Liraglutide ameliorates TAC-induced cardiac hypertrophy and heart failure by upregulating expression level of ANP expression.

Recent studies have underscored the cardioprotective properties of liraglutide. This research explores its impact on cardiac hypertrophy and heart failure following transverse aortic constriction (TAC). We found that liraglutide administration markedly ameliorated cardiac hypertrophy, fibrosis, and function. These benefits correlated with increased ANP expression and reduced activity in the calcineurin A/NFATc3 signaling pathway. Moreover, liraglutide mitigated ER stress and cardiomyocyte apoptosis, and enhanced autophagy. Notably, the positive effects of liraglutide diminished when co-administered with A71915, an ANP inhibitor, suggesting that ANP upregulation is critical to its cardioprotective mechanism.

Liraglutide attenuates angiotensin II-induced aortic dissection and aortic aneurysm via inhibiting M1 macrophage polarization in APOE -/- mice.

BACKGROUND: Aortic Aneurysm and Dissection (AAD) are severe cardiovascular conditions with potentially lethal consequences such as aortic rupture. Existing studies suggest that liraglutide, a long-acting glucagon-like peptide receptor (GLP-1R) agonist, offers protective benefits across various cardiovascular diseases. However, the efficacy of liraglutide in mitigating AAD development is yet to be definitively elucidated. METHODS: Ang II (Angiotension II) infusion of APOE-/- mouse model with intraperitoneal injection of liraglutide (200 µg/kg) to study the role of GLP-1R in AAD formation. Bone Marrow Derived Macrophages (BMDM) and Raw264.7 were incubated with LPS, liraglutide, exendin 9-39 or LY294002 alone or in combination. SMC phenotype switching was examined in a macrophage and vascular smooth muscle cell (VSMC) co-culture system. An array of analytical methods, including Western Blot, Immunofluorescence Staining, Enzyme-LinkedImmunosorbent Assay, Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, and so on were employed. RESULTS: Our investigation revealed a significant increase in M1 macrophage polarization and GLP-1R expression in aortas of AD patients and Ang II-induced AAD APOE-/- mice. Administering liraglutide in APOE-/- mice notably reduced Ang II-induced AAD incidence and mortality. It was found that liraglutide inhibits M1 macrophage polarization primarily via GLP-1R activation, and subsequently modulates vascular smooth muscle cell phenotypic switching was the primary mechanism. RNA-Seq and subsequent KEGG enrichment analysis identified CXCL3, regulated by the PI3K/AKT signaling pathway, as a key element in liraglutide's modulation of M1 macrophage polarization. CONCLUSION: Our study found liraglutide exhibits protective effects against AAD by modulating M1 macrophage polarization, suppressing CXCL3 expression through the PI3K/AKT signaling pathway. This makes it a promising therapeutic target for AAD, offering a new avenue in AAD management.

Larixyl acetate, a TRPC6 inhibitor, attenuates pressure overload­induced heart failure in mice.

Heart failure is a primary cause of global mortality. In the present study, whether larixyl acetate, an inhibitor of transient receptor potential cation channel subfamily C member 6, attenuates pressure overload­induced heart failure in mice was investigated. To test this hypothesis, a transverse aortic constriction (TAC) animal model and an angiotensin II (Ang II)­treated H9c2 cell model were used. Cardiac and cellular structure, function and the expression levels of hypertrophy, endoplasmic reticulum (ER) stress, apoptosis, autophagy and pmTOR/mTOR related mRNAs or proteins were assessed to explore the underlying molecular mechanisms. The results indicated that treatment with TAC or Ang II leads to significant hypertrophy and dysfunction of the heart or H9c2 cells, accompanied by an increase in ER stress, apoptosis and activation of the mTOR signaling pathway, and a decrease in autophagy. The administration of larixyl acetate attenuated these impairments, which can be reversed by inhibiting autophagy through the activation of the mTOR signaling pathway. These findings suggested that larixyl acetate can effectively protect against pressure overload­induced heart failure by enhancing autophagy and limiting ER stress and apoptosis through inhibition of the mTOR pathway.

Increased A1 astrocyte activation-driven hippocampal neural network abnormality mediates delirium-like behavior in aged mice undergoing cardiac surgery.

Delirium is the most common neurological complication after cardiac surgery with adverse impacts on surgical outcomes. Advanced age is an independent risk factor for delirium occurrence but its underlying mechanisms are not fully understood. Although increased A1 astrocytes and abnormal hippocampal networks are involved in neurodegenerative diseases, whether A1 astrocytes and hippocampal network changes are involved in the delirium-like behavior of aged mice remains unknown. In the present study, a mice model of myocardial ischemia-reperfusion mimicking cardiac surgery and various assessments were used to investigate the different susceptibility of the occurrence of delirium-like behavior between young and aged mice and the underlying mechanisms. The results showed that surgery significantly increased hippocampal A1 astrocyte activation in aged compared to young mice. The high neuroinflammatory state induced by surgery resulted in glutamate accumulation in the extrasynaptic space, which subsequently decreased the excitability of pyramidal neurons and increased the PV interneurons inhibition through enhancing N-methyl-D-aspartate receptors' tonic currents in the hippocampus. These further induced the abnormal activities of the hippocampal neural networks and consequently contributed to delirium-like behavior in aged mice. Notably, the intraperitoneal administration of exendin-4, a glucagon-like peptide-1 receptor agonist, downregulated A1 astrocyte activation and alleviated delirium-like behavior in aged mice, while IL-1α, TNF-α, and C1q in combination administered intracerebroventricularly upregulated A1 astrocyte activation and induced delirium-like behavior in young mice. Therefore, our study suggested that cardiac surgery increased A1 astrocyte activation which subsequently impaired the hippocampal neural networks and triggered delirium development.

Nuciferine improves cardiac function in mice subjected to myocardial ischemia/reperfusion injury by upregulating PPAR-γ.

Ischemic heart disease and myocardial infarction contribute to the leading cause of death in worldwide. The prevention and management of myocardial ischemia/reperfusion (I/R) injury is an essential part of coronary heart disease surgery and is becoming a major clinical problem in the treatment of ischemic heart disease. Nuciferine has potent anti-inflammatory and antioxidative stress effects, but its role in myocardial ischemia-reperfusion (I/R) is unclear. In this study, we found that nuciferine could reduce the myocardial infarct size in a mouse myocardial ischemia-reperfusion model and improve cardiac function. Furthermore, nuciferine could effectively inhibit hypoxia and reoxygenation (H/R) stimulated apoptosis of primary mouse cardiomyocytes. In addition, nuciferine significantly reduced the level of oxidative stress. The peroxisome proliferator-activated receptor gamma (PPAR-γ) inhibitor GW9662 could reverse the protective effect of nuciferine on cardiomyocytes. These results indicate that nuciferine can inhibit the apoptosis of cardiomyocytes by upregulating PPAR-γ and reducing the I/R-induced myocardial injury in mice.

Excessive DNA damage mediates ECM degradation via the RBBP8/NOTCH1 pathway in sporadic aortic dissection.

Stanford type A aortic dissection (TA-AD) is a life-threatening disease. Most cases of aortic dissection (AD) are sporadic rather than inherited. Unlike that of inherited AD, the pathogenesis of sporadic AD is still unclear. In the current study, we aimed to explore the pathogenesis of sporadic AD through transcriptome sequencing data analyses. We downloaded sporadic TA-AD transcriptome profiles from Gene Expression Omnibus (GEO) and found response to DNA damage stimulus was activated in AD. Furthermore, by conducting mouse AD tissue single cell RNA sequencing and immunostaining, we found that DNA damage mainly occurred in smooth muscle cells (SMCs) and fibroblasts. Next, we examined the repair patterns in response to DNA damage and found the linker molecules RBBP8/NOTCH1 between DNA damage/repair and extracellular matrix (ECM) organization through protein-protein interaction analysis. Thus, we proposed that DNA damage could contribute to AD by regulating ECM changes. To explore the underlying mechanism, we knocked down the DNA repair-related gene RBBP8 in aortic SMCs, which could exacerbate DNA damage, and observed decreased expression level of NOTCH1. Inhibition of NOTCH1 with crenigacestat in vivo accelerated ß-aminopropionitrile-induced formation of AD and increased mortality. Meanwhile, phenotype switching of SMCs was induced by Notch1 knockdown or inhibition; this switching occurred via a pathway involving downregulation of contractile marker gene expression and upregulation of MMP2 expression, which might aggravate ECM degradation. In conclusion, excessive DNA damage is a characteristic pathological change of sporadic aortic dissection, which might contribute to ECM changes and AD development via action on the NOTCH1 pathway.

LncRNA NEAT1 acts as a key regulator of cell apoptosis and inflammatory response by the miR-944/TRIM37 axis in acute lung injury.

Acute lung injury (ALI), a common complication of sepsis, is characterized by the impairment and injury of pulmonary function. The nuclear factor kappa-B (NF-κB) pathway is activated in ALI. Tripartite motif-containing 37 (TRIM37) can activate the NF-κB pathway and is closely associated with inflammation. The purpose of our study is to reveal the role of TRIM37 in ALI. The present study revealed that TRIM37 presented high levels in lung tissues of ALI mice, and knockdown of TRIM37 alleviated lipopolysaccharide (LPS)-induced lung injury, inflammatory response, and cell apoptosis in vivo. In addition, knockdown of TRIM37 inhibited the inflammatory response, and cell apoptosis of LPS-treated WI-38 cells. Mechanistically, miR-944 was identified to bind with and negatively regulate TRIM37. Furthermore, NEAT1 was indicated to act as a competitive endogenous RNA to promote TRIM37 expression by sequestering miR-944. Detailly, NEAT1 bound with miR-944, negatively modulated miR-944 expression, and positively modulated TRIM37 expression. The rescue assays suggested that overexpression of TRIM37 rescued the influence of NEAT1 knockdown on cell apoptosis and inflammatory response. Overall, NEAT1 facilitated cell apoptosis and inflammatory response of WI-38 cells by the miR-944/TRIM37 axis in sepsis-induced ALI, implying that NEAT1 may provide a novel insight for the treatment of sepsis-induced ALI.

S­allyl­cysteine sulfoxide (alliin) alleviates myocardial infarction by modulating cardiomyocyte necroptosis and autophagy.

S­allyl­cysteine sulfoxide (alliin) is the main organosulfur component of garlic and its preparations. The present study aimed to examine the protective effect of alliin on cardiac function and the underlying mechanism in a mouse model of myocardial infarction (MI). Notably, alliin treatment preserved heart function, attenuated the area of infarction in the myocardium of mice and reduced lesions in the myocardium, including cardiomyocyte fibrosis and death. Further mechanistic experiments revealed that alliin inhibited necroptosis but promoted autophagy in vitro and in vivo. Cell viability assays showed that alliin dose­dependently reduced the necroptotic index and inhibited the expression of necroptosis­related receptor­interacting protein 1, receptor­interacting protein 3 and tumor necrosis factor receptor­associated factor 2, whereas the levels of Beclin 1 and microtubule­associated protein 1 light chain 3, which are associated with autophagy, exhibited an opposite trend upon treatment with alliin. In addition, the level of peroxisome proliferator­activated receptor γ was increased by alliin. Collectively, these findings demonstrate that alliin has the potential to protect cardiomyocytes from necroptosis following MI and that this protective effect occurs via the enhancement of autophagy.

Macroautophagy occurs in distal TMV-uninfected root tip tissue of tomato taking place systemic PCD.

Autophagy is an important mechanism for recycling cell materials upon encountering stress conditions. Our previous studies had shown that TMV infection could lead to systemic PCD in the distal uninfected tissues, including root tip and shoot tip tissues. But it is not clear whether there is autophagy in the distal apical meristem of TMV-induced plants. To better understand the autophagy process during systemic PCD, here we investigated the formation and type of autophagy in the root meristem cells occurring PCD. Transmission electron microscopy assay revealed that the autophagic structures formed by the fusion of vesicles, containing the sequestered cytoplasm, multilamellar bodies, and degraded mitochondria. In the PCD progress, many mitochondria appeared degradation with blurred inner membrane structure. And the endoplasmic reticulum was broke into small fragments. Finally, the damaged mitochodria were engulfed and degraded by the autophagosomes. These results indicated that during the systemic PCD process of root tip cells, the classical macroautophagy occurred, and the cell contents and damaged organelles (mitochondria) would be self-digested by autophagy.

Function Identification of the Nucleotides in Key cis-Element of DYSFUNCTIONAL TAPETUM1 (DYT1) Promoter.

As a core regulatory gene of the anther development, DYSFUNCTIONAL TAPETUM1 (DYT1) was expressed in tapetum preferentially. Previous study had confirmed that a "CTCC" sequence within DYT1 promoter was indispensable for correct DYT1 expression. However, precise analysis on the function of each nucleotide of this sequence still lacks. Here we employed site mutation assay to identify the function roles of the nucleotides. As a result, the "T" and final "C" of "CTCC" were found essential for the temporal and spatial specificity of DYT1 expression, whereas the other two "C" nucleotides exhibited substitutable somewhat. The substitutes of two flanking nucleotides of "CTCC," however, hardly affected the normal promoter function, suggesting that the "CTCC" sequence as a whole did meet the standard of a canonical cis-element by definition. In addition, it was found that as short as 497 bp DYT1 promoter was sufficient for tissue-specific expression, while longer 505 bp DYT1 promoter sequence was sufficient for species-specific expression.

Cell cycle transcription factor E2F2 mediates non-stress temperature response of AtHSP70-4 in Arabidopsis.

AtHSP70 expression exhibits both stress and non-stress temperature response, however, the molecular mechanisms underlying these temperature signaling pathways remain elusive. Here we performed truncation and deletion assay to investigate the cis-elements within the promoter region of AtHSP70-4 (AT3G12580). And found the region between -1000 and -1100 bp from the translation initiation site (TIS) was indispensable for the non-stress temperature response of AtHSP70. Further deletion assay of several candidate motifs within this region suggested that one 'GCGCCAAA' sequence played the critical role. This motif was found as the reverse DNA-binding motif of cell cycle transcription factor E2F family. EMSA assay verified one number of Arabidopsis E2F family-E2F2 could bind to AtHSP70-4 promoter via this motif. These results indicated the temperature regulated expression of AtHSP70-4 may be mediated by cell cycle transcription factors and participate in plant acclimations to non-stress temperature changes.