-angiogenic effect of nilotinib should be considered in the treatment of patients with comorbidities associated with pathological angiogenesis, such as ocular disease, arthritis or obesity.

Ventricular septal defect (VSD) is the most common type of congenital heart disease. HAND1 gene plays a crucial role in the development of the heart, but the role of the variants in the HAND1 gene promoter region in patients with VSD has not been explored yet. From 588 participants (300 with isolated and sporadic VSD and 288 healthy controls), DNA was extracted from blood samples. Variants at the HAND1 gene promoter region were analyzed through Sanger sequencing. Subsequently, cell functional validation was conducted through cell experiments, including dual-luciferase reporter gene analysis, electrophoretic mobility shift analysis, and bioinformatics analysis was also conducted. The promoter region of HAND1 gene had a total of 9 identified variant sites. Among them, 4 variants were exclusively found in VSD patients, and 1 variant (g.3631A>C) was newly discovered. Cell functional experiments indicated that all four variants decreased the transcriptional activity of HAND1 gene promoter with three of them reached statistical significance (p < 0.05). Subsequent analysis using JASPAR (a transcription factor binding profile database) suggests that these variants may alter the binding sites of transcription factors, potentially contributing to the formation of VSD. Our study for the first time identified variants in the promoter region of HAND1 gene in Chinese patients with isolated and sporadic VSD. These variants significantly decreased the expression of HAND1 gene, impacting transcription factor binding sites, and thereby demonstrating pathogenicity. This study offers new insights into the role of HAND1 gene promoter region, contributing to a better understanding of the genetic basis of VSD formation.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.

The sodium-glucose-cotransporter 2 inhibitors (SGLT2i) are the blockbuster antidiabetic drugs that exert cardiovascular protection via pleiotropic effects. We have previously demonstrated that empagliflozin decreased monoamine oxidase (MAO) expression and oxidative stress in human mammary arteries. The present study performed in overweight, non-diabetic cardiac patients was aimed to assess whether the two widely prescribed SGLT2i decrease atrial MAO expression and alleviate oxidative stress elicited by exposure to angiotensin 2 (ANG2) and high glucose (GLUC). Right atrial appendages isolated during cardiac surgery were incubated ex vivo with either empagliflozin or dapagliflozin (1, 10 µm, 12 h) in the presence or absence of ANG2 (100 nm) and GLUC (400 mg/dL) and used for the evaluation of MAO-A and MAO-B expression and ROS production. Stimulation with ANG2 and GLUC increased atrial expression of both MAOs and oxidative stress; the effects were significantly decreased by the SGLT2i. Atrial oxidative stress positively correlated with the echocardiographic size of heart chambers and negatively with the left ventricular ejection fraction. In overweight patients, MAO contributes to cardiac oxidative stress in basal conditions and those that mimicked the renin-angiotensin system activation and hyperglycemia and can be targeted with empagliflozin and dapagliflozin, as novel off-target class effect of the SGLT2i.

Myostatin, a potent negative regulator of skeletal muscle mass, has garnered significant attention as a therapeutic target for muscle dystrophies. Despite extensive research and promising preclinical results, clinical trials targeting myostatin inhibition in muscle dystrophies have failed to yield substantial improvements in muscle function or fitness in patients. This review details the mechanisms behind myostatin's function and the various inhibitors that have been tested preclinically and clinically. It also examines the challenges encountered in clinical translation, including issues with drug specificity, differences in serum myostatin concentrations between animal models and humans, and the necessity of neural input for functional improvements. Additionally, we explore promising avenues of research beyond muscle dystrophies, particularly in the treatment of metabolic syndromes and orthopedic disorders. Insights from these alternative applications suggest that myostatin inhibition may hold the potential for addressing a broader range of pathologies, providing new directions for therapeutic development.

In this Perspective, I discuss the limitations of a soft primary endpoint that is used in some of the recent randomized phase II/III clinical trials. Unfortunately, many clinicians and investigators do not interpret the data critically to recognize the limitations of such findings. I advise against over-interpreting the effects of an intervention on a soft primary endpoint.

Cardiac fibrosis is a commonly seen pathophysiological process in various cardiovascular disorders, such as coronary heart disorder, hypertension, and cardiomyopathy. Cardiac fibroblast trans-differentiation into myofibroblasts (MFs) is a key link in myocardial fibrosis. LncRNA PVT1 participates in fibrotic diseases in multiple organs; however, its role and mechanism in cardiac fibrosis remain largely unknown. Human cardiac fibroblasts (HCFs) were stimulated with TGF-β1 to induce myofibroblast; Immunofluorescent staining, Immunoblotting, and fluorescence in situ hybridization were used to detect the myofibroblasts phenotypes and lnc PVT1 expression. Cell biological phenotypes induced by lnc PVT1 knockdown or overexpression were detected by CCK-8, flow cytometry, and Immunoblotting. A mouse model of myocardial fibrosis was induced using isoproterenol (ISO), and the cardiac functions were examined by echocardiography measurements, cardiac tissues by H&E, and Masson trichrome staining. In this study, TGF-β1 induced HCF transformation into myofibroblasts, as manifested as significantly increased levels of α-SMA, vimentin, collagen I, and collagen III; the expression level of lnc PVT1 expression showed to be significantly increased by TGF-β1 stimulation. The protein levels of TGF-β1, TGFBR1, and TGFBR2 were also decreased by lnc PVT1 knockdown. Under TGF-β1 stimulation, lnc PVT1 knockdown decreased FN1, α-SMA, collagen I, and collagen III protein contents, inhibited HCF cell viability and enhanced cell apoptosis, and inhibited Smad2/3 phosphorylation. Lnc PVT1 positively regulated MYC expression with or without TGF-β1 stimulation; MYC overexpression in TGF-β1-stimulated HCFs significantly attenuated the effects of lnc PVT1 knockdown on HCF proliferation and trans-differentiation to MFs. In the ISO-induced myocardial fibrosis model, lnc PVT1 knockdown partially reduced fibrotic area, improved cardiac functions, and decreased the levels of fibrotic markers. In addition, lnc PVT1 knockdown decreased MYC and CDK4 levels but increased E-cadherin in mice heart tissues. lnc PVT1 is up-regulated in cardiac fibrosis and TGF-β1-stimulated HCFs. Lnc PVT1 knockdown partially ameliorates TGF-β1-induced HCF activation and trans-differentiation into MFs in vitro and ISO-induced myocardial fibrosis in vivo, potentially through interacting with MYC and up-regulating MYC.

The extensive application of plastics in different sectors such as packaging, building, textiles, consumer products, and several industries has increased in recent years. Emerging data have confirmed that plastic wastes and segregates are problematic issues in aquatic and terrestrial ecosystems. The decomposition of plastic particles (PPs) leads to the release of microplastics (MPs) and nanoplastics (NPs) into the surrounding environment and entry of these particles will be problematic in unicellular and multicellular creatures. It was suggested that PPs can easily cross all biological barriers and reach different organs, especially the cardiovascular system, with the potential to modulate several molecular pathways. It is postulated that the direct interaction of PPs with cellular and subcellular components induces genotoxicity and cytotoxicity within the cardiovascular system. Meanwhile, being inert carriers, PPs can intensify the toxicity of other contaminants inside the cardiovascular system. Here, in this review article, several underlying mechanisms related to PP toxicity in the cardiovascular system were discussed in detail.

Cardiovascular diseases remains leading cause of death and disabilities. Coronary artery occlusion and consequent ischemia leads to acute myocardial infarction, but restoration of blood flow, paradoxically, provokes further myocardial damage known as reperfusion injury. Minocycline is possessing anti-inflammatory and anti-apoptotic activity, immune-modulating and antioxidative properties besides its primary antibacterial effect. Recently it gained significant interest in preventing cardiac damage especially due to myocardial ischemia/reperfusion injury (MI/RI). The aim of this study was to assess the protective ability of pre-treatment and post-treatment of isolated hearts from healthy and spontaneously hypertensive rats with minocycline, on functional recovery and redox status after MI/RI using Langendorff technique. Using sensor in the left ventricle, the cardiodynamic parameters were recorded and in the samples of the coronary venous effluent oxidative stress biomarkers were analyzed. Minocycline was injected directly into the coronary vessels, in pre-treatment 5 min before global ischemia, and in post-treatment during the first 5 min of reperfusion. Changes in redox balance induced by minocycline were more prominent in post-treatment fashion of application. Cardioprotective effects of minocycline due to MI/RI are even more significant in hypertensive hearts. Minocycline showed significant cardioprotective effects, which was more pronounced in hypertensive compared to healthy hearts. Reduction of pro-oxidative biomarkers was more prominent in hypertensive hearts compared to the normotensive, especially if it is applied in the form of post-treatment. Minocycline could be important tool in reduction of heart damage induced by MI/RI due to its antioxidative potential, if these results are confirmed by clinical study.