MAT1A Suppression by the CTBP1/HDAC1/HDAC2 Transcriptional Complex Induces Immune Escape and Reduces Ferroptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains a significant health burden globally due to its high prevalence and morbidity. C-terminal-binding protein 1 (CTBP1) is a transcriptional corepressor that modulates gene transcription by interacting with transcription factors or chromatin-modifying enzymes. High CTBP1 expression has been associated with the progression of various human cancers. In this study, bioinformatics analysis suggested the existence of a CTBP1/histone deacetylase 1 (HDAC1)/HDAC2 transcriptional complex that regulates the expression of methionine adenosyltransferase 1A (MAT1A), whose loss has been associated with ferroptosis suppression and HCC development. Thus, this study aims to investigate the interactions between the CTBP1/HDAC1/HDAC2 complex and MAT1A and their roles in HCC progression. First, high expression of CTBP1 was observed in HCC tissues and cells, where it promoted HCC cell proliferation and mobility while inhibiting cell apoptosis. CTBP1 interacted with HDAC1 and HDAC2 to suppress the MAT1A transcription, and silencing of either HDAC1 or HDAC2 or overexpression of MAT1A led to the inhibition of cancer cell malignancy. In addition, MAT1A overexpression resulted in increased S-adenosylmethionine levels, which promoted ferroptosis of HCC cells directly or indirectly by increasing CD8+ T-cell cytotoxicity and interferon-γ production. In vivo, MAT1A overexpression suppressed growth of CTBP1-induced xenograft tumors in mice while enhancing immune activity and inducing ferroptosis. However, treatment with ferrostatin-1, a ferroptosis inhibitor, blocked the tumor-suppressive effects of MAT1A. Collectively, this study reveals that the CTBP1/HDAC1/HDAC2 complex-induced MAT1A suppression is liked to immune escape and reduced ferroptosis of HCC cells.

Integrating network analysis and experimental validation to reveal the mitophagy-associated mechanism of Yiqi Huoxue (YQHX) prescription in the treatment of myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (I/R) injury is the main cause of increasing postischemic heart failure and currently there is no definite treatment for myocardial I/R injury. It has been suggested that oxidative stress-induced mitochondrial dysfunction plays an important role in the pathological development of myocardial I/R. In this study, Yiqi Huoxue (YQHX) prescription, as a kind of Chinese herbal formula, was developed and shown to alleviate I/R injury. Network analysis combined with ultrahigh-performance liquid chromatography-high resolution mass spectrometry expounded the active components of YQHX and revealed the mitophagy-regulation mechanism of YQHX treating I/R injury. In vivo experiments confirmed YQHX significantly alleviated I/R myocardial injury and relieved oxidative stress. In vitro experiments validated that YQHX could relieve hypoxia/reoxygenation injury and attenuate oxidative stress via improving the structure and function of mitochondria, which was strongly related to regulating mitophagy. In summary, this study demonstrated that YQHX, which could alleviate I/R injury via targeting mitophagy, might be a potential therapeutic strategy for myocardial I/R injury.

Chinese herbal formula ruangan granule enhances the efficacy of entecavir to reverse advanced liver fibrosis/early cirrhosis in patients with chronic HBV infection: A multicenter, randomized clinical trial.

BACKGROUND: Nucleotide analogs treatment can reverse liver fibrosis in chronic hepatitis B (CHB). However, it has limited effect on fibrosis resolution in patients with CHB, particularly in preventing progression to hepatocellular carcinoma (HCC). Ruangan granule (RG), a Chinese herbal formula, has proven to produce a therapeutic effect against liver fibrosis in animal experiment. Thus, we aimed to evaluate the effect of our Chinese herbal formula (RG) combined with entecavir (ETV) to reverse advanced liver fibrosis/early cirrhosis from CHB. METHODS: A total of 240 CHB patients with histologically confirmed advanced liver fibrosis/early cirrhosis from 12 centers were randomly and blindly allocated to consume either ETV (0.5 mg/day) plus RG (2 times/day) or control (ETV) for 48 weeks (wk) treatment. Changes in histopathology, serology and imageology were observed. Liver fibrosis reversion, defined as a reduction in the Knodell HAI score by ≥ 2 points and Ishak score by ≥ 1 grade, was assessed. RESULTS: The rate of fibrosis regression and inflammation remission after 48 wk of treatment in histopathology was significantly higher in the ETV + RG group (38.73% vs. 23.94%, P = 0.031). The ultrasonic semiquantitative scores decreased by ≥ 2 points and were 41 (28.87%) and 15 (21.13%) in the ETV+RG and ETV groups, respectively (P = 0.026). The ETV+RG group had a significantly lower Fibrosis-4 score (FIB-4) index (P = 0.028). There was a significant difference between the ETV+RG and ETV groups in the liver function normalization rate (P < 0.01). Moreover, ETV plus RG combination treatment further reduced the risk of HCC in median 55-month follow-up (P < 0.01). CONCLUSIONS: This study illustrates that the Chinese herbal formula RG with ETV can improve advanced liver fibrosis/early cirrhosis regression in patients with CHB, further reducing the risk of HCC.

Hypertensive heart disease and myocardial fibrosis: How traditional Chinese medicine can help addressing unmet therapeutical needs.

Long-term elevated blood pressure will increase the cardiac load and lead to myocardial fibrosis (MF). A variety of pathological mechanisms and signal transduction pathways are involved in the process of hypertensive MF, which is of great significance for the occurrence and development of ventricular dilatation and heart failure. MF is the pathological basis of hypertensive heart disease (HHD), and blood pressure control is the key to delaying MF and reducing the occurrence of cardiovascular events. Although a large number of experimental results suggest that anti-MF drug therapy has made great progress, the conclusions of relevant clinical trials are still not optimistic, and it is urgent to find new effective anti-MF medicine. The clinical efficacy of traditional Chinese medicine (TCM) in the treatment of MF in HHD is obvious, and some achievements have been made in the mechanism research. Studies have confirmed that a variety of TCM compound prescription and natural compounds play different degrees of inhibitory effect on MF. In this study, we reviewed the pathogenesis of MF in HHD and the current drug treatment strategies, summarized the latest research progress of TCM in the treatment of MF in HHD, and demonstrated the mechanism of its cardiac protective effect. Finally, we pointed out the limitations of the current study and prospected the future research of TCM.

Traditional Chinese medicine in the treatment of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease in clinical practice. It has been considered that NASH is one of the main causes of chronic liver disease, cirrhosis and carcinoma. The mechanism of the NASH progression is complex, including lipid metabolism dysfunction, insulin resistance, oxidative stress, inflammation, apoptosis, fibrosis and gut microbiota dysbiosis. Except for lifestyle modification and bariatric surgery, there has been no pharmacological therapy that is being officially approved in NASH treatment. Traditional Chinese medicine (TCM), as a conventional and effective therapeutic strategy, has been proved to be beneficial in treating NASH in numbers of studies. In the light of this, TCM may provide a potential therapy for treating NASH. In this review, we summarized the associated mechanisms of action TCM treating NASH in preclinical studies and systematically analysis the effectiveness of TCM treating NASH in current clinical trials.

[Meta-analysis of Zhibitai Capsules combined with statin in reducing blood lipid levels in patients with coronary heart disease].

To systematically review the efficacy and safety of Zhibitai Capsules combined with chemical drugs versus chemical drugs alone in regulating blood lipid of patients of coronary heart disease, so as to provide evidence-based reference for clinical treatment. In this study, PubMed, EMbase, Cochrane Library, China Knowledge Network Database(CNKI), Technology Journal Database(VIP) and WanFang Database(WanFang) were retrieved to find the randomized controlled trials(RCT) about therapeutic efficacy of Zhibitai Capsules combined with statins(experimental group)versus statins alone(control group)in the treatment of regulating blood lipid of patients with coronary heart disease. The retrieval time was restricted to be from the inception to October 2019. The data were extracted from the randomized controlled trials. Meta-analysis was conducted by RevMan 5.3 statistical software after quality evaluation by Cochrane 5.1.0 quality evaluation tool(blood lipid level, inflammation indicators, traditional Chinese medicine syndrome score and adverse reactions). A total of 11 RCT were included, involving 1 538 patients. The results of Meta-analysis showed that in terms of decrease of total cholesterol(MD=-0.15,95%CI[-0.25,-0.05],P=0.004), decrease of triglycerides improvement(MD=-0.16,95%CI[-0.23,-0.10],P<0.000 01), decrease of low-density lipoprotein(MD=-0.08,95%CI[-0.15,-0.01],P=0.03), and increase of high-density lipoprotein(MD=0.06,95%CI[0.03,0.10],P=0.000 2), experimental group was better than control group. At the same time, the incidence of adverse reactions were low in the experimental group(OR=0.40,95%CI[0.18,0.85],P=0.02). As a result, in treatment of coronary heart disease, the therapeutic efficacy of Zhibitai Capsules combined with statins is better than statins alone in lowering total cholesterol level, triglyceride level, low-density lipoprotein level, and increasing high-density lipoprotein level. Patients in the experimental group had a low incidence of adverse events, but the heterogeneity was slightly higher, and the result had a poor stability. However, due to the small sample size of studies included, some experimental designs were not perfect, which reduces the recommendation level and evidence intensity of this system evaluation. Therefore, high-quality multi-center, large-sample, randomized, double-blind randomized controlled trials are needed for providing more reliable basis.

The PU.1-Modulated MicroRNA-22 Is a Regulator of Monocyte/Macrophage Differentiation and Acute Myeloid Leukemia.

MicroRNA-22 (miR-22) is emerging as a critical regulator in organ development and various cancers. However, its role in normal hematopoiesis and leukaemogenesis remains unclear. Here, we detected its increased expression during monocyte/macrophage differentiation of HL-60, THP1 cells and CD34+ hematopoietic stem/progenitor cells, and confirmed that PU.1, a key transcriptional factor for monocyte/macrophage differentiation, is responsible for transcriptional activation of miR-22 during the differentiation. By gain- and loss-of-function experiments, we demonstrated that miR-22 promoted monocyte/macrophage differentiation, and MECOM (EVI1) mRNA is a direct target of miR-22 and MECOM (EVI1) functions as a negative regulator in the differentiation. The miR-22-mediated MECOM degradation increased c-Jun but decreased GATA2 expression, which results in increased interaction between c-Jun and PU.1 via increasing c-Jun levels and relief of MECOM- and GATA2-mediated interference in the interaction, and thus promoting monocyte/macrophage differentiation. We also observed significantly down-regulation of PU.1 and miR-22 as well as significantly up-regulation of MECOM in acute myeloid leukemia (AML) patients. Reintroduction of miR-22 relieved the differentiation blockage and inhibited the growth of bone marrow blasts of AML patients. Our results revealed new function and mechanism of miR-22 in normal hematopoiesis and AML development and demonstrated its potential value in AML diagnosis and therapy.

Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis.

Aplastic anaemia (AA) is a life-threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM-derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM-MSCs through lentivirus-mediated ZFP36L1 knock-down and overexpression assay. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3'-untranslated region bears adenine-uridine-rich elements was verified as a direct downstream target of ZFP36L1, and knock-down of PPARGC1B impaired the adipogenesis of AA BM-MSCs. Collectively, our work demonstrated that ZFP36L1-mediated post-transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM-MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.

Hypoxia induces peroxisome proliferator-activated receptor γ expression via HIF-1-dependent mechanisms in HepG2 cell line.

Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes in response to hypoxia. It has been shown that the levels of peroxisome proliferator-activated receptor γ (PPARγ) are influenced by changes in oxygen tension, and PPARγ plays a critical role in metabolism regulation and cancers. In this research, we observed an increased PPARγ mRNA and protein levels in company with increased HIF-1 protein levels in HepG2 cells in hypoxia as compared with in normoxia. Enforced expression of HIF-1α induced PPARγ1 and PPARγ2 expression, while knockdown of HIF-1α by small interference RNA deduced PPARγ1 and PPARγ2 expression in HepG2 cells under hypoxic conditions. By dual-luciferase reporter assay and chromatin immunoprecipitation assay we confirmed a functional hypoxic response element (HRE) localized at 684bp upstream of the transcriptional start site (TSS) of PPARγ1 and a functional HRE localized at 204bp downstream of the TSS of PPARγ2 in HepG2 cells. Additionally we observed an increase and co-presence of PPARγ and HIF-1α, and a highly positive correlation between PPARγ expression and HIF-1α expression (r=0.553, p<0.0001), in the same tumor tissue areas of hepatocellular carcinoma patients. Our data suggested a new mechanism of hepatocellular carcinoma cells response to hypoxia.

[Screening and Identification of lncRNA Related to Adipocity of Bone Marrow Microenvironment in Aplastic Anemia].

OBJECTIVE: To systematically screen and identify long noncoding RNA (lncRNA) associated with bone marrow adiposity changes in aplastic anemia (AA). METHODS: The PPARγ and C/EBPα ChIP-Seq data in ChIPBase was analyzed by bioinformatics and the potential lncRNA co-transcriptionally regulated by PPARγ and C/EBPα was screened. The expression of candidate lncRNA was verified by qRT-PCR in the in vitro adipogenic differentiation model of BM-MSC, BM-MSC infected with lenti-shPPARγ and lenti-shC/EBPα as well as clinical BM-MSC samples derived from AA and controls. RESULTS: PPARγ and C/EBPα were significantly highly expressed in AA BM-MSC, and knock-down of PPARγ and C/EBPα impaired the adipogenic capacity of AA BM-MSC. PPARγ and C/EBPα cotranscriptionally activate LINC01230 promoter activity in binding sites dependant manner. The LINC01230 was also aberrantly highly expressed in AA BM-MSC compared with controls. CONCLUSION: PPARγ and C/EBPα are aberrantly expressed in AA BM-MSC and may promote the adipogenic differentiation of AA BM-MSC, and to a certain extent mediate the bone marrow adiposity alteration by transcriptionally activating LINC01230 expression.

Emodin suppresses adipogenesis of bone marrow derived mesenchymal stem cells from aplastic anemia via increasing TRIB3 expression.

BACKGROUND: Increasing evidence indicate that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) could contribute to the adiposity alteration in marrow microenvironment of aplastic anemia (AA). Identifying small molecule drugs with role in inhibiting adipogenesis of BM-MSCs may represent a novel direction in AA therapy by improving BM-MSCs mediated marrow microenvironment. METHODS: For the purpose, we isolated AA BM-MSCs through whole bone marrow cell culture, evaluated a series of small molecule drugs using the in vitro adipogenic differentiation model of BM-MSCs, and finally focused on emodin, a natural anthraquinone derivative. Subsequently, we systematically investigated the molecular mechanism of emodin in attenuating adipogenic process by means of microarray profiling, bioinformatics analysis and lentivirus-mediated functional studies and rescue assay. RESULTS: We found that emodin presented significantly suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Further mechanistic investigation revealed that emodin could increase the expression of Tribbles homolog 3 (TRIB3) which exhibited remarkably decreased expression in AA BM-MSCs compared with the normal counterparts and was subsequently demonstrated as a negative regulator in adipogenesis of AA BM-MSCs. Besides, TRIB3 depletion alleviated the suppressive effect of emodin on the adipogenic differentiation of AA BM-MSCs. CONCLUSION: Our findings propose that emodin mediated TRIB3 up-regulation alleviates the adipogenic capacity of AA BM-MSCs, and emodin could serve as a potential therapeutic regimen for AA therapy.

Hirudin inhibit the formation of NLRP3 inflammasome in cardiomyocytes via suppressing oxidative stress and activating mitophagy.

Context: Cardiomyocyte hypertrophy due to hemodynamic overload eventually leads to heart failure. Hirudin has been widely used in the treatment of cardiovascular diseases and NLRP3 inflammasome was proven to induce cardiomyocyte pyroptosis. However, the mechanism by which it inhibits cardiomyocyte hypertrophy remains unclear. Objective: To explore the mechanism of hirudin inhibiting cardiomyocyte hypertrophy based on NLRP3 inflammasome activation and mitophagy. Materials & methods: 1 µM AngII was used for cardiac hypertrophy modeling in H9C2 cells, and cell viability was quantified by CCK-8 assay to screen the appropriate action concentrations of hirudin. After that, we cultured AngII induced-H9C2 cells for 24 h with 0, 0.3, 0.6, and 1.2 mM hirudin, respectively. Next, we marked H9C2 cells with phalloidine and observed them using fluorescence microscope. IL-1ß, IL-18, IL-6, TNF-α, ANP, BNP, ß-MHC, and mtDNA were analyzed by qRT-PCR; ROS were quantified by Flow cytometry; SOD, MDA, and GSH-Px were detected by ELISA; and proteins including NLRP3, ASC, caspase-1, pro-caspase-1, IL-1ß, IL-18, PINK-1, Parkin, beclin-1, LC3-Ⅰ, LC3-Ⅱ, p62, were quantified by western blotting. Results: It was discovered that hirudin reduced the superficial area of AngII-induced H9C2 cells and inhibited the AngII-induced up-regulation of ANP, BNP, and ß-MHC. Besides, hirudin down-regulated the expressions of NLRP3 inflammasome-related cytokines, containing IL-1ß, IL-18, IL-6, TNF-α. It also down-regulated the expression of mtDNA and ROS, decreased the expression levels of NLRP3 inflammasome activation related proteins, including NLRP3, ASC, caspase-1, pro-caspase-1, IL-1ß, IL-18; and increased the expressions of PINK-1, Parkin, beclin-1, LC3-Ⅱ/LC3-Ⅰ, p62 in AngII-induced H9C2 cells. Discussion: Hirudin promoted the process of mitophagy, inhibited the development of inflammation and oxidative stress, and inhibited the activation of the NLRP3 inflammasome and the PINK-1/Parkin pathway. Conclusion: Hirudin has the activity to suppress cardiac hypertrophy may benefit from the inhibition of NLRP3 inflammasome and activating of PINK-1/Parkin related-mitophagy.

Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes.

In China, the traditional Chinese medicine "YiSui ShenXu Granule" has been used for treating ß-thalassemia over 20 years and known to be effective in clinic. Several purified components from "YiSui ShenXu Granule" are tested in K562 cells to reveal its effect on globin expression and erythroid differentiation, and one of the purified components, emodin, was demonstrated to increase the expression of α-, ε-, γ-globin, CD235a, and CD71 in K562 cells. Moreover, the increase of their expression is emodin concentration-dependent. The mRNA and microRNA (miRNA) expression profiles are further analyzed and 417 mRNAs and 35 miRNAs with differential expression between untreated and emodin-treated K562 cells were identified. Among them, two mRNAs that encode known positive regulators of erythropoiesis, ALAS2, and c-KIT respectively, increased during emodin-induced K562 erythroid differentiation, meanwhile, two negative regulators, miR-221 and miR-222, decreased during this process. These results indicate that emodin can improve the expression of globin genes in K562 cells and also induce K562 cells to erythroid differentiation possibly through up-regulating ALAS2 and c-KIT and down-regulating miR-221 and miR-222.

Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia.

Metabolism under hypoxia is significantly different from that under normoxia. It has been well elucidated that HIF-1 (hypoxia-inducible factor-1) plays a central role in regulating glucose metabolism under hypoxia; however, the role of HIF-1 in lipid metabolism has not yet been well addressed. In the present study we demonstrate that HIF-1 promotes LDL (low-density lipoprotein) and VLDL (very-LDL) uptake through regulation of VLDLR (VLDL receptor) gene expression under hypoxia. Increased VLDLR mRNA and protein levels were observed under hypoxic or DFO (deferoxamine mesylate salt) treatment in MCF7, HepG2 and HeLa cells. Using dual-luciferase reporter and ChIP (chromatin immunoprecipitation) assays we confirmed a functional HRE (hypoxia-response element) which is localized at +405 in exon 1 of the VLDLR gene. Knockdown of HIF1A (the α subunit of HIF-1) and VLDLR, but not HIF2A (the α subunit of HIF-2), attenuated hypoxia-induced lipid accumulation through affecting LDL and VLDL uptake. Additionally we also observed a correlation between HIF-1 activity and VLDLR expression in hepatocellular carcinoma specimens. The results of the present study suggest that HIF-1-mediated VLDLR induction influences intracellular lipid accumulation through regulating LDL and VLDL uptake under hypoxia.

Material basis and integrative pharmacology of danshen decoction in the treatment of cardiovascular diseases.

BACKGROUND: Cardiovascular diseases (CVDs) are among the primary and predominant threats to human health with increasing incidence. Danshen Decoction (DSD) as an adjuvant therapy can benefit CVDs patients by improving clinical efficacy. PURPOSE: The purpose of this study was to identify the active components and potential pharmacological mechanisms of DSD by combining mass spectrometry with a network pharmacology strategy and to review the use of DSD in the treatment of CVDs. METHOD: First, the composition of DSD was analyzed by ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). Second, the network pharmacology method was used to elucidate the underlying material basis and possible pharmacological mechanism of DSD for the treatment of CVDs. Finally, clinical and experimental studies on DSD in the past ten years were retrieved from the PubMed and CNKI database, and the content of these studies was used to summarize the latest progress in DSD treatment of CVDs. OUTCOME: A total of 35 compounds were found in DSD by manual identification from the analysis of MS, which may be the material basis for the therapeutic effect of DSD. After taking the intersection of 2086 targets related to CVDs, these 35 compounds are considered to play a role in the treatment of CVDs through 210 targets including signal transducer and activator of transcription 3 (STAT3), sarcoma (SRC) and phosphoinositide-3-kinase regulatory subunit (PIK3R), and a total of 168 signaling pathways were involved in the regulation of CVDs by DSD, including PI3K-AKT signaling pathway, Alzheimer disease, and Rap1 signaling pathway. A total of 29 clinical studies using DSD in the treatment of CVDs were included in the literature review, and these studies showed the positive significance of DSD as adjuvant therapy, while 14 experimental studies included in the literature review also demonstrated the effectiveness of DSD in the treatment of CVDs. CONCLUSION: DSD plays a role in the treatment of CVDs through a variety of active ingredients. Large-scale clinical research and more in-depth experimental research will help to further reveal the mechanism of DSD in the treatment of CVDs.

Clinical effect of Danshen decoction in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The incidence of heart failure (HF) is increasing year by year, posing a great threat to human health. Although pharmacotherapy has been able to significantly prolong patient survival, pharmacotherapy for HF still has limitations due to its complex pathogenesis and considerable individual variability, there is a great need to explore complementary and alternative therapies to slow down the progression of HF. Danshen decoction is used to treat several cardiovascular diseases including HF, but the efficacy of stabilization is uncertain. This meta-analysis evaluated the clinical efficacy of Danshen Decoction for the treatment of HF. METHODS: The registration number assigned to this meta-analysis on the PROSPERO platform is CRD42022351918. Four databases were searched, and randomized controlled trials (RCTs) of Danshen decoction combined with conventional treatment (CT) of HF were screened, CT included medical treatments other than Danshen Decoction to which the patient was treated (including but not limited to angiotensin converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor neprilysin inhibitors, ß-blockers, diuretics, mineralcorticoid recept antagonist etc.). The clinical efficacy rate (CER), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), brain natriuretic peptide (BNP), N-terminal pro-B type natriuretic peptide (NT-proBNP) and hypersensitive C-reactive protein (hs-CRP) were included as outcome indicators. The GRADE grading scale was used to grade the above indicators. The Cochrane risk-of-bias tool and the Jadad quality scale were used to assess the methodological quality of RCTs. Finally, RevMan V.4.5 software was used for data synthesis, 95% confidence intervals (CI) for dichotomous data, risk ratios (RR), and mean differences (MD) for continuous variables were calculated, Chi-square and I2 were used for heterogeneity assessment. RESULTS: Nine RCTs with a total of 855 patients were included in this study, and all included RCTs had a low overall quality risk of bias and high quality of reported information. The results of the meta-analysis showed that compared with the use of CT, CER (%) was significantly improved due to Danshen decoction combined with CT (MD = 3.95, 95% CI [2.58, 6.04], P < 0.00001), LVEF (%) was significantly improved (MD = 5.46, 95% CI [5.32, 5.60], P < 0.00001), LVEDD (mm) was significantly reduced (MD = -5.27, 95% CI [-6.21, -4.32], P < 0.00001), LVESD (mm) was significantly reduced (MD = -4.60, 95% CI [-5.87, -3.32], P < 0.00001), BNP (pg/mL) was significantly reduced (MD = -88.61, 95% CI [-121.98, -55.24], P < 0.00001), NT-proBNP (pg/mL) was significantly decreased (SMD = -3.33, 95% CI [-5.92, -0.73], P = 0.01), hs-CRP (mg/L) was significantly decreased (MD = -2.73, 95% CI [-4.11, -1.34], P = 0.0001). The quality of the GRADE evidence for all outcomes was moderate to low and no RCTs reported adverse events. CONCLUSION: Our research demonstrates that Danshen decoction is an effective and safe treatment option for HF. Nevertheless, considering the limitations of methodological and the quality of RCTs, more rigorous, large-scale, multicenter randomized clinical trials are needed to further evaluate the efficacy and safety of Danshen decoction in the treatment of HF patients.

Zhilong Huoxue Tongyu capsule inhibits rabbit model of hyperlipidemia and atherosclerosis through NF-κB/NLRP3 signaling pathway.

Objective: Zhilong Huoxue Tongyu capsule (ZL) is a Chinese patent medicine for treating cardio-cerebral diseases. However, the pharmacological mechanism by which it regulates blood lipids and treats atherosclerosis (AS) is unclear. Therefore, the purpose of this study is to explore the mechanism of ZL inhibiting hyperlipidemia and treating AS through NF-κB/NLRP3 signaling pathway. Methods: Fifty New Zealand white rabbits were divided into control, model, model + ZL (3.12 g/kg/d, i.g.), model + atorvastatin (0.51 mg/kg/d, i.g.), and model + ZL + atorvastatin groups. Except for the control group, all other groups underwent carotid intima air drying and received a high-fat diet for 28 days to establish hyperlipidemia AS model, and drug treatment was given for the same period of time after modeling. Pathological changes and blood lipids were detected, NF-κB/NLRP3-related protein or gene expression levels were analyzed in carotid tissue. Results: ZL significantly reduced blood lipids and delayed the progression of AS. TC, TG, and LDL-C were decreased while HDL-C was increased in blood, IMT thickening and plaque formation of carotid arteries were inhibited, VRI was alleviated, and pathological features were improved. NF-κB, NLRP3 and IL-1ß in the carotid artery were significantly down-regulated after intervention with ZL. RT-PCR and western blot analysis showed that NF-κB (p-NF-κB), NLRP3, caspase-1, IL-1ß and IL-18 were significantly downregulated by ZL. Conclusions: ZL can be used effectively as adjuvant therapy for hyperlipidemia and AS, combining it with atorvastatin yielded more optimized efficacy, but its anti-inflammatory and pharmacological mechanisms of inhibiting pyroptosis should be studied further.

Chidamide suppresses adipogenic differentiation of bone marrow derived mesenchymal stem cells via increasing REEP2 expression.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation at the expense of osteogenesis has been implicated in obesity, diabetes, and age-related osteoporosis as well as various hematopoietic disorders. Defining small molecules with role in rectifying the adipo-osteogenic differentiation imbalance is of great significance. Here, we unexpectedly found that Chidamide, a selective histone deacetylases inhibitor, exhibited remarkably suppressive effect on the in vitro induced adipogenic differentiation of BM-MSCs. Multifaceted alterations in the spectrum of gene expression were observed in Chidamide-managed BM-MSCs during adipogenic induction. Finally, we focused on REEP2, which presented decreased expression in BM-MSCs-mediated adipogenesis and was restored by Chidamide treatment. REEP2 was subsequently demonstrated as a negative regulator of adipogenic differentiation of BM-MSCs and mediated the suppressive effect of Chidamide on adipocyte development. Our findings provide the theoretical and experimental foundation for the clinical application of Chidamide for disorders associated with excessive marrow adipocytes.

Apicidin confers promising therapeutic effect on acute myeloid leukemia cells via increasing QPCT expression.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by abnormal cell proliferation, apoptosis repression and myeloid differentiation blockade of hematopoietic stem/progenitor cells. Developing and identifying novel therapeutic agents to reverse the pathological processes of AML are of great significance. Here in this study, we found that a fungus-derived histone deacetylase inhibitor, Apicidin, presents promising therapeutic effect on AML by inhibiting cell proliferation, facilitating apoptosis and inducing myeloid differentiation of AML cells. Mechanistic investigation revealed that QPCT is identified as a potential downstream target of Apicidin, which exhibits significantly decreased expression in AML samples compared with the normal controls and is remarkably up-regulated in AML cells upon Apicidin management. Functional study and rescue assay demonstrated that QPCT depletion further promotes cell proliferation, inhibits apoptosis and impairs myeloid differentiation of AML cells, alleviating the anti-leukemic effect of Apicidin on AML. Our findings not only provide novel therapeutic target for AML, but also lay theoretical and experimental foundation for the clinical application of Apicidin in AML patients.

A classical herbal formula alleviates high-fat diet induced nonalcoholic steatohepatitis (NASH) via targeting mitophagy to rehabilitate dysfunctional mitochondria, validated by UPLC-HRMS identification combined with in vivo experiment.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) has caused a significant burden on public health care systems, the economy and society. However, there has still been no officially approved pharmacotherapy for NASH. It has been suggested that oxidative stress and mitochondrial dysfunction play vital roles in NASH pathological progression. Shugan Xiaozhi (SG) formula, as a kind of classical herbal formula, was shown to attenuate NASH. PURPOSE: This study aimed to explore the potential mechanisms of SG formula treating NASH. STUDY DESIGN AND METHODS: Ultra-high-performance liquid chromatography-high resolution mass spectrometry combined with bioinformatics analysis was applied to explore the therapeutic targets and main components of SG formula. Moreover, in vivo NASH model was utilized to confirmed the therapeutic effects of SG formula. Molecular docking analysis and further validation experiments were conducted to verify the results of bioinformatics analysis. RESULTS: The in vivo experiments confirmed SG formula significantly attenuated hepatic pathological progression and relieved oxidative stress in high-fat diet (HFD) induced - NASH model. Ultra-high-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) combined with bioinformatics analysis expounded the components of SG formula and revealed the mitochondrial regulation mechanism of SG formula treating NASH. Further in vivo experiments validated that SG formula could alleviate oxidative stress by rehabilitating the structure and function of mitochondria, which was strongly related to regulating mitophagy. CONCLUSION: In summary, this study demonstrated that SG formula, which could attenuate NASH by regulating mitochondria and might be a potential pharmacotherapy for NASH.