Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead.

Hypoplastic left heart syndrome (HLHS) is a lethal congenital heart disease (CHD) affecting 8-25 per 100,000 neonates globally. Clinical interventions, primarily surgical, have improved the life expectancy of the affected subjects substantially over the years. However, the etiological basis of HLHS remains fundamentally unclear to this day. Based upon the existing paradigm of studies, HLHS exhibits a multifactorial mode of etiology mediated by a complicated course of genetic and signaling cascade. This review presents a detailed outline of the HLHS phenotype, the prenatal and postnatal risks, and the signaling and molecular mechanisms driving HLHS pathogenesis. The review discusses the potential limitations and future perspectives of studies that can be undertaken to address the existing scientific gap. Mechanistic studies to explain HLHS etiology will potentially elucidate novel druggable targets and empower the development of therapeutic regimens against HLHS in the future.

The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells.

BACKGROUND AND PURPOSE: Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. EXPERIMENTAL APPROACH: Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. KEY RESULTS: GL-V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. Mechanistic studies revealed that GL-V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL-V9 stabilized GATA4 by promoting autophagic degradation of P62. CONCLUSION AND IMPLICATIONS: GL-V9 exerted potent anti-fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, and by avoiding its activation and ultimately inhibiting liver fibrosis. This action indicated that the flavonoid GL-V9 is a potential therapeutic candidate for the treatment of liver fibrosis.

ALDOA maintains NLRP3 inflammasome activation by controlling AMPK activation.

ABBREVIATIONS: ALDOA: aldolase A; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG5: autophagy related 5; ATP: adenosine triphosphate; BMDMs: bone marrow-derived macrophages; CALCOCO2: calcium binding and coiled-coil domain 2; CASP1: caspase 1; CQ: chloroquine; FOXO3: forkhead box O3; IL1B: interleukin 1 beta; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MT: mutant; mtDNA: mitochondrial DNA; MTORC1: mechanistic target of rapamycin kinase complex 1; mtROS: mitochondrial reactive oxygen species; NLRP3: NLR family, pyrin domain containing 3; OPTN: optineurin; PBS: phosphate-buffered saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SN: supernatant; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; v-ATPase: vacuolar type H+-ATPase; WT: wild-type.

Oroxylin A maintains the colonic mucus barrier to reduce disease susceptibility by reconstituting a dietary fiber-deprived gut microbiota.

Dietary fiber intake helps to maintain gut homeostasis. Fiber deficiency causes commensals to utilize mucins as an energy source to destroy mucus layer, thus promoting susceptibility to inflammatory bowel disease. Here, we reported that oroxylin A, a natural flavonoid, ameliorated low-grade colonic inflammation caused by fiber deficiency, alleviated colitis, and further prevented colitis-associated colon cancer in mice. The anti-inflammatory effect of oroxylin A was due to its alteration of gut microbiota. We found that the levels of Eubacterium coprostanoligenes was significantly increased by oroxylin A and the colonized Eubacterium coprostanoligenes significantly protected against colitis and carcinogenesis in colon of mice. Together, our results in this study suggest that oroxylin A may reduce the susceptibility to intestinal diseases by increasing the level of Eubacterium coprostanoligenes which could provide a therapeutic alternation for the treatment of intestinal diseases.

Oroxylin A suppresses ACTN1 expression to inactivate cancer-associated fibroblasts and restrain breast cancer metastasis.

Tumor initiation and progression are not only ascribed to the behavior of cancer cells, but also profoundly influenced by the tumor microenvironment. Inside, cancer-associated fibroblasts (CAFs) have become key factors to accelerate growth and metastasis for the abundance in most solid tumors. Our group previously reported that Oroxylin A (OA), a flavone from Scutellaria Baicalensis Georgi, possess the ability to suppress growth and invasion of several tumor cells. However, the regulatory effect of OA on stromal microenvironment is poorly understood. In this study, breast cancer-induced fibroblasts and primary breast CAFs from MMTV-PyMT mice were used to evaluate the influence of OA on the activation of fibroblasts. Results showed that OA could decrease the expression of α-SMA, fibronectin, vimentin and matrix metalloproteinases (MMPs). Thus, OA-deactivated CAFs did not further promote the proliferation and invasion in breast cancer cells. In vivo experiments, OA could also impede tumor metastasis through exhausting progressive CAFs. Mechanically, OA could specifically bind ACTN1 and significantly inhibit its expression to prevent CAF activation. As a consequence, OA could decrease the phosphorylation of FAK and STAT3, and reduce the secretion of CCL2 in CAFs. Altogether, OA could remodel stromal microenvironment and it is a potential therapeutic agent in breast cancer.

The Application of Ferroptosis in Diseases.

Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Ferroptosis involves various biology processes, such as iron metabolism, lipid metabolism, oxidative stress and biosynthesis of nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH) and coenzyme Q10 (CoQ10). A growing body of evidence suggests that ferroptosis is associated with cancer and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and Huntington's disease). This finding has helped develop a novel cytoprotective strategy to protect cells in neurodegenerative, blood and heart diseases by inhibiting ferroptosis. Meanwhile, the selective induction of ferroptosis has been adopted as a potential treatment strategy in some kinds of cancer. This review aims to summarize the mechanism of ferroptosis regulation and relevance to pathological physiology.