Qian Yang Yu Yin granule improves hypertensive renal damage: A potential role for TRPC6-CaMKKß-AMPK-mTOR-mediated autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Qian Yang Yu Yin granules (QYYYG) have a long history in the treatment of hypertensive renal damage (HRD) in China. Clinical studies have found that QYYYG stabilizes blood pressure and prevents early renal damage. However, the exact mechanism is not entirely clear. AIM OF THE STUDY: To evaluate the therapeutic effect and further explore the therapeutic mechanism of QYYYG against HRD. MATERIALS AND METHODS: The efficacy of QYYYG in treating HRD was assessed in spontaneous hypertension rats (SHR). Renal autophagy and the TRPC6-CaMKKß-AMPK pathway in rats were evaluated. The regulatory role of QYYYG in angiotensin II (Ang II) induced abnormal autophagy in rat podocytes was determined by detecting autophagy-related proteins, intracellular Ca2+ content, and the TRPC6-CaMKKß-AMPK-mTOR pathway expressions. Finally, we established a stable rat podocyte cell line overexpressing TRPC6 and used the cells to verify the regulatory effects of QYYYG. RESULTS: QYYYG alleviated HRD and reversed the abnormal expression of autophagy-related genes in the SHR. In vitro, QYYYG protected against Ang II-induced podocyte damage. Furthermore, treatment of podocytes with QYYYG reversed Ang II-induced autophagy and inhibited Ang II-stimulated TRPC6 activation, Ca2+ influx and activation CaMKKß-AMPK pathway. Overexpression of TRPC6 resulted in pronounced activation of CaMKKß, AMPK, and autophagy induction in rat podocytes, which were significantly attenuated by QYYYG. CONCLUSIONS: The present study suggested that QYYYG may exert its HRD protective effects in part by regulating the abnormal autophagy of podocytes through the TRPC6-CaMKKß-AMPK-mTOR pathway.

Meta-Analysis of Naoxintong Capsule for Patients with Vascular Dementia.

Background: Vascular dementia (VaD) is the second most common form of dementia among the elderly. There is currently no unequivocal recommendation of an effective treatment option for VaD. Objective: The purpose of this study was to evaluate the efficacy and safety of Naoxintong capsule (NXT) in the treatment of VaD patients. Methods: We searched for randomized controlled trials (RCTs) published before September 2021 in PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, and Wanfang databases. The trials assessed the efficacy and/or safety of NXT in treating patients with VaD. A meta-analysis was then performed using Stata 14.0 software. Results: A total of 33 studies comprising 2,947 patients with VaD were included in this study. The meta-analysis revealed that NXT improved cognitive function in VaD patients, increased the mini-mental state examination (MMSE) score by 3.33 points (WMD = 3.33, 95% CI (2.72, 3.94)), the Montreal Cognitive Assessment (MoCA) score by 4.31 points (WMD = 4.31, 95% CI (2.72, 5.90)), and the Hasegawa dementia scale (HDS) by 2.71 points (WMD = 2.71, 95% CI (1.26, 4.17)). Furthermore, NXT significantly improved the daily lives of VaD patients, lowering the activities of daily living (ADL) score by 5.85 points (WMD = -5.85, 95% CI (-7.03, -4.66)). NXT improved the total effective rate (TER) (OR = 2.62, 95% CI (2.09, 3.29)) of the patients without increasing the occurrence of adverse events (AEs; OR = 0.72, 95% CI (0.43, 1.22)). Subgroup analysis revealed that whether NXT was used alone or in combination with western medicine, it could enhance the overall curative effect. Conclusions: NXT may be an effective and safe treatment option for VaD. However, because of the limited number and quality of articles included, this study's findings need to be validated by additional high-quality, large-sample, and multicenter RCTs (Systematic Review Registration Number: PROSPERO; https://clinicaltrials.gov/ct2/show/CRD42021233199).

[Network Meta-analysis of oral blood-activating and stasis-removing Chinese patent medicines in treatment of hypertensive left ventricular hypertrophy].

This study was designed to assess the clinical efficacy of oral blood-activating and stasis-removing Chinese patent medicines in treating hypertensive left ventricular hypertrophy(LVH) based on network Meta-analysis. The clinical randomized controlled trials(RCTs) concerning the treatment of hypertensive LVH with oral blood-activating and stasis-removing Chinese patent medicines were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, and Cochrane Library from their inception to September 2021. Two researchers independently completed the literature screening, data extraction, and quality evaluation. The data were then analyzed by RevMan 5.3, Stata 15.1, and ADDIS 1.16.8. Finally, a total of 31 RCTs were included, involving 3 001 patients and four oral blood-activating and stasis-removing Chinese patent medicines. In terms of the alleviation of heart damage, the Chinese patent medicines combined with conventional western medicine groups were superior to the conventional western medicine groups in lo-wering the left ventricular mass index(LVMI). There was no significant difference in LVMI, left ventricular ejection fraction(LVEF), or the ratio of early diastolic peak flow velocity to late diastolic peak flow velocity(E/A) between different Chinese patent medicines combined with conventional western medicine groups. Xinnao Shutong Capsules/Tablets combined with conventional western medicine had the best efficacy in reducing LVMI and elevating LVEF, while Xinkeshu Capsules/Tablets combined with conventional western medicine had the best effect in improving E/A. In the control of blood pressure, when all Chinese patent medicines except for Xinnao Shutong Capsules/Tablets were combined with conventional western medicine, the resulting systolic blood pressure(SBP) and diastolic blood pressure(DBP) were significantly lower than those in the conventional western medicine group. Xinkeshu Capsules/Tablets combined with conventional western medicine produced the best effect in reducing SBP and DBP, followed by Xinnao Shutong Capsules/Tablets. In terms of safety, no serious adverse reactions occurred in all trials. The four oral blood-activating and stasis-removing Chinese patent medicines included in this study exhibited obvious advantages in the treatment of hypertensive LVH when they were combined with conventional western medicine, with the best effects observed in the Xinnao Shutong Capsules/Tablets combined with conventional western medicine group. However, due to the limitation of the quantity and quality of the included articles, the conclusion of this study still needs to be verified by more high-quality, multi-center, and large-sample RCTs.

[Network Meta-analysis of Chinese patent medicines of Ziziphi Spinosae Semen in treatment of primary insomnia].

To systematically evaluate the efficacy of oral Chinese patent medicines of Ziziphi Spinosae Semen in the treatment of primary insomnia by using network Meta-analysis. Nine databases(CNKI, Wanfang, VIP, CBM, PubMed, EMbase, Web of Science, Medline and Cochrane Library) were systematically and comprehensively undertaken to identify the literatures published from the establishment of each database to August, 2020. Randomized controlled trials(RCTs) on oral Chinese patent medicine of Ziziphi Spinosae Semen in the treatment of primary insomnia, either alone or in combination with conventional sedative hypnotics, were screened out according to inclusion criteria and exclusion criteria. Literature screening, data extraction and the evaluation of the risk of bias for the included studies were conducted independently by 2 researchers. Traditional Meta-analysis and Bayesian network Meta-analysis were then conducted with use of Stata 15.0 and R software. Finally, a total of 42 RCTs were included, involving 9 kinds of oral Chinese patent medicines and 4 196 patients. The results of Meta-analysis showed that(1) in terms of improving Pittsburgh sleep quality index scale score, the efficacy of the combination of drugs was significantly superior to that of sedative-hypnotics or most of Chinese patent medicines used alone, and Bailemian Capsules combined with sedative-hypnotics had the best effect; both the efficacy of Shenqi Wuweizi Tablets and Compound Zaoren Anshen Capsules alone were significantly superior to that of conventional sedative-hypnotics treatment, and Shenqi Wuweizi Tablets had the best effect.(2)In terms of safety, single use or combined use of Chinese patent medicine had a certain improvement as compared with conventional sedative-hypnotics treatment. Due to the large clinical heterogeneity, the studies could not be combined quantitatively, and no serious adverse reactions occurred in all patients enrolled in the study. The results showed that Chinese patent medicine of Ziziphi Spinosae Semen combined with conventional sedative-hypnotics could significantly improve the short-term sleep quality of patients with primary insomnia. In the comparison among single use of drugs, Shenqi Wuweizi Tablets had the largest possibility for best effect. However, the lack of evidences for international promotion, the influence of different types of sedative-hypnotics treatment and intervention time on the curative effect, and the patients' different acceptance of combined treatment should be considered before clinical application. Limited by the number and quality of the included studies, the above conclusions need to be further verified by more large sample-size and high-quality studies.

Qian Yang Yu Yin Granule Improves Renal Injury of Hypertension by Regulating Metabolic Reprogramming Mediated by HIF-1α/PKM2 Positive Feedback Loop.

Protection against hypoxia injury is an important therapeutic strategy for treating hypertensive nephropathy. In this study, the effects of Qian Yang Yu Yin granule (QYYY) on spontaneously hypertensive rats fed with high salt diet and HEK293T cells exposed to hypoxia were investigated. After eight weeks' treatment of QYYY, blood pressure, serum creatinine, serum cystatin C, blood urea nitrogen, urinary ß2-microglobulin, urinary N-acetyl-ß-glucosaminidase, and urinary microalbumin were assessed. The changes of hypoxia-inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2), glucose transport 1 (GLUT1), lactate dehydrogenase A (LDH-A), connective tissue growth factor (CTGF), transforming growth factor-ß1 (TGF-ß1), ATP, lactate, pyruvate, and pathology were also assessed in vivo. HEK293T cells pre-treated with QYYY and/or HIF-1α over expressing cells were cultured in a three gas hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 h and then the expressions of HIF-1α, PKM2, GLUT1, LDH-A, CTGF, TGF-ß1, ATP, lactate, and pyruvate were detected. Our results showed that QYYY promoted the indicators of renal inflammation and fibrosis mediated by HIF-1α/PKM2 positive feedback loop in vivo and vitro. Our findings indicated that QYYY treated hypertensive nephropathy by regulating metabolic reprogramming mediated by HIF-1α/PKM2 positive feedback loop.

Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway.

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.

Study of the active ingredients and mechanism of Sparganii rhizoma in gastric cancer based on HPLC-Q-TOF-MS/MS and network pharmacology.

Sparganii rhizoma (SL) has potential therapeutic effects on gastric cancer (GC), but its main active ingredients and possible anticancer mechanism are still unclear. In this study, we used HPLC-Q-TOF-MS/MS to comprehensively analyse the chemical components of the aqueous extract of SL. On this basis, a network pharmacology method incorporating target prediction, gene function annotation, and molecular docking was performed to analyse the identified compounds, thereby determining the main active ingredients and hub genes of SL in the treatment of GC. Finally, the mRNA and protein expression levels of the hub genes of GC patients were further analysed by the Oncomine, GEPIA, and HPA databases. A total of 41 compounds were identified from the aqueous extract of SL. Through network analysis, we identified seven main active ingredients and ten hub genes: acacetin, sanleng acid, ferulic acid, methyl 3,6-dihydroxy-2-[(2-hydroxyphenyl) ethynyl]benzoate, caffeic acid, adenine nucleoside, azelaic acid and PIK3R1, PIK3CA, SRC, MAPK1, AKT1, HSP90AA1, HRAS, STAT3, FYN, and RHOA. The results indicated that SL might play a role in GC treatment by controlling the PI3K-Akt and other signalling pathways to regulate biological processes such as proliferation, apoptosis, migration, and angiogenesis in tumour cells. In conclusion, this study used HPLC-Q-TOF-MS/MS combined with a network pharmacology approach to provide an essential reference for identifying the chemical components of SL and its mechanism of action in the treatment of GC.

Effectiveness and Safety of Oral Chinese Patent Medicines Combined with Chemotherapy for Gastric Cancer: A Bayesian Network Meta-Analysis.

OBJECTIVES: This network meta-analysis (NMA) was designed to assess the comparative effectiveness and safety of oral Chinese patent medicines combined with chemotherapy for gastric cancer on the National Basic Medical Insurance Drugs List of China. METHODS: A comprehensive literature search was performed in seven electronic databases from their inception to February 25, 2020, aiming to collect all related randomized controlled trials (RCTs) to evaluate the effectiveness and safety of oral Chinese patent medicines as an adjuvant for gastric cancer. Two researchers independently screened the literature, extracted data, and assessed the risk of bias of included studies using the Cochrane Risk of Bias Scale. NMA was then performed by using STATA 16.0 software and ADDIS 1.16.8 software. RESULTS: Finally, 30 RCTs were included, involving seven kinds of oral Chinese patent medicines, with a total of 2602 patients. For improvement of clinical efficacy, Bazhen granule combined with chemotherapy was ranked first for effectiveness, followed by the Cinobufacin capsule combined with chemotherapy and Xiao'aiping tablet combined with chemotherapy. Meanwhile, Bazhen granules combined with chemotherapy also were ranked first in reducing gastrointestinal reactions. In terms of improving performance status, the Xiao'aiping tablet was the best and significantly better than other oral Chinese patent medicines. Besides, the Zhenqi Fuzheng granule combined with chemotherapy was best for reducing the incidence of leucopenia. CONCLUSIONS: Since only one RCT of Bazhen granule was included in this study for analysis, its statistical efficiency is low. Therefore, this study recommends that the Cinobufacin capsule combined with chemotherapy should be a priority in improving clinical efficacy. In terms of improving patients' quality of life, Xiao'aiping tablet is the best choice. Safety was best for Zhenqi Fuzheng granule and Bazhen granule combined with chemotherapy. Limited by the quantity, quality, and possible bias of included studies, the above conclusions need to be further verified by more high-quality RCTs.

Danhong Injection for the Treatment of Hypertensive Nephropathy: A Systematic Review and Meta-Analysis.

OBJECTIVE: Danhong Injection (DHI) has been widely used to treat various diseases in China for many years. The objective of this systematic review was to evaluate the efficacy of DHI combined with antihypertensive drugs for treatment of hypertensive nephropathy. METHODS: Seven databases were searched from inception to September 21st, 2019. Randomized controlled trials comparing DHI combined with antihypertensive drugs versus antihypertensive drugs alone were extracted. The primary outcome was microalbuminuria (mALB). Secondary outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum creatinine (SCr). RESULTS: Fifteen studies were included in the meta-analysis, which indicated that DHI combined with antihypertensive drugs has advantages compared with antihypertensive drugs alone for reducing mALB [weighted mean difference (WMD) = -12.86, 95% confidence interval (CI) (-14.72, -11.0), P < 0.01], lowering SBP [WMD = -2.84, 95% CI (-4.56, -1.12), P = 0.001] and DBP [WMD = -2.38, 95% CI (-4.34, -0.43), P = 0.017], and decreasing SCr [WMD = -40.45, 95% CI (-55.69, -25.21), P < 0.01]. CONCLUSION: The combination of DHI with antihypertensive drugs appears to be more effective than antihypertensive drugs alone for treatment of hypertensive nephropathy. A moderate duration (≤4 weeks) of DHI administration is reasonable, and longer treatment with DHI should be avoided, according to the results of subgroup analysis.