Steroid receptor coactivator 1 promotes human hepatocellular carcinoma invasiveness through enhancing MMP-9.

SRC-1 functions as a transcriptional coactivator for steroid receptors and various transcriptional factors. Notably, SRC-1 has been implicated in oncogenic roles in multiple cancers, including breast cancer and prostate cancer. Previous investigations from our laboratory have established the high expression of SRC-1 in human HCC specimens, where it accelerates HCC progression by enhancing Wnt/beta-catenin signalling. In this study, we uncover a previously unknown role of SRC-1 in HCC metastasis. Our findings reveal that SRC-1 promotes HCC metastasis through the augmentation of MMP-9 expression. The knockdown of SRC-1 effectively mitigated HCC cell metastasis both in vitro and in vivo by suppressing MMP-9 expression. Furthermore, we observed a positive correlation between SRC-1 mRNA levels and MMP-9 mRNA levels in limited and larger cohorts of HCC specimens from GEO database. Mechanistically, SRC-1 operates as a coactivator for NF-κB and AP-1, enhancing MMP-9 promoter activity in HCC cells. Higher levels of SRC-1 and MMP-9 expression are associated with worse overall survival in HCC patients. Treatment with Bufalin, known to inhibit SRC-1 expression, significantly decreased MMP-9 expression and inhibited HCC metastasis in both in vitro and in vivo settings. Our results demonstrated the pivotal role of SRC-1 as a critical modulator in HCC metastasis, presenting a potential therapeutic target for HCC intervention.

Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment.

Steroid receptor coactivator 3 (SRC-3) is a member of the p160 SRC family. This factor can interact with multiple nuclear hormone receptors and transcription factors to regulate the expression of their target genes. Although many physiological roles of SRC-3 have been revealed, its role in atherosclerosis is not clear. In this study, we found that SRC-3-/-ApoE-/- mice have reduced atherosclerotic lesions and necrotic areas in their aortas and aortic roots compared with SRC-3+/+ApoE-/- mice after Western diet (WD) feeding for 12 weeks. RNA-Seq and Western blot analyses of the aorta revealed that SRC-3 was required for maintaining the expression of ICAM-1, which was required for macrophage recruitment and atherosclerosis development. siRNA-mediated knockdown of SRC-3 in endothelial cells significantly reduced WD-induced atherosclerotic plaque formation. Additionally, treatment of ApoE-/- mice with SRC-3 inhibitor bufalin prevented atherosclerotic plaque development. SRC-3 deficiency reduced aortic macrophage recruitment. Accordingly, ICAM-1 expression was markedly decreased in the aortas of SRC-3-/-ApoE-/- mice and ApoE-/- mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus. Mechanistically, SRC-3 coactivated NF-κB p65 to increase ICAM-1 transcription in endothelial cells. Collectively, these findings demonstrate that inhibiting SRC-3 ameliorates atherosclerosis development, at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.

Rhein ameliorates transverse aortic constriction-induced cardiac hypertrophy via regulating STAT3 and p38 MAPK signaling pathways.

The progression from compensatory hypertrophy to heart failure is difficult to reverse, in part due to extracellular matrix fibrosis and continuous activation of abnormal signaling pathways. Although the anthraquinone rhein has been examined for its many biological properties, it is not clear whether it has therapeutic value in the treatment of cardiac hypertrophy and heart failure. In this study, we report for the first time that rhein can ameliorate transverse aortic constriction (TAC)-induced cardiac hypertrophy and other cardiac damage in vivo and in vitro. In addition, rhein can reduce cardiac hypertrophy by attenuating atrial natriuretic peptide, brain natriuretic peptide, and ß-MHC expression; cardiac fibrosis; and ERK phosphorylation and transport into the nucleus. Furthermore, the inhibitory effect of rhein on myocardial hypertrophy was similar to that of specific inhibitors of STAT3 and ERK signaling. In addition, rhein at therapeutic doses had no significant adverse effects or toxicity on liver and kidney function. We conclude that rhein reduces TAC-induced cardiac hypertrophy via targeted inhibition of the molecular function of ERK and downregulates STAT3 and p38 MAPK signaling. Therefore, rhein might be a novel and effective agent for treating cardiac hypertrophy and other cardiovascular diseases.

Injectable selenium-containing polymeric hydrogel formulation for effective treatment of myocardial infarction.

Myocardial infarction (MI) is a serious threat to people's life and health, which is significantly hindered by effective treatment formulations. Interestingly, our recent endeavour of designing selenium-containing polymeric hydrogel has been experimentally proved to be helpful in combating inflammatory responses and treating MI. The design was inspired by selenium with anti-inflammatory and anti-fibrosis activities, and the formulation could also serve as a support of myocardial tissue upon the failure of this function. In details, an injectable selenium-containing polymeric hydrogel, namely, poly[di-(1-hydroxylyndecyl) selenide/polypropylene glycol/polyethylene glycol urethane] [poly(DH-SE/PEG/PPG urethane)], was synthesised by combining a thermosensitive PPG block, DH-Se (which has oxidation-reduction properties), and hydrophilic PEG segments. Based on the established mouse model of MI, this formulation was experimentally validated to effectively promote the recovery of cardiac function. At the same time, we confirmed by enzyme-linked immunosorbent assay, Masson staining and Western blotting that this formulation could inhibit inflammation and fibrosis, so as to significantly improve left ventricular remodelling. In summary, a selenium-containing polymeric hydrogel formulation analysed in the current study could be a promising therapeutic formulation, which can provide new strategies towards the effective treatment of myocardial infarction or even other inflammatory diseases.

Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Genetic Characteristics and Transcriptional Regulation of Sodium Channel Related Genes in Chinese Patients With Brugada Syndrome.

Objective: To investigate the genetic characteristics and transcriptional regulation of the SCN5A gene of Brugada syndrome (BrS) patients in China. Methods: Using PubMed, Medline, China National Knowledge Internet (CNKI), and Wanfang Database, Chinese patients with BrS who underwent SCN5A gene testing were studied. Results: A total of 27 suitable studies involving Chinese BrS patients who underwent the SCN5A gene test were included. A total of 55 SCN5A gene mutations/variations were reported in Chinese BrS patients, including 10 from southern China and 45 from northern China. Mutations/variations of BrS patients from southern China mostly occurred in the regions of the α-subunit of Nav1.5, including DIII (Domain III), DIV, DIII-DIV, C-terminus regions, and the 3'UTR region. Furthermore, we analyzed the post-transcriptional modifications (PTMs) throughout the Nav1.5 protein encoded by SCN5A and found that the PTM changes happened in 72.7% of BrS patients from southern China and 26.7% from northern China. Conclusions: SCN5A mutations/variations of BrS patients in southern China mostly occurred in the DIII-DIV to C-terminus region and the 3'-UTR region of the SCN5A gene, different from northern China. PTM changes were consistent with the mutation/variation distribution of SCN5A, which might be involved in the regulation of the pathogenesis of BrS patients.

Loganin Inhibits Angiotensin II-Induced Cardiac Hypertrophy Through the JAK2/STAT3 and NF-κB Signaling Pathways.

Loganin is an iridoid glycoside extracted from Cornus officinalis, which is a traditional oriental medicine, and many biological properties of loganin have been reported. Nevertheless, it is not clear whether loganin has therapeutic effect on cardiovascular diseases. Hence, the aim of the present study was to investigate the effect of loganin on Ang II-induced cardiac hypertrophy. In the present study, we reported for the first time that loganin inhibits Ang II-provoked cardiac hypertrophy and cardiac damages in H9C2 cells and in mice. Furthermore, loganin can achieve cardioprotective effects through attenuating cardiac fibrosis, decreasing pro-inflammatory cytokine secretion, and suppressing the phosphorylation of critical proteins such as JAK2, STAT3, p65, and IκBα. Besides, the outstanding findings of the present study were to prove that loganin has no significant toxicity or side effects on normal cells and organs. Based on these results, we conclude that loganin mitigates Ang II-induced cardiac hypertrophy at least partially through inhibiting the JAK2/STAT3 and NF-κB signaling pathways. Accordingly, the natural product, loganin, might be a novel effective agent for the treatment of cardiac hypertrophy and heart failure.

Impact of environmental factors on pulmonary tuberculosis in multi-levels industrial upgrading area of China.

In the present paper, an association between the growth rate of PTB and the environmental impacting elements in the pearl river delta region and the closed industry related cities in China is studied. We summarized the characteristics of different industry characteristics in this region by three echelons of urban agglomerations conducted by K-means clustering model on the time series of their monthly AQI data. To determine the impact of environmental factors on the increase of PTB, the SMLR in GLM has been applied. We then measured the seasonal effect and suggest the spring to be the leading season which keep the highest possibility of the incidence of PTB. Besides giving the analysis by fixed meteorological factors, we presented a sensitive analysis with a variation of precipitation. The Genetic algorithms (GAs) is used to determine the "tolerant" interval and as the results, the width of "tolerant" almost keep a declining trend as the precipitation increasing except when the precipitation comes the interval [68,74]. In addition, with the precipitation increasing higher than 64 mm, the "tolerant" for the AQI values from the first and the second echelon both trend to decline, and a lenient environmental policy currently may easily cause a rapid development of PTB growth rate.