NLRP3, a member of the nucleotide-binding oligomerization domain (NOD)-like receptor family, is involved in cardiac inflammation. However, the functional role of NLRP3 in cardiac remodeling is not clear. To investigate the roles of NLRP3 in pressure overload-induced cardiac remodeling, NLRP3 knockout and wild-type mice were subjected to aortic banding to induce cardiac remodeling. The data showed that NLRP3 expression was downregulated in the remodeling process. NLRP3 deficiency accelerated cardiac hypertrophy, fibrosis, and inflammation responses with deteriorating cardiac dysfunction in the pressure overload-induced cardiac remodeling mouse model. Neonatal rat cardiomyocytes were isolated and stimulated with phenylephrine (PE). We identified NLRP3 as a negative regulator of cardiomyocyte remodeling in PE-stimulated cardiomyocyte remodeling using adenovirus-NLRP3 and NLRP3 siRNA. Mechanistically, we found that the expression of Toll-like receptor (TLR) 4 was upregulated in NLRP3-deficient mouse hearts and PE-stimulated cardiomyocytes. NLRP3 knockout mice subjected to a TLR4 inhibitor revealed a relieved cardiac remodeling response with improved cardiac dysfunction. Our data suggested that NLRP3 could be a therapeutic target for cardiac remodeling and heart failure. KEY MESSAGES: NLRP3 expression was downregulated in the remodeling process. NLRP3 deficiency accelerated pressure overload-induced cardiac remodeling. NLRP3 acted as a negative regulator of cardiomyocyte remodeling via downregulating TLR4.

Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high mortality worldwide. Recent evidence has documented the regulatory role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) during the inflammatory process, the effects of which in the development of sepsis have become the focus of the current study. An in vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were developed. High expression of lncRNA MALAT1 along with low expression of breast cancer susceptibility gene 1 (BRCA1) were identified in septic mice and human skeletal muscle cells of sepsis. Then, lncRNA MALAT1 expression was altered in vivo and in vitro to examine serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. lncRNA MALAT1 was noted to regulate the expression and export from the nucleus of BRCA1 by recruiting zeste homolog 2 (EZH2) in skeletal muscle cells of sepsis. Silencing lncRNA MALAT1 resulted in reduced serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), neutrophil migration, skeletal muscle cell apoptosis, and AKT-1 phosphorylation. Taken together, lncRNA MALAT1 interacting with EZH2 stimulated AKT-1 phosphorylation and decreased BRCA1 expression, consequently aggravating the progression of sepsis, highlighting a promising therapeutic option for sepsis.

Orientin is a flavonoid extracted from Chinese traditional herb, Polygonum orientale L. Previous study has reported that orientin protected myocardial from ischemia reperfusion injury. However, whether orientin could protect against cardiac remodeling after myocardial injury remains unclear. The aim of our study is to investigate the effects of orientin in the progression of cardiac remodeling after myocardial infarction (MI). Mice cardiac remodeling model was established by left coronary artery ligation surgery. Experimental groups were as follows: vehicle-sham, orientin-sham, vehicle-MI, and orientin-MI. Animals were treated with vehicle or orientin (40 mg/kg) for 25 days starting 3 days after surgery. After 4 weeks of MI, mice with orientin treatment had decreased mortality and improved cardiac function. Significantly, at 4 weeks post-MI, orientin treatment decreased fibrosis, inflammatory response, and cardiomyocyte apoptosis. Furthermore, orientin treatment attenuated the hypoxia-induced neonatal rat cardiomyocyte apoptosis and increased cell viability. Additionally, orientin supplementation mitigated oxidative stress in remodeling heart tissue and cardiomyocytes exposed to hypoxia as measured by 2′,7′-dichlorodihydrofluorescein diacetate fluorescent probe. Mechanistically, orientin promotes cardioprotection by activating the eNOS/NO signaling cascades, which was confirmed by eNOS inhibitor (L-NAME) in vitro and in vivo. Inhibition of oxidative stress by orientin via eNOS/NO signaling cascades in the heart may represent a potential therapy for cardiac remodeling.

Type 2 diabetes mellitus (T2DM) is a burdensome global disease. In-depth understanding of its mechanism will help to optimize diagnosis and treatment, which reduces the burden. Multi-omics research has unparalleled advantages in contributing to the overall understanding of the mechanism of this chronic metabolic disease. In the past two decades, the study of multi-omics on T2DM-related intestinal flora perturbation and plasma dyslipidemia has shown tremendous potential and is expected to achieve major breakthroughs. The regulation of intestinal flora in diabetic patients has been confirmed by multiple studies. The use of metagenomics, 16S RNA sequencing, and metabolomics has comprehensively identified the overall changes in the intestinal flora and the metabolic disturbances that could directly or indirectly participate in the intestinal flora-host interactions. Lipidomics combined with other “omics” has characterized lipid metabolism disorders in T2DM. The combined application and cross-validation of multi-omics can screen for dysregulation in T2DM, which will provide immense opportunities to understand the mechanisms behind T2DM.

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