Huoxue Qianyang Qutan Recipe Protects against Early Renal Damage Induced by Obesity-Related Hypertension via the SIRT1/NF-κB/IL-6 Pathway: Integrating Network Pharmacology and Experimental Validation-Based Strategy.

Obesity is recognized as not only a major contributing factor to cardiovascular diseases but also an independent risk factor for end-stage renal disease. Previous studies have found that Huoxue Qianyang Qutan Recipe (HQQR) could reduce urinary microalbumin in patients with obesity-related hypertension (OBH). However, the renal protective activity of HQQR in OBH and its molecular targets involved remains ambiguous. In this work, we investigate the mechanism of HQQR against OBH-induced early renal damage using integrating network pharmacology and experimental validation-based strategy. First, via network pharmacology, IL-6 is identified as one of the key targets of HQQR against early renal damage in hypertension, and inhibition of inflammation is a crucial process. Second, in in vivo experiments, HQQR can lower blood pressure, lose weight, and restore metabolic abnormalities in OBH rats, which could be associated with the effects on protecting early renal damage. Finally, in the mechanism, HQQR increases SIRT1 mRNA and protein expression consistent with reduction of NF-κB acetylation and suppressed the p65-mediated inflammatory signaling pathway. As a result, HQQR robustly inhibits OBH-induced renal inflammation by reducing IL-6 mRNA and protein levels in the renal tissue and the release of IL-6 in serum of OBH rats. This study aims to provide a multimethod (network pharmacology-animal experiment) and multilevel (component-target-pathway) strategy for the prevention and treatment of OBH-induced target organ damage by traditional Chinese medicine.

Modified Yuejuwan Inhibited Cholesterol Accumulation and Inflammation in THP-1 Macrophage-Derived Foam Cells by Inhibiting the Activity of the TRIM37/TRAF2/NF-κB Pathway.

Background: This study aimed to explore the function of modified Yuejuwan (MYJ) on THP-1 macrophage-derived foam cells. Methods: First, human THP-cells were obtained, and then, grouping was made to the following: control group, foaming group, foaming group +0.2 mg/mL Jiawei Yueju pill, foaming group +0.5 mg/mL Jiawei Yueju pill, and foaming group +1 mg/mL Jiawei Yueju pill. An Oil Red O staining assay was used to examine the uptake of oxidatively modified low-density lipoprotein (oxLDL). The secretion of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were determined using an enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (qRT-PCR) and Western blot were used to quantify genes and proteins expression levels. Results: Our results indicated that MYJ inhibited the accumulation of total cholesterol (TC), free cholesterol (FC), and cholesteryl ester (CE) in foam cells. Moreover, the secretion of IL-1ß and TNF-α also downregulated in foam cells after treatment of MYJ. Furthermore, we found that tripartite motif-containing 37 (TRIM37) was significantly upregulated in foam cells. Knockdown of TRIM37 promoted cholesterol efflux and presented an anti-inflammation effect in foam cells. Furthermore, TRIM37 positively mediated the translocation of NF-κB to nuclear. It negatively regulated its ubiquitination in foam cells after interacting with TRAF2. Importantly, MYJ profoundly suppressed the function of TRIM37 in foam cells and functioned as a TRIM37 inhibitor. Conclusions: This study demonstrated that MYJ might alleviate oxLDL-induced foam cell formation by inhibiting the TRIM37/TRAF2/NF-κB pathway activity. MYJ was a potential agent in preventing atherosclerosis and indicated its potential signaling pathway in foam cells.

The efficacy of ginseng-containing traditional Chinese medicine in patients with acute decompensated heart failure: A systematic review and meta-analysis.

Objective: To evaluate the efficacy of ginseng-containing traditional Chinese medicine (TCM) for acute decompensated heart failure (ADHF). Methods: Seven databases were included from establishment until 10 July 2022. Pooled data were analyzed with random-effects model. The risk of bias was measured by the risk of bias tool for randomized trials (RoB 2). Modified Jadad scale score was used to assess the quality of including studies. The meta-analysis was performed with RevMan 5.3. Trial sequential analysis was assessed to avoid type I errors. We have registered our protocol in PROSPERO (CRD42021267742). Results: Twenty-eight articles were included. The results demonstrated that compared with conventional western therapy (WT), ginseng-containing TCM combined with WT further improved clinical efficacy (RR: 1.25, 95% CI: 1.20-1.29, p < 0.00001, I2 = 8%), left ventricular ejection fraction (LVEF) (MD: 5.80, 95% CI: 4.86-6.74, p < 0.00001, I2 = 89%), stroke volume (MD: 13.80, 95% CI: 12.66-14.95, p < 0.00001, I2 = 93%), 6-min walk test (MD: 53.03, 95% CI: 20.76-85.29, p = 0.001, I2 = 97%), decreased 6-month rehospitalization (RR: 0.44, 95% CI: 0.18-1.11, p = 0.08, I2 = 0%), brain natriuretic peptide (MD: 188.12, 95% CI: 248.13 to -128.11, p < 0.00001, I2 = 94%), N-terminal pro-B-type natriuretic peptide (MD = -503.29; 95% CI: 753.18 to -253.40, p < 0.0001, I2 = 89%) and Minnesota living heart failure questionnaire scores (MD: 9.68, 95% CI: 13.67 to -5.70, p < 0.00001, I2 = 83%). The ROB2 assessment and modified Jaded scores showed most studies included were with some concerns. Conclusion: Compared with WT alone, ginseng-containing TCM is a possible way to benefit ADHF patients. However, limited by the quality of including trials, more high-quality studies are needed to provide reliable evidence.

Huoxue Qianyang Qutan recipe attenuates cardiac fibrosis by inhibiting the NLRP3 inflammasome signalling pathway in obese hypertensive rats.

CONTEXT: HuoXue QianYang QuTan Recipe (HQQR) is used to manage hypertension and cardiac remodelling, but the mechanism is elusive. OBJECTIVE: To determine the mechanism of HQQR on obesity hypertension (OBH)-related myocardial fibrosis. MATERIALS AND METHODS: OBH models were prepared using spontaneously hypertensive rats (SHRs) and divided (n = 6) into saline, low-dose (19.35 g/kg/d) HQQR, high-dose (38.7 g/kg/d) HQQR, and valsartan (30 mg/kg/d) groups for 10 weeks. Systolic blood pressure (SBP), and Lee's index were measured. Heart tissues were examined by histology. HQQR's effects were examined on cardiac fibroblasts (CFs) stimulated with angiotensin II and treated with HQQR, a caspase-1 inhibitor, siNLRP3, and oeNLRP3. RESULTS: HQQR(H) reduced SBP (201.67 ± 21.00 vs. 169.00 ± 10.00), Lee's index (321.50 ± 3.87 vs. 314.58 ± 3.88), and left ventricle mass index (3.26 ± 0.27 vs. 2.71 ± 0.12) in vivo. HQQR reduced percentage of fibrosis area (18.99 ± 3.90 vs. 13.37 ± 3.39), IL-1ß (10.07 ± 1.16 vs. 5.35 ± 1.29), and inhibited activation of NLRP3/caspase-1/IL-1ß pathway. HQQR also inhibiting the proliferation (1.09 ± 0.02 vs. 0.84 ± 0.01), fibroblast to myofibroblast transition (14.74 ± 3.39 vs. 3.97 ± 0.53), and collagen deposition (Col I; 0.50 ± 0.02 vs. 0.27 ± 0.05 and Col III; 0.48 ± 0.21 vs. 0.26 ± 0.11) with different concentrations selected based on IC50 in vitro (all ps < 0.05). NLRP3 interference further confirmed HQQR inhibiting NLRP3 inflammasome signalling. CONCLUSION: HQQR blunted cardiac fibrosis development in OBH and suppressed CFs proliferation by directly interfering with the NLRP3/caspase-1/IL-1ß pathway.

Shengxian decoction decreases doxorubicin­induced cardiac apoptosis by regulating the TREM1/NF­κB signaling pathway.

Shengxian decoction (SXT) is a traditional Chinese medicine that is clinically used for treating cardiovascular diseases. It is known for its beneficial effect on cardiomyocyte injuries, some of which can be induced by anticancer agents including doxorubicin (DOX). To determine the molecular mechanisms involved in the cardioprotective effects of SXT, DOX­induced H9c2 cells were analyzed for apoptosis and expression levels of apoptosis biomarkers. Cell viability and apoptosis were measured by CCK­8 and flow cytometry. Triggering receptors expressed on myeloid cells 1 (TREM1), cleaved caspase­3, survivin and NF­κBp65 expression levels were measured by reverse transcription­quantitative PCR and/or western blotting. A total of 30 adult male Sprague­Dawley rats were randomly allocated into five groups (n=6 each); control group receiving 0.9% saline, 1 DOX group receiving 2.5 mg/kg of DOX and 3 DOX + SXT groups, receiving a DOX dose equivalent to the DOX­only group and either 0.4, 0.8 or 1.6 g/kg of SXT. It was found that DOX increased apoptosis and NF­κB activation of H9c2 cells by increasing TREM1 expression and that SXT inhibited apoptosis and NF­κB activation of H9c2 cells induced by DOX or Trem1 overexpression. SXT also significantly reversed DOX­induced cardiotoxicity in rats. The results suggested that the protective effects of SXT against DOX­induced apoptosis may be attributed to its downregulation of TREM1.

Huoxue Qianyang decoction ameliorates cardiac remodeling in obese spontaneously hypertensive rats in association with ATF6-CHOP endoplasmic reticulum stress signaling pathway regulation.

OBJECTIVE: Endoplasmic reticulum (ER) stress is involved in hypertension related cardiac remodeling. We aimed to evaluate the effects of Huoxue Qianyang (HXQY) decoction on cardiac remodeling in obese spontaneously hypertensive rats (SHRs), and explore its impacts on the activating transcription factor 6 (ATF6)-C/EBP homologous protein (CHOP) ER stress signaling pathway. METHODS: Twenty-seven obese SHRs were randomly divided into Obese SHR, Obese SHR + HXQY and Obese SHR + Valsartan groups, and treated with the indicated drugs for 8 weeks. Nine age-matched male SHRs were used as controls. Systolic blood pressure (SBP), body weight (BW), and the left ventricular mass index (LVMI) were measured weekly or at end point. Then, angiotensin II (Ang II), fasting glucose (FPG) and fasting insulin (FIN), total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglyceride (TG) levels were evaluated with commercial kits. Apoptotic cardiomyocytes were detected by the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. The expression levels of GRP78, ATF6, PERK/pPERK and CHOP were assessed by quantitative PCR and Western blot. RESULTS: Treatment with HXQY decoction resulted in significantly reduced SBP, BW, LVMI, Ang II, TC and LDL-C levels, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) score in obese SHRs. Apoptosis in heart tissues of obese SHRs was significantly attenuated after HXQY decoction administration, paralleling reduced expression of GRP78, ATF6, PERK/pPERK and CHOP at both mRNA and protein levels. CONCLUSION: Cardiac remodeling in obese SHRs is ameliorated by intervention with HXQY decoction in association with inhibited ATF6-CHOP ER stress signaling pathway.

HuoXue QianYang QuTan Recipe attenuates left ventricular hypertrophy in obese hypertensive rats by improving mitochondrial function through SIRT1/PGC-1α deacetylation pathway.

Mitochondrial dysfunction plays a vital role in the progression of left ventricular hypertrophy (LVH). Previous studies have confirmed that the disorder of SIRT1/PGC-1α deacetylation pathway aggravated mitochondrial dysfunction. HuoXue QianYang QuTan Recipe (HQQR) is a commonly used prescription that has shown therapeutic effects on obesity hypertension and its complications. However, the potential mechanisms are still unclear. In the present study, obesity hypertension (OBH) was established in rats and we investigated the efficacy and mechanisms of HQQR on LVH. Rats were divided into the five groups: (1) WKY-ND group, (2) SHR-ND group, (3) OBH-HF group, (4) OBH-HF/V group and (5) OBH-HF/H group. We evaluated body weight, Lee index and blood pressure (BP) before and every 2 weeks after treatment. After 10 weeks of treatment, we mainly detected glycolipid metabolic index, the severity of LVH, mitochondrial function along with SIRT1/PGC-1α deacetylation pathway. Our results showed that HQQR significantly lowered body weight, Lee index, BP and improved the disorder of glycolipid metabolism in OBH rats. Importantly, we uncovered HQQR could alleviate mitochondrial dysfunction in OBH rats by regulating SIRT1/PGC-1α deacetylation pathway. These changes could be associated with the inhibition of LVH.