Exploring the inflammation-related mechanisms of Lingguizhugan decoction on right ventricular remodeling secondary to pulmonary arterial hypertension based on integrated strategy using UPLC-HRMS, systems biology approach, and experimental validation.

BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF. STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD. RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE. CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.

Mechanism of Zhenwu Decoction modulating TLR4/NF-κB/HIF-1α loop through miR-451 to delay renal fibrosis in type 2 CRS.

BACKGROUND: Type 2 cardiorenal syndrome (CRS) is a progressive renal insufficiency in patients with chronic heart failure, but its pathophysiology is still unclear. The Chinese medicine Zhenwu Decoction plays an important role in the prevention and treatment of 2-CRS, however, its mechanism of action remains unknown. PURPOSE: The aim of this study was to investigate whether the ameliorative effect of ZWD on 2-CRS renal fibrosis is related to the modulation of miR-451 expression and thus mediating the TLR4/NF-κB/HIF-1α loop. STUDY DESIGN AND METHODS: A type 2 CRS rat model was constructed using ligation of the left anterior descending branch of the coronary artery + 3/4 nephrectomy, and randomly divided into Control, Sham, Model, Captopril, ZWD-L, ZWD-M and ZWD-H groups.After 4 weeks of ZWD intervention, its effects on cardiac and renal functions of type 2 CRS rats were observed by hematuria and cardiac ultrasonography. Changes in kidney tissue morphology were observed by HE, Masson and PASM staining. The protein and mRNA expression of TLR4, NF-κB, HIF-1α and IκBα in kidney tissues were detected by immunohistochemistry and qPCR. Immunofluorescence was used to detect the protein expression of NF-κB and HIF-1α in renal tissues. Western blot and qPCR were used to detect the protein expression of MCP-1, ICAM-1, IL-1ß, IL-6, TGF-ß, α-SMA, FN, Smad2, Smad3, and E-cadherin in renal tissues. PCR was used to detect the protein expression of miR-451mRNA expression level in kidney tissues. RESULTS: In this study, we found that ZWD was able to reduce the expression of Scr, BUN, NT-proBNP, and 24-hour quantitative urine protein, elevate LVEF, FS, CO, and reduce the level of LVIDS in type 2 CRS rats, as well as attenuate renal interstitial fibrosis and improve tubular swelling. In addition, Zhenwu Decoction up-regulated the expression of miR-451 in renal tissues and inhibited the expression of TLR4, NF-κB, and HIF-1α proteins and genes, which in turn inhibited the expression of inflammatory factors and fibrosis-related factors. CONCLUSION: ZWD was able to up-regulate the expression of miR-451 in renal tissues, inhibit the TLR4/NF-κB/HIF-1α response loop, and then inhibit the expression of inflammatory factors and fibrosis-related factors, improve renal fibrosis, and delay the pathological process of type 2 CRS.

Prediction and Interpretability of Melting Points of Ionic Liquids Using Graph Neural Networks.

Ionic liquids (ILs) have wide and promising applications in fields such as chemical engineering, energy, and the environment. However, the melting points (MPs) of ILs are one of the most crucial properties affecting their applications. The MPs of ILs are affected by various factors, and tuning these in a laboratory is time-consuming and costly. Therefore, an accurate and efficient method is required to predict the desired MPs in the design of novel targeted ILs. In this study, three descriptor-based machine learning (DBML) models and eight graph neural network (GNN) models were proposed to predict the MPs of ILs. Fingerprints and molecular graphs were used to represent molecules for the DBML and GNNs, respectively. The GNN models demonstrated performance superior to that of the DBML models. Among all of the examined models, the graph convolutional model exhibited the best performance with high accuracy (root-mean-squared error = 37.06, mean absolute error = 28.79, and correlation coefficient = 0.76). Benefiting from molecular graph representation, we built a GNN-based interpretable model to reveal the atomistic contribution to the MPs of ILs using a data-driven procedure. According to our interpretable model, amino groups, S+, N+, and P+ would increase the MPs of ILs, while the negatively charged halogen atoms, S-, and N- would decrease the MPs of ILs. The results of this study provide new insight into the rapid screening and synthesis of targeted ILs with appropriate MPs.

Blood urea nitrogen to creatinine ratio and long-term survival in patients with chronic heart failure.

OBJECTIVES: To explore the correlation between Blood urea nitrogen to creatinine ratio (BUN/Scr ratio) and prognosis of patients with chronic heart failure complicated with renal injury. METHODS: A retrospective analysis of 504 patients hospitalized in Guang 'anmen Hospital, Chinese Academy of Traditional Chinese Medicine from March 2006 to June 2014 was conducted. The baseline data were analyzed, and the cutoff value was obtained by receiver operator characteristic curve (ROC) analysis, according to the cutoff value, all the participants were divided into two groups, BUN/Scr < 19.37 group (280 cases) and BUN/Scr ≥ 19.37 group (224 cases). The main end point was defined as all-cause death. The long-term mortality of the two groups was evaluated, and Kaplan-Meier survival curve was drawn. Univariate analysis was performed on all the variables affecting the patient's prognosis, and the variables with P < 0.05 were put into Cox regression model, and subgroup analysis was performed on the variables that might affect the patient's prognosis. RESULTS: The baseline data of 504 patients were analyzed and found that the median follow up was 683. Through ROC analysis of 504 subjects, the cutoff value of BUN/Scr was 19.37. The results of Kaplan-Meier survival curve showed that the mortality rate of patients with ratio ≥ 19.37 was higher than that of patients with ratio < 19.37. After multivariate analysis, COX regression model showed that the mortality of patients with BUN/Scr ≥ 19.37 was 1.885 times that of patients with BUN/Scr < 19.37 [HR = 1.885 (1.298-2.737), P = 0.001]. Subgroup analysis showed that the relationship between BUN/Scr and the prognosis of CHF was influenced by NYHA and eGRF (P < 0.05). CONCLUSIONS: BUN/Scr ratio is related to the poor prognosis of patients with CHF, and is an independent predictor of all-cause death.

Qi-Po-Sheng-Mai granule ameliorates Ach-CaCl2 -induced atrial fibrillation by regulating calcium homeostasis in cardiomyocytes.

BACKGROUND: Atrial fibrillation (AF) is one of the most common arrhythmias encountered in clinical settings. Currently, the pathophysiology of AF remains unclear, which severely limits the effectiveness and safety of medical therapies. The Chinese herbal formula Qi-Po-Sheng-Mai Granule (QPSM) has been widely used in China to treat AF. However, its pharmacological and molecular mechanisms remain unknown. PURPOSE: The purpose of this study was to investigate the molecular mechanisms and potential targets of QPSM for AF. STUDY DESIGN AND METHODS: The AF model was induced by Ach (66 µg/ml) and CaCl2 (10 mg/kg), and the dose of 0.1 ml/100 g was injected into the tail vein for 5 weeks. QPSM was administered daily at doses of 4.42 and 8.84 g/kg, and amiodarone (0.18 g/kg) was used as the positive control. The effect of QPSM on AF was assessed by electrocardiogram, echocardiography, and histopathological analysis. Then, we employed network pharmacology with single nucleus RNA sequencing (snRNA-Seq) to investigate the molecular mechanisms and potential targets of QPSM for AF. Furthermore, high performance liquid chromatography (HPLC) method was used for component analysis of QPSM, and molecular docking was used to verify the potential targets. Using the IonOptix single cell contraction and ion synchronization test equipment, single myocyte length and calcium ion variations were observed in real time. The expression levels of calcium Transporter-related proteins were detected by western blot and immunohistochemistry. RESULTS: Based on an Ach-CaCl2-induced AF model, we found that QPSM treatment significantly reduced atrial electrical remodeling-related markers, such as AF inducibility and duration, and attenuated atrial dilation and fibrosis. Network pharmacology identified 52 active ingredients and 119 potential targets for QPSM in the treatment of AF, and 45 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched, among which calcium pathway had the greatest impact. Using single nucleus sequencing (snRNA-seq), we identified cardiomyocytes as the most differentially expressed in response to drug treatment, with nine differentially expressed genes enriched in calcium signaling pathways. High performance liquid chromatography and molecular docking confirmed that the core components of QPSM strongly bind to the key factors in the calcium signaling pathway. Additional experiments have shown that QPSM increases calcium transients (CaT) and contractility in the individual cardiomyocyte. This was accomplished by increasing the expression of CACNA1C and SERCA2a and decreasing the expression of CAMK2B and NCX1. CONCLUSION: The present study has systematically elucidated the role of QPSM in maintaining calcium homeostasis in cardiomyocytes through the regulation of calcium transporters, which could lead to new drug development ideas for AF.

Effects of garlic supplementation on components of metabolic syndrome: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

BACKGROUND: Garlic (Allium sativum), the underground bulb of the Allium genus, has been consumed on Earth for thousands of years. Many clinical trials of garlic supplementation on components of metabolic syndrome (MetS) have emerged in recent years, but there is no consensus on the effect. This meta-analysis aimed at systematically evaluating the effect of garlic supplementation on components of MetS. METHODS: In this meta-analysis, we searched Pubmed, Embase, Cochrane, Medline, Web of Science databases, and clinical trials online sites from inception to November 1, 2022, with language restrictions to English. We engaged participants > 18 years and eligible for the clinical diagnosis of MetS or those with metabolic disorders and garlic was the only intervention. Outcomes included waist circumference, and body mass index, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, and fasting blood glucose. Meta-regression and subgroup analyses were conducted based on six covariates (total sample size, the mean age, the mean dose, the duration of intervention, the oral form of garlic, and the dietary intervention). RESULTS: Results from 19 RCTs were included engaging 999 participants. Compared to placebo, garlic significantly reduced TG [SMD (95%CI) = -0.66 (-1.23, -0.09)], TC [SMD (95%CI) = -0.43 (-0.86, -0.01)], LDL [SMD (95%CI) = -0.44(-0.88, -0.01)], DBP [SMD (95%CI) = -1.33 (-2.14, -0.53)], BMI [SMD (95%CI) = -1.10(-1.90, -0.20)], and WC [SMD (95%CI) = -0.78(-1.09, -0.47)]. Meta-regression showed age and sample size are potential effect modifiers. CONCLUSION: According to the results of meta-analysis, the modulatory effect of garlic on some MetS components is evident. More high-quality, large-scale RCTs are needed to confirm iat based on the high heterogeneity and potential publication bias of the current data. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=373228 , ID: CRD42022373228.

Renal fibrosis in type 2 cardiorenal syndrome: An update on mechanisms and therapeutic opportunities.

Cardiorenal syndrome (CRS) is a state of coexisting heart failure and renal insufficiency in which acute or chronic dysfunction of the heart or kidney lead to acute or chronic dysfunction of the other organ.It was found that renal fibrosis is an important pathological process in the progression of type 2 CRS to end-stage renal disease, and progressive renal impairment accelerates the deterioration of cardiac function and significantly increases the hospitalization and mortality rates of patients. Previous studies have found that Hemodynamic Aiteration, RAAS Overactivation, SNS Dysfunction, Endothelial Dysfunction and Imbalance of natriuretic peptide system contribute to the development of renal disease in the decompensated phase of heart failure, but the exact mechanisms is not clear. Therefore, in this review, we focus on the molecular pathways involved in the development of renal fibrosis due to heart failure and identify the canonical and non-canonical TGF-ß signaling pathways and hypoxia-sensing pathways, oxidative stress, endoplasmic reticulum stress, pro-inflammatory cytokines and chemokines as important triggers and regulators of fibrosis development, and summarize the therapeutic approaches for the above signaling pathways, including SB-525334 Sfrp1, DKK1, IMC, rosarostat, 4-PBA, etc. In addition, some potential natural drugs for this disease are also summarized, including SQD4S2, Wogonin, Astragaloside, etc.

Research trends and hotspots evolution of cardiac amyloidosis: a bibliometric analysis from 2000 to 2022.

In the new century, cardiac amyloidosis has received more attention from many countries and institutions, leading to innovations in the essence of the pathology, biological markers, noninvasive tests, and staging diagnoses and treatments for this disease. However, few reviews have summarized the research trends and hotspots in cardiac amyloidosis. Bibliometrics analysis is a statistically based approach to research that visualizes the contributions of academic institutions and changes in research hotspots. Therefore, in this paper, we used Citespace and VOSviewer software to conduct co-occurrence analysis and collaborative network analysis on the countries, institutions, and authors in the articles related to cardiac amyloidosis since the new century. And further find out burst keywords and references to obtain the research history, disciplinary development, and new hotspots and topics.

Frontier and Hotspot Evolution in Cardiorenal Syndrome: A Bibliometric Analysis From 2003 to 2022.

In the last 20 years, the cardiorenal syndrome (CRS) field has received growing attention. There have been innovations in cardiorenal interaction patterns, biological markers and management of CRS, and even significant changes in its concept and the paradigm of CRS pathophysiology, which considerably increases the difficulties in understanding and in-depth study of this field. However, few study summarized the development process of CRS and critical issues. This review focuses on topical evolutions and emerging trends in CRS pathophysiology, diagnostic pathways, and treatment strategies. A quantitative retrospective analysis, visual review, and evaluation of 1452 articles published in the domain of CRS from 2003 to 2022 was conducted using a bibliometric analysis based on the classic CiteSpace and VOSviewer software rather than a general review, aiming to provide reasonable ideas and directions for future research on CRS.

Opportunities and Challenges in Cardio-Oncology: A Bibliometric Analysis From 2010 to 2022.

Cardio-oncology has grown rapidly worldwide as an emerging interdisciplinary discipline over the past decade. In the present bibliometric review, we employed VOSviewer and Citespace software to describe the literature landscape concerning cardio-oncology from 2010 to 2022. As a result, a total of 1,194 relevant publications were identified in the Web of Science database with an increasing trend. The United States dominated the field during the research period, and Italy, England and Canada had emerged as significant contributors to the study. Ky. Bonnie, Herrmann. Joerg and Fradley. Michael G were the most productive researchers. JACC: CardioOncology was the journal dedicated to the discipline of cardio-oncology and had published the greatest number of papers. Vascular disease and atrial fibrillation have attracted much attention as the main cardiovascular burden. Immune checkpoint inhibitor-specific cardiovascular toxicity, biomarkers and imaging examination together with the prevention of cardio-oncology are potential research hotspots. Notably, basic research is lagging behind, for which more researches are needed to fill the gap. In conclusion, bibliometric analysis provided valuable information for the development of cardio-oncology, which is full of opportunities and challenges.

Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities.

Patients with heart failure (HF) usually present with skeletal muscle diseases of varying severity, ranging from early fatigue on exercise to sarcopenia, sarcopenic obesity or cachexia, and frailty, which are significant predictors of HF prognosis. Abnormal mitochondrial metabolism has been identified as one of the earliest signs of skeletal muscle injury in HF and is associated with pathological alterations in muscle, manifested as muscle wasting, myocyte atrophy and apoptosis, fiber type shift, impaired contractile coupling, and muscle fat infiltration. In this review, we update the evidence for skeletal muscle mitochondrial remodeling in HF patients or animal models, including the impairments in mitochondrial ultrastructure, oxidative metabolism, electron transport chain (ETC), phosphorylation apparatus, phosphotransfer system, and quality control. We also focus on molecular regulatory mechanisms upstream of mitochondria, including circulating factors (e.g., RAAS, TNF-α IL-6, IGF-1, GH, ghrelin, adiponectin, NO) and molecular signals within myocytes (e.g., PGC-1α, PPARs, AMPK, SIRT1/3, ROS, and MuRF1). Besides the therapies targeting the signaling pathways mentioned above, such as AdipoRon and elamipretide, we further summarize other potential pharmacological approaches like inhibitors of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4), as well as some natural products, which may have the beneficial effects on improving the skeletal muscle mitochondrial function of HF. Targeting myocyte mitochondrial biogenesis, oxidative metabolism, oxidative phosphorylation, and reduction of oxidative stress injury are promising future opportunities for the prevention and management of skeletal muscle myopathy in HF.

The Future Landscape of Macrophage Research in Cardiovascular Disease: A Bibliometric Analysis.

Cardiovascular disease (CVD) refers to a group of diseases involving the heart or blood vessels and is currently the leading cause of morbidity and mortality in many countries around the world and poses a serious economic burden. Macrophages are key effectors of inflammatory and innate immune responses, and their aberrant expression contributes to the development of various types of CVD.This study retrieved articles published from 1990-2022 on macrophages in CVD from the Web of Science core collection, based on CiteSpace and VOSviewer on these literature The annual output, countries and regions, institutions, authors, core journals, keywords and co-cited literature were analyzed. A total of 7,197 articles and reviews were retrieved, with a general upward trend despite slight fluctuations in annual publications. Europe, the United States and Asia are the main countries and regions publishing articles, especially the United States, with the highest number of articles (2,581), citations (173,692) and H-index (197), which also has the world's largest number of elite institutions, professional The country also has the world's largest number of elite institutions, professional researchers and high-impact journals, and is the leading country in this field of research. Keywords "inflammation", "immunology", "autophagy", "lipid-peroxidation" are the main pathogenesis of CVD caused by macrophages. "NLRP3", "nf kappa b" and "TNF-α" are the most frequently studied signalling pathways. Atherosclerosis, myocarditis and myocardial injury are the most studied disease types in this field. In addition, the study of macrophage-related CVD induced by COVID-19 seems to be a recent hot topic, and the mechanisms involved are mainly macrophage polarization, inflammatory factor storm, ACE2 and so on. The present study reveals hot spots and new trends in research on macrophages in CVD, which can provide scholars with key information in this field of research and help further explore new research directions.

The Application of Angiotensin Receptor Neprilysin Inhibitor in Cardiovascular Diseases: A Bibliometric Review From 2000 to 2022.

Cardiovascular disease (CVD) has become a huge challenge for the global public health system due to its high morbidity, mortality and severe economic burden. In recent years, angiotensin receptor neprilysin inhibitor (ARNI), a new class of drugs, has shown good therapeutic effects on CVD patients in several clinical studies, reducing the morbidity and mortality of CVD patients. In this study, we retrieved publications on ARNI research in the cardiovascular field from the Web of Science core collection and analyzed the annual output, spatial and temporal distribution, institutions and authors, core journals, keywords and co-cited literature based on CiteSpace. As a result, 604 publications were retrieved, and the number of annual publications generally increased year by year, with the largest number of articles. The analysis of the co-occurrence of output countries and authors showed that a few developed countries such as the United States, Canada, and United Kingdom are the most active in this field, forming academic groups represented by John Joseph Valentine McMurray and Scott D. Solomon, and New England Journal of Medicine, Cirulation, and Journal of the American College of Cardiology are the most popular journals in the field, with research hotspots focused on ARNI in the treatment of total ejection fraction heart failure, hypertension and its target organ damage, with the potential for future benefit throughout the cardiovascular event chain as research progresses. This study reveals the prospective application of ARNI in the cardiovascular field and the research hotspots, providing broader and deeper guidance for its use in the clinic, which is beneficial to improve the treatment and prognosis of CVD patients.

Role of puerarin in pathological cardiac remodeling: A review.

Pathological cardiac remodeling normally involves changes in structure, function, and energy metabolism of the heart induced by cardiac injury or load, terminally leading to heart failure. Cardiac remodeling plays an essential role in the progression of cardiovascular disease, thus increasingly identified as an important therapeutic target for heart failure of all pathogenesis. Puerarin, as a natural isoflavone mainly from Pueraria lobata （Willd.）Ohwi, has been developed as injections, eye drops, microemulsions, etc., and is widely used in the clinical treatment of cardiovascular diseases in eastern Asia countries. In recent years, a growing number of studies have shown that puerarin significantly inhibits myocardial hypertrophic growth, myocyte death, fetal gene expression, fibroblast proliferation and activation, improves energy metabolism, promotes post-infarction angiogenesis, and suppresses inflammation and oxidative stress, consequently attenuating or preventing cardiac remodeling in response to multiple stimuli ( e.g., pressure overload, MIRI, MI, Iso, and Ang II stimulation). This review summarized the roles and underlying molecular mechanisms of puerarin in cardiac remodeling induced by diverse etiologies, aiming to help develop novel therapeutic strategies to prevent or reverse pathological ventricular remodeling.

Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome.

The crosstalk between the heart and kidney is carried out through various bidirectional pathways. Cardiorenal syndrome (CRS) is a pathological condition in which acute or chronic dysfunction in the heart or kidneys induces acute or chronic dysfunction of the other organ. Complex hemodynamic factors and biochemical and hormonal pathways contribute to the development of CRS. In addition to playing a critical role in generating metabolic energy in eukaryotic cells and serving as signaling hubs during several vital processes, mitochondria rapidly sense and respond to a wide range of stress stimuli in the external environment. Impaired adaptive responses ultimately lead to mitochondrial dysfunction, inducing cell death and tissue damage. Subsequently, these changes result in organ failure and trigger a vicious cycle. In vitro and animal studies have identified an important role of mitochondrial dysfunction in heart failure (HF) and chronic kidney disease (CKD). Maintaining mitochondrial homeostasis may be a promising therapeutic strategy to interrupt the vicious cycle between HF and acute kidney injury (AKI)/CKD. In this review, we hypothesize that mitochondrial dysfunction may also play a central role in the development and progression of CRS. We first focus on the role of mitochondrial dysfunction in the pathophysiology of HF and AKI/CKD, then discuss the current research evidence supporting that mitochondrial dysfunction is involved in various types of CRS.

SGLT2 inhibitors in the treatment of type 2 cardiorenal syndrome: Focus on renal tubules.

The pathogenesis of type 2 cardiorenal syndrome (CRS) is mostly associated with reduced cardiac output, increased central venous pressure (CVP), activation of the renin-angiotensin-aldosterone system (RAAS), inflammation, and oxidative stress. As a drug to treat diabetes, sodium-glucose transporter 2 inhibitor (SGLT2i) has been gradually found to have a protective effect on the heart and kidney and has a certain therapeutic effect on CRS. In the process of chronic heart failure (CHF) leading to chronic renal insufficiency, the renal tubular system, as the main functional part of the kidney, is the first to be damaged, but this damage can be reversed. In this review, we focus on the protective mechanisms of SGLT2i targeting renal tubular in the treatment of CRS, including natriuresis and diuresis to relieve renal congestion, attenuate renal tubular fibrosis, improve energy metabolism of renal tubular, and slow tubular inflammation and oxidative stress. This may have beneficial effects on the treatment of CRS and is a direction for future research.

Efficacy and safety of Linggui Zhugan decoction in the treatment of chronic heart failure with Yang deficiency: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic heart failure (CHF) is an advanced stage of various heart diseases and has become a major global health problem. In 2018, the Chinese guideline for the diagnosis and treatment of HF suggested adding traditional Chinese medicine (TCM) as an adjunct to the treatment of CHF, but also pointed out the need for more convincing clinical evidences. Linggui Zhugan decoction (LGZGD) is one of the widely used TCM for CHF treatment, especially for patients with Yang deficiency. Given that treatment based on syndrome differentiation is an important principle in TCM, we provide a protocol to systematically evaluate efficacy and safety of LGZGD for CHF with Yang deficiency. METHODS: We will search the following electronic databases from inception to April 30, 2021, including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, VIP Information Database, Chinese Biomedical Literature Database (CBM), and Wanfang Database. Randomized controlled trials (RCT) examining the LGZGD on CHF patients with Yang deficiency will be included. Study selection, data extraction and quality assessment will be conducted by 2 researchers, respectively. The primary outcome measures will be n-terminal brain natriuretic peptide and left ventricular ejection fraction. The risk of bias will be evaluated by the Cochrane Collaboration tool. We will use the fixed-effects model or random-effects model of RevMan V.5.3 based on the results of heterogeneity assessment. The evidence quality of results will be assessed by Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: It will provide the results about efficacy and safety of LGZGD in the treatment of CHF with Yang deficiency by various comprehensive assessments. CONCLUSIONS: This study will provide reliable evidences about the efficacy and safety of LGZGD in the treatment of CHF with Yang deficiency. ETHICS AND DISSEMINATION: Ethical approval is not necessary for this study because the data extracted does not involve any individual privacy. We plan to presented the results of this review in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD 42019140797.

Chinese medicine for diabetic kidney disease in China.

Diabetic kidney disease (DKD) is a major global public health concern due to its high prevalence and mortality, and high healthcare cost. Conventional Western therapies for DKD fail to provide favourable efficacy. Chinese medicine (CM) has been widely used to combat DKD in China and other Asian countries. The clinical effects and mechanism of CM in treating DKD have not been fully elucidated. This review summarizes current knowledge of CM therapeutic modalities for DKD, especially Chinese herbal medicine (CHM), and potential mechanisms.

Effects of Tangshen Formula on urinary and plasma liver-type fatty acid binding protein levels in patients with type 2 diabetic kidney disease: post-hoc findings from a multi-center, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Tangshen Formula in patients with type 2 diabetic kidney disease.

BACKGROUND: Tangshen Formula (TSF) is a traditional Chinese medicine for the treatment of diabetic kidney disease (DKD). Liver-type fatty acid binding protein (L-FABP) is expressed in various tissues, including the kidney, where it is known as urinary L-FABP. Other studies demonstrated that urinary L-FABP may be a useful biomarker for monitoring DKD. This post-hoc analysis and cross-sectional study evaluated the changes in urinary L-FABP in DKD patients treated with TSF and conventional medicine. METHODS: Post-hoc analysis was conducted on a multicenter, randomized, double-blind, placebo-controlled trial. A total of 180 participants with DKD including 98 with microalbuminuria and 82 with macroalbuminuria were enrolled in the original study. In addition to conventional treatment, 122 participants were randomly assigned to receive TSF and 58 to receive placebo. After 24-weeks of treatment, the intention-to-treat population in microalbuminuria stage was 56 in the TSF group and 25 in the placebo group, and in the macroalbuminuria stage 42 and 19, respectively. The primary outcome in the original trial was urinary protein level. In the current study, urinary and plasma L-FABP levels were measured in 30 microalbuminuria patients (15 in the TSF group and 15 in the placebo group) and 30 macroalbuminuria patients (15 in the TSF group and 15 in the placebo group). In addition, another 30 patients with normoalbuminuria (urinary albumin excretion rate (UAER) < 20 µg/min) were recruited for the cross-sectional study. RESULTS: (1) In microalbuminuria patients, UAER in the TSF group displayed a significant decrease after 24 weeks of treatment (P = 0.045). Levels of urinary L-FABP in the TSF group were markedly lower than in the placebo group after 12 and 24 weeks (P = 0.004 and P = 0.047, respectively). (2) In macroalbuminuria patients, 24-h urinary protein levels decreased significantly compared with baseline in the TSF group at week 12 (P = 0.042) and week 24 (P = 0.041). The TSF group showed a significant decrease in urinary L-FABP after 12 and 24 weeks (P = 0.036 and P = 0.046, respectively). (3) Levels of urinary L-FABP increased markedly, correlating with severity of DKD. L-FABP in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria were 5.9 (5.2, 7.8) µg/ml, 11.4 (6.8, 13.4) µg/ml and 18.5 (10.9, 23.4) µg/ml, respectively (P = 0.000). CONCLUSIONS: TSF combined with conventional therapy appeared to be effective in reducing urinary protein and urinary L-FABP. Urinary L-FABP levels appear to be associated with the severity of DKD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-10000843 . Registered 15 April 2010.

Chinese herbal medicine Tangshen Formula treatment of patients with type 2 diabetic kidney disease with macroalbuminuria: study protocol for a randomized controlled trial.

BACKGROUND: Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus and the main cause of end-stage renal disease. Present medications for DKD are not entirely satisfactory. Preliminary studies indicate that the Chinese herbal formula Tangshen Formula (TSF) appears to decrease the proteinuria and improve the estimated glomerular filtration rate (eGFR) in DKD patients. METHODS/DESIGN: This trial is a five-center, randomized, double-blind, placebo-controlled study. DKD patients with a 24-h urinary protein (24 h UP) level between 0.5 and 3.5 g and serum creatinine < 265 µmol/L (3 mg/dl) will be included. A sample size of 144 participants will be randomly distributed into the treatment group (TSF plus irbesartan) and the control group (placebo plus irbesartan) at a ratio of 1:1. The study duration will be 50 weeks, comprising a 2-week run-in period, 24 weeks of intervention, and 24 weeks of follow-up. The primary endpoint will be the 24 h UP. Secondary endpoints will be an evaluation of renal function, management of blood lipids, improvement in traditional Chinese medicine symptoms, and safety assessments. Adverse events will also be evaluated. DISCUSSION: This study will provide evidence for the effectiveness and safety of TSF compared to placebo in treating DKD patients with macroalbuminuria. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR-TRC-13003566 . Registered 9 August 2013.