TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation.

Myocardial infarction (MI) results in high mortality. The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes. Thioredoxin-interacting protein (TXNIP) is involved in various fibrotic diseases. Its role in post-MI cardiac fibrosis, however, remains poorly understood. In the present study, we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type (WT), Txnip-knockout ( Txnip-KO) type and Txnip-knock-in ( Txnip-KI) type. After MI, the animals present with significantly upregulated TXNIP levels, and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function. These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals. MI also leads to increased protein levels of the fibrosis indices Collagen I, Collagen III, actin alpha 2 (ACTA2), and connective tissue growth factor (CTGF). The Txnip-KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the Txnip-KO mice. Furthermore, Txnip-KI significantly upregulates the levels of transforming growth factor (TGF)B1, p-Smad3, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Cleaved Caspase-1, and interleukin (IL)1B after MI, but these effects are markedly offset by Txnip-KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the Txnip-KI mice. TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome, followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway. As such, TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis.

Txnip Gene Knockout Ameliorated High-Fat Diet-Induced Cardiomyopathy Via Regulating Mitochondria Dynamics and Fatty Acid Oxidation.

ABSTRACT: Epidemic of obesity accelerates the increase in the number of patients with obesity cardiomyopathy. Thioredoxin interacting protein (TXNIP) has been implicated in the pathogenesis of multiple cardiovascular diseases. However, its specific role in obesity cardiomyopathy is still not well understood. Here, we evaluated the role of TXNIP in obesity-induced cardiomyopathy by feeding wild-type and txnip gene knockout mice with either normal diet or high-fat diet (HFD) for 24 weeks. Our results suggested that TXNIP deficiency improved mitochondrial dysfunction via reversing the shift from mitochondrial fusion to fission in the context of chronic HFD feeding, thus promoting cardiac fatty acid oxidation to alleviate chronic HFD-induced lipid accumulation in the heart, and thereby ameliorating the cardiac function in obese mice. Our work provides a theoretical basis for TXNIP exerting as a potential therapeutic target for the interventions of obesity cardiomyopathy.

TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives.

Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced ß cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect ß cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic ß cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.

Pathogenic fungi-induced susceptibility is mitigated by mutual Lactobacillus plantarum in the Drosophila melanogaster model.

BACKGROUND: Since animals frequently encounter a variety of harmful fungi in nature, their ability to develop sophisticated anti-fungal strategies allows them to flourish across the globe. Extensive studies have highlighted the significant involvement of indigenous microbial communities in human health. However, the daunting diversity of mammalian microbiota and host genetic complexity are major obstacles to our understanding of these intricate links between microbiota components, host immune genotype, and disease phenotype. In this study, we sought to develop a bacterium-fungus-Drosophila model to systematically evaluate the anti-fungal effects of commensal bacteria. RESULTS: We isolated the pathogenic fungal strain, Diaporthe FY, which was detrimental to the survival and development of Drosophila upon infection. Using Drosophila as a model system, Drosophila-associated Lactobacillus plantarum functioned as a probiotic, and protected the flies from mortality induced by Diaporthe FY. Our results show that L. plantarum hindered the growth of Diaporthe FY in vitro, and decreased the mortality rate of Diaporthe FY-infected flies in vivo, consequently mitigating the toxicity of Diaporthe FY to the hosts. Additionally, the presence of L. plantarum overrode the avoidance of oviposition on Diaporthe FY-associated substrates. CONCLUSIONS: Diaporthe FY was identified as a potential Drosophila pathogen. Commensal L. plantarum mitigated the susceptibility of Drosophila to pathogenic fungi, providing insight into the natural interplay between commensal and pathogenic microbial communities that contribute to animal health and pathogenesis.

Long Noncoding RNA-DACH1 (Dachshund Homolog 1) Regulates Cardiac Function by Inhibiting SERCA2a (Sarcoplasmic Reticulum Calcium ATPase 2a).

Heart failure (HF) is a major cause of morbidity and mortality in patients with various cardiovascular diseases. Restoration of cardiac function is critical in improving the clinical outcomes of patients with HF. Long noncoding RNAs are widely involved in the development of multiple cardiac diseases, whereas their role in regulating cardiac function remains unclear. In this study, we found that the expression of long noncoding RNA-DACH1 (dachshund homolog 1) was upregulated in the failing hearts of mice and human. We tested the hypothesis that the intronic long noncoding RNA of DACH1 (LncDACH1) can participate in the regulation of cardiac function and HF. Transgenic overexpression of LncDACH1 in the cardiac myocytes of mice led to impaired cardiac function, reduced calcium transient and cell shortening, and decreased SERCA2a (sarcoplasmic reticulum calcium ATPase 2a) protein expression. In contrast, conditional knockout of LncDACH1 in cardiac myocytes resulted in increased calcium transient, cell shortening, SERCA2a protein expression, and improved cardiac function of transverse aortic constriction induced HF mice. The same qualitative data were obtained by overexpression or knockdown of LncDACH1 with adenovirus carrying LncDACH1 or its siRNA. Moreover, therapeutic administration of adenovirus carrying LncDACH1 siRNA to transverse aortic constriction mice abolished the development of HF. Mechanistically, LncDACH1 directly binds to SERCA2a. Overexpression of LncDACH1 augments the ubiquitination of SERCA2a. LncDACH1 upregulation impairs cardiac function by promoting ubiquitination-related degradation of SERCA2a.

Increase of late sodium current contributes to enhanced susceptibility to atrial fibrillation in diabetic mice.

Studies demonstrated that the incidence of atrial fibrillation is significantly increased in patients with diabetes mellitus. Increase of late sodium current (INaL) has been associated with atrial arrhythmias. However, the role of INaL in the setting of atrial fibrillation in diabetes mellitus remained unknown. In this study, we investigated the alteration of INaL in the atria of diabetic mice and the therapeutic effect of its inhibitor (GS967) on the susceptibility of atrial fibrillation. The whole-cell patch-clamp technique was used to detect single cell electrical activities. The results showed that the density of INaL in diabetic cardiomyocytes was larger than that of the control cells at the holding potential of -100 mV. The action potential duration at both 50% and 90% repolarization, APD50 and APD90, respectively, was markedly increased in diabetic mice than in controls. GS967 application inhibited INaL and shortened APD of diabetic mice. High-frequency electrical stimuli were used to induce atrial arrhythmias. We found that the occurrence rate of atrial fibrillation was significantly increased in diabetic mice, which was alleviated by the administration of GS967. In GS967-treated diabetic mice, the INaL current density was reduced and APD was shortened. In conclusion, the susceptibility to atrial fibrillation was increased in diabetic mice, which is associated with the increased late sodium current and the consequent prolongation of action potential. Inhibition of INaL by GS967 is beneficial against the occurrence of atrial fibrillation in diabetic mice.

Valsartan reduced the vulnerability to atrial fibrillation by preventing action potential prolongation and conduction slowing in castrated male mice.

INTRODUCTION: Deficiency of testosterone was associated with the susceptibility of atrial fibrillation (AF). Angiotensin-II (AngII) receptor antagonists were shown to reduce AF by improving atrial electrical remodeling. This study investigated the effects and mechanism of valsartan, an AngII receptor antagonist, on the susceptibility to AF with testosterone deficiency. METHODS AND RESULTS: Five-week-old male ICR mice were castrated and valsartan was administered orally (50 mg/kg/d). High-frequency electrical stimulation method was used to induce atrial arrhythmia. Patch-clamp technique was used for recording action potential duration (APD), transient outward potassium current ( I to ), sustained outward potassium current ( I ksus ), and late sodium current ( I Na-L ). Optical mapping technique was used to examine atrial conduction velocity (CV). The expression of connexin40 (Cx40) and Cx43 were detected by Western blot analysis. The occurrence rate of AF was significantly increased in castrated mice and APDs measured at 50% and 90% repolarization were markedly prolonged in castrated mice than controls, which were alleviated by the administration of valsartan. Valsartan suppressed the increase of INa-L and rescued the reduction of Ito and Iksus in castrated mice. The left atrial CV in castrated mice was decreased and the expression of Cx43 reduced than controls, which were restored after valsartan treatment. CONCLUSIONS: Valsartan reduced the susceptibility of AF in castrated mice, which may be related to the inhibition of action potential prolongation and improvement of atrial conduction impairment. This study indicates that valsartan may represent a useful agent for the prevention of AF pathogenesis in elderly male patients.

Enterococci Mediate the Oviposition Preference of Drosophila melanogaster through Sucrose Catabolism.

Sucrose, one of the main products of photosynthesis in plants, functions as a universal biomarker for nutritional content and maturity of different fruits across diverse ecological niches. Drosophila melanogaster congregates to lay eggs in rotting fruits, yet the factors that influence these decisions remains uncovered. Here, we report that lactic acid bacteria Enterococci are critical modulators to attract Drosophila to lay eggs on decaying food. Drosophila-associated Enterococci predominantly catabolize sucrose for growing their population in fly food, and thus generate a unique ecological niche with depleted sucrose, but enriched bacteria. Female flies navigate these favorable oviposition sites by probing the sucrose cue with their gustatory sensory neurons. Acquirement of indigenous microbiota facilitated the development and systemic growth of Drosophila, thereby benefiting the survival and fitness of their offspring. Thus, our finding highlights the pivotal roles of commensal bacteria in influencing host behavior, opening the door to a better understanding of the ecological relationships between the microbial and metazoan worlds.