Different High-Intensity Interval Training Programs versus Moderate Intensity Continuous Training for Heart Failure Patients: a systematic review and meta-analysis.

OBJECTIVE: To explore the effect sizes of different HIIT protocols on cardiorespiratory parameters when compared with the MICT in different HF subtypes. DATA SOURCES: Electronic databases were searched from their inception date until January 23rd, 2023. STUDY SELECTION: Randomized controlled trials (RCTs) were included if they compared HIIT to MICT in HF patients. The primary outcomes was peak oxygen consumption (VO2peak). Two reviewers independently evaluated 99 initially identified studies, resulting in the selection of 15 RCTs that met the eligibility criteria. DATA EXTRACTION: Data was extracted independently by two observers using data extraction form drafted based on the CONSORT statement and the TIDieR; and the The methodological quality of the studies was analyzed individually based on the TESTEX scale. DATA SYNTHESIS: Fifteen RCTs with 553 HF patients were included in the systematic review. The studies included had moderate to good overall methodological quality. The results showed that HIIT was generally more effective than MICT at improving VO2peak in HF patients (n=541, 15 RCT; MD: 1.49 mL/kg/min, I2=66%, p<0.001). However, the effect size varied depending on the HF subtype and HIIT protocol used. For HFrEF patients, the long-interval (high-intensity interval lasting≥ 4 min) and high-volume HIIT (high-intensity efforts in total ≥ 15 min) showed the largest benefits over the MICT (n=261, 6 RCT; MD: 2.11 mL/kg/min, p<0.001); followed by the short-interval (≤ 1 min) and high-volume HIIT (≥ 15 min; n=71, 3 RCT; MD: 0.91 mL/kg/min, p=0.12); and the short-interval and low-volume HIIT showed the least superiority over MICT (n=68, 3 RCT; MD: 0.54 mL/kg/min; p=0.05). For HFpEF patients, there was a modest beneficial effect from HIIT over MICT (n=141, 3 RCT; MD: 0.55 mL/kg/min; p=0.32). CONCLUSIONS: The long-interval and high-volume HIIT protocol may produce greater benefits than MICT for improving cardiopulmonary fitness in HFrEF patients. Further research is needed to determine the optimal HIIT protocol for different HF subtypes and to provide definitive recommendations for clinical practice.

The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.

Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.

Proteomics Analysis of Serum Reveals Potential Biomarkers for Heart Failure Patients with Phlegm-Blood Stasis Syndrome.

Heart failure (HF), a complex clinical syndrome, has become a global burden on health and economics around the world. Phlegm-blood stasis syndrome, one of the Traditional Chinese Medicine (TCM) syndrome differentiation, is the core pathogenesis dynamically throughout the occurrence, development, and prognosis of HF. Biomarkers having high sensitivity and specificity are highly demanded to facilitate the accurate differentiation of HF patients with phlegm-blood stasis syndrome. In the present study, serum samples were collected from 20 healthy controls and 40 HF patients (20 with and 20 without phlegm-blood stasis syndrome). We implemented data-independent acquisition mass spectrometry (DIA-MS) for discovery and parallel reaction monitoring (PRM) for validation of biomarkers for heart failure with phlegm-blood stasis syndrome. A total of 84 different proteins were found in the HF with phlegm-blood stasis syndrome (HF-TY) group compared with healthy controls. 37 candidate proteins were selected for the PRM assay, and five validated proteins with high sensitivity and specificity, including insulin-like growth factor-binding protein 4 (IGFBP4), ß-2-microglobulin (B2M), dystroglycan (DAG1), immunoglobulin J chain (JCHAIN), and kallikrein B1 (KLKB1), were considered potential biomarkers for heart failure patients with phlegm-blood stasis syndrome. Newly identified biomarkers might provide insights into the diagnosis and treatment of HF with TCM syndrome differentiation.

Xin-Li formula attenuates heart failure induced by a combination of hyperlipidemia and myocardial infarction in rats via Treg immunomodulation and NLRP3 inflammasome inhibition.

Background and aim: Heart failure (HF) is a complex clinical syndrome that represents the end result of several pathophysiologic processes. Despite a dramatic evolution in diagnosis and management of HF, most patients eventually become resistant to therapy. Xin-Li Formula (XLF) is a Chinese medicine formula which shows great potential in the treatment of HF according to our previous studies. The present study was designed to investigate the effects of XLF on HF induced by a combination of hyperlipidemia and myocardial infarction (MI) in rats and reveal the underlying mechanism. Experimental procedure: A rat model of HF induced by hyperlipidemia and MI was established with intragastric administration of XLF and Perindopril. In vitro, CD4+ T cells from mouse spleen and LPS/ATP-stimulated THP-1 macrophages were employed. Results and conclusion: XLF was shown to have markedly protective effects on MI-induced HF with hyperlipidemia in rats, including improvement of left ventricular function, reduction of left ventricular fibrosis and infarct size. Moreover, XLF administration significantly increased the number of Foxp3+ Tregs, and inhibited mTOR phosphorylation and NLRP3 signaling pathway. In vitro, we found that XLF had induced Treg activation via the inhibition of mTOR phosphorylation in CD4+ T cells. Additionally, XLF inhibited NLRP3 inflammasome activation in LPS/ATP-stimulated THP-1 macrophages. Taken together, this study raises the exciting possibility that Xin-Li Formula may benefit HF patients due to its immunomodulatory and anti-inflammatory effects via Treg activation and NLRP3 inflammasome inhibition.

MitraClip used for severe mitral regurgitation after surgery for type A aortic dissection combined with Marfan syndrome.

Mitral regurgitation is a rare but catastrophic condition in patients after surgery for type A aortic dissection. The second thoracotomy to complete the mitral valve operation could be fatal. Here, we report a case of severe mitral regurgitation treated with MitraClip in a 53-year-old woman after surgery for type A aortic dissection combined with Marfan syndrome. She was discharged uneventfully, and a significant reduction of regurgitation of mitral valve and tricuspid valve was observed at the 6-month follow-up. MitraClip could be an alternative device for such high-risk patients.

Corrigendum: Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

[This corrects the article DOI: 10.3389/fphar.2023.1145407.].

Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

Background: Ferroptosis is a new form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides and membrane damages. Recent studies have identified an important role for cancer cell ferroptosis in antitumor therapy. On the other hand, polyphyllin I (PPI) has been reported to exert antitumor effects on some types of cancers. However, it remains unknown whether or not PPI regulates cancer cell ferroptosis. Methods: Two types of human gastric cancer cells (AGS and MKN-45) were used to establish tumor xenograft models in nude mice that were treated with polyphyllin I (PPI) to observe tumor growth, while cells also were cultured for in vitro studies. Ferroptosis, based on the intracellular ROS/lipid ROS production and accumulation of ferrous ions, was detected using a fluorescence microscope and flow cytometer, while the expression of NRF2/FTH1 was measured using Western blotting assays. Results: Here we found that PPI inhibited the gastric cancer growth in vivo and in vitro while increasing the intracellular reactive oxygen species (ROS)/lipid peroxides and ferrous ions in the gastric cancer cells. PPI also decreased the levels of nuclear factor erythroid 2-related factor 2 (NRF2) and ferritin heavy chain 1 (FTH1) in gastric cancer cells in vitro. Moreover, liproxstain-1, an inhibitor of cell ferroptosis, mostly reversed the cell ferroptosis and tumor growth arrest induced by PPI. Finally, the effects of PPI on cancer cell ferroptosis were diminished by the overexpression of NRF2. Conclusion: For the first time, our results have demonstrated that PPI exerts its antitumor activity on the gastric cancer by, at least partially, inducing cancer cell ferroptosis via regulating NRF2/FTH1 pathway. These findings may be implicated for clinical replacement therapy of the gastric cancer.

Left atrial dysfunction can independently predict exercise capacity in patients with chronic heart failure who use beta-blockers.

BACKGROUND: Beta-blockers are first-line clinical drugs for the treatment of chronic heart failure (CHF). In the guidelines for cardiac rehabilitation, patients with heart failure who do or do not receive beta-blocker therapy have different reference thresholds for maximal oxygen uptake (VO2max). It has been reported that left atrial (LA) strain can be used to predict VO2max in patients with heart failure, which can be used to assess exercise capacity. However, most existing studies included patients who did not receive beta-blocker therapy, which could have a heterogeneous influence on the conclusions. For the vast majority of CHF patients receiving beta-blockers, the exact relationship between LA strain parameters and exercise capacity is unclear. METHODS: This cross-sectional study enrolled 73 patients with CHF who received beta-blockers. All patients underwent a thorough resting echocardiogram and a cardiopulmonary exercise test to obtain VO2max, which was used to reflect exercise capacity. RESULTS: LA reservoir strain, LA maximum volume index (LAVImax), LA minimum volume index (LAVImin) (P < 0.0001) and LA booster strain (P < 0.01) were all significantly correlated with VO2max, and LA conduit strain was significantly correlated with VO2max (P < 0.05) after adjusting for sex, age, and body mass index. LA reservoir strain, LAVImax, LAVImin (P < 0.001), and LA booster strain (P < 0.05) were significantly correlated with VO2max after adjusting for left ventricular ejection fraction, the ratio of transmitral E velocity to tissue Doppler mitral annulus e' velocity (E/e'), and tricuspid annular plane systolic excursion. LA reservoir strain with a cutoff value of 24.9% had a sensitivity of 74% and specificity of 63% for the identification of patients with VO2max < 16 mL/kg/min. CONCLUSION: Among CHF patients receiving beta-blocker therapy, resting LA strain is linearly correlated with exercise capacity. LA reservoir strain is a robust independent predictor of reduced exercise capacity among all resting echocardiography parameters. CLINICAL TRIAL REGISTRATION: This study is a part of the Baduanjin-Eight-Silken-Movement with Self-efficacy Building for Patients with Chronic Heart Failure (BESMILE-HF) trial NCT03180320 (ClinicalTrials.gov, registration date: 08/06/2017).

Xin-Li-Fang efficacy and safety for patients with chronic heart failure: A study protocol for a randomized, double-blind, and placebo-controlled trial.

Introduction: Xin-Li-Fang (XLF), a representative Chinese patent medicine, was derived from years of clinical experience by academician Chen Keji, and is widely used to treat chronic heart failure (CHF). However, there remains a lack of high-quality evidence to support clinical decision-making. Therefore, we designed a randomized controlled trial (RCT) to evaluate the efficacy and safety of XLF for CHF. Methods and design: This multicenter, double-blinded RCT will be conducted in China. 300 eligible participants will be randomly assigned to either an XLF group or a control group at a 1:1 ratio. Participants in the XLF group will receive XLF granules plus routine care, while those in the control group will receive placebo granules plus routine care. The study period is 26 weeks, including a 2-week run-in period, a 12-week treatment period, and a 12-week follow-up. The primary outcome is the proportion of patients whose serum NT-proBNP decreased by more than 30%. The secondary outcomes include quality of life, the NYHA classification evaluation, 6-min walking test, TCM symptom evaluations, echocardiography parameters, and clinical events (including hospitalization for worsening heart failure, all-cause death, and other major cardiovascular events). Discussion: The results of the study are expected to provide evidence of high methodological and reporting quality on the efficacy and safety of XLF for CHF. Clinical trial registration: Chinese Clinical Trial Registration Center (www.chictr.org.cn). The trial was registered on 13 April 2022 (ChiCTR2200058649).

Nontargeted Metabolomic Profiling of Huo-Tan-Chu-Shi Decoction in the Treatment of Coronary Heart Disease with Phlegm-damp Syndrome.

Background: Considered an effective supplementary therapy, traditional Chinese medicine (TCM) has been widely applied in the treatment of coronary heart disease (CHD). In this study, we aim to investigate the effects and mechanisms of Huo-Tan-Chu-Shi decoction (HTCSD, an in-hospital TCM prescription) in the treatment of CHD with the phlegm-damp syndrome in mice by non-targeted metabolomics with liquid chromatography-mass spectrometry (LC-MS)/MS. Methods: A CHD with phlegm-damp syndrome model was established with ApoE-/- mice by subcutaneous injection with isoproterenol combined with high temperature, high humidity, and a high-fat diet, and divided into the HTCSD and Tanshi groups. C57BL/6 mice were set as the control group with an ordinary environment and diet. After administration, electrocardiogram (ECG), interventricular septum thickness (IVS) and left ventricular posterior wall thickness (LVPW), serum levels of creatine phosphokinase-Mb (CK-MB), cardiac troponin T (cTnT), lactic dehydrogenase (LDH) and oxidized low-density lipoprotein (oxLDL), and myocardial histopathological changes were recorded to assess myocardial damage. LC-MS/MS was applied to demonstrate the serum metabolic profile and explore potential mechanisms. Results: The obvious depressions of the ST segment and T wave presented in the ECG of Tanshi mice, while the depressions in ECG of HTCSD mice were significantly reduced. Compared with the control group, IVS, LVPW, and serum levels of CK-MB, cTnT, LDH, and oxLDL increased greatly in the Tanshi group, while these indicators decreased remarkably in the HTCSD group compared with those of the Tanshi group. Histopathology showed severe structural disorder, necrosis, and fibrosis of myocardial cells in Tanshi mice, which were alleviated in HTCSD mice. Metabonomics analysis showed obvious metabolic alterations among the experimental mice and revealed that the relevant metabolic pathways mainly included phospholipid metabolism, necroptosis, and autophagy. Conclusions: HTCSD has a certain therapeutic effect in mice with CHD with phlegm-damp syndrome via reducing myocardial ischemia, hypertrophy, and fibrosis. The underlying mechanisms involve the regulation of phospholipid metabolism, necroptosis, and autophagy.

Metabolism disorder promotes isoproterenol-induced myocardial injury in mice with high temperature and high humidity and high-fat diet.

BACKGROUND: Isoproterenol (ISO), a synthetic on selective ß-adrenergic agonist, provides a simple and non-invasive method for inducing myocardial injury with lower mortality and higher reproducibility. Phlegm-damp syndrome, as known as "Tanshi" in Chinese, is one of Traditional Chinese Medicine (TCM) syndrome differentiation, which plays an important role in the development of cardiovascular diseases. However, the underlying mechanism remains unknown. METHODS: In our present study, a myocardial injury mouse model was introduced by ISO administration combined with high temperature and high humidity and high-fat diet to simulate phlegm-damp syndrome. Nontargeted metabolomics with LC-MS/MS was adopted to reveal serum metabolism profile for elucidating the possible molecular mechanism. RESULTS: The results of our study showed that phlegm-damp syndrome promoted ISO-induced myocardial injury by aggravating left ventricular hypertrophy and fibrosis, and increasing cardiac index. Our study also confirmed the presence of specific metabolites and disturbed metabolic pathways by comparing ISO mice and Tanshi mice, mainly including glycerophospholipid metabolism, arginine-proline metabolism, and sphingolipid signaling pathway. The lysoPCs, PCs, SMs, Sphingosine, and L-Arginine were the main metabolites that showed a difference between ISO and Tanshi mice, which might be the result of the underlying mechanism in the promotion of ISO-induced myocardial injury in mice with high temperature and high humidity and high-fat diet. CONCLUSION: Our current study provides new insights into contribution of metabolism disorder in promotion of ISO-induced myocardial injury in mice with high temperature and high humidity and high-fat diet, and new targets for clinical diagnosis and pharmacologic treatment of cardiovascular disease with phlegm-damp syndrome.

Deciphering mechanism of the herbal formula WuShen in the treatment of postinfarction heart failure.

BACKGROUND: Numerous clinical studies reported the effectiveness of herbal formula WuShen (WS) in treating cardiovascular diseases, yet relevant basic research was rarely conducted. METHODS AND RESULTS: Twelve main bioactive compounds of WS decoction were identified using the ultra-performance liquid chromatography-LTQ-Orbitrap mass spectrometer. A total of 137 active compounds with 613 targets were predicted by network pharmacology; their bioinformatic annotation and human microarray data suggested that wounding healing, inflammatory response, and gap junction were potentially the major therapeutic modules. A rat model of post-myocardial infarction (MI) heart failure (HF) was used to study the effects of WS on cardiac function, adverse cardiac remodeling, and experimental arrhythmias. Rats treated with WS led to a significantly improved pump function and reduced susceptibility to both ventricular tachycardia and atrial fibrillation, and restricted adverse cardiac remodeling partly via inhibiting TGFß1/SMADs mediated extracellular matrix deposition and Rac1/NOX2/CTGF/Connexin43 -involved gap junction remodeling. CONCLUSIONS: The present study highlights that WS can be applied to the treatment of heart failure and the upstream therapy for atrial fibrillation and ventricular tachycardia through its preventive effect on adverse cardiac remodeling.

Differences in Peak Oxygen Uptake in Bicycle Exercise Test Caused by Body Positions: A Meta-Analysis.

Background: As demand for cardiopulmonary exercise test using a supine position has increased, so have the testing options. However, it remains uncertain whether the existing evaluation criteria for the upright position are suitable for the supine position. The purpose of this meta-analysis is to compare the differences in peak oxygen uptake (VO2peak) between upright and supine lower extremity bicycle exercise. Methods: We searched PubMed, Web Of Science and Embase from inception to March 27, 2021. Self-control studies comparing VO2peak between upright and supine were included. The quality of the included studies was assessed using a checklist adapted from published papers in this field. The effect of posture on VO2peak was pooled using random/fixed effects model. Results: This meta-analysis included 32 self-control studies, involving 546 participants (63% were male). 21 studies included only healthy people, 9 studies included patients with cardiopulmonary disease, and 2 studies included both the healthy and cardiopulmonary patients. In terms of study quality, most of the studies (n = 21, 66%) describe the exercise protocol, and we judged theVO2peak to be valid in 26 (81%) studies. Meta-analysis showed that the upright VO2peak exceeded the supine VO2peak [relative VO2peak: mean difference (MD) 2.63 ml/kg/min, 95% confidence interval (CI) 1.66-3.59, I 2 = 56%, p < 0.05; absolute VO2peak: MD 0.18 L/min, 95% CI 0.10-0.26, I 2 = 63%, p < 0.05). Moreover, subgroup analysis showed there was more pooled difference in healthy people (4.04 ml/kg/min or 0.22 L/min) than in cardiopulmonary patients (1.03 ml/kg/min or 0.12 L/min). Conclusion: VO2peak in the upright position is higher than that in supine position. However, whether this difference has clinical significance needs further verification. Systematic Review Registration: identifier, CRD42021233468.

Regulatory T Cells: A New Target of Chinese Medicine in Treatment of Atherosclerosis.

Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis (AS). With the role of regulatory T cells (Tregs) in immune regulation attracting attention, it has been widely accepted that Treg decrease and dysfunction are involved in AS pathogenesis. Chinese medicine (CM) has the advantages of being dual-directional, multi-targeted, and having minimal side effects in immune regulation. The anti-atherosclerosis effects of CM via Treg modulation have been revealed in clinical and animal studies. Therefore, this article reviews existing research on Tregs, the relationship between Tregs and AS, and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating Tregs. Although the underlying mechanisms remain to be elucidated, CM treatment targeting Treg cells might provide a promising and novel future approach for prevention and treatment of AS.

Feasibility and Preliminary Effects of the BESMILE-HF Program on Chronic Heart Failure Patients: A Pilot Randomized Controlled Trial.

Aims: The Baduanjin Eight-Silken-Movements wIth Self-Efficacy building for Heart Failure (BESMILE-HF) program is a contextually adapted cardiac rehabilitation program. It uses a traditional Chinese exercise, Baduanjin, to solve the unmet demand of exercise-based cardiac rehabilitation programs due to their scarcity and unaffordability in China. This pilot study assesses BESMILE-HF's feasibility and preliminary effects. Methods: Eighteen patients with chronic heart failure were included: 8 in a BESMILE-HF group (age: 67 ± 5 years, EF: 40.4 ± 13.6%) and 10 in a control group (age: 70 ± 13 years, EF: 42.9 ± 12.5%). Both received the usual medications, with the intervention group receiving additionally the BESMILE-HF program for 6 weeks. Feasibility was explored by participants' involvement in the intended intervention. Clinical outcome assessments were conducted at baseline and post-intervention, while adverse events were captured throughout the study period. Results: The BESMILE-HF program was well-received by patients, and adherence to the intervention was good. The intervention group completed all required home exercises and total home-practice time was correlated with baseline self-efficacy (r = 0.831, p = 0.011). Moreover, after 6 weeks, self-efficacy increased in the BESMILE-HF group (p = 0.028) and the change was higher than in the control [mean difference (MD): 3.2; 95% confidence interval (CI) 0.6-5.9, p = 0.004]. For the exercise capacity, the control group demonstrated a significant decline in peak oxygen consumption (p =0.018) whereas, the BESMILE-HF group maintained their exercise capacity (p = 0.063). Although the between-group difference was not statistically significance, there was clear clinical improvement in the BESMILE-HF group (1.5 mL/kg/min, 95% CI, -0.3 to 3.2 vs. minimal clinically important difference of 1 mL/kg/min). Throughout the study period, no adverse events related to the intervention were captured. Conclusions: BESMILE-HF is feasible for patients with chronic heart failure in Chinese settings. A larger sample size and a longer follow-up period is needed to confirm its benefit on clinical outcomes. Clinical Trial Registration:ClinicalTrials.gov: NCT03180320.

TaiChi and Qigong for Depressive Symptoms in Patients with Chronic Heart Failure: A Systematic Review with Meta-Analysis.

BACKGROUND: Depression is a debilitating comorbidity of heart failure (HF) that needs assessment and management. Along with mind-body exercise to deal with HF with depression, the use of TaiChi and/or Qigong practices (TQPs) has increased. Therefore, this systematic review assesses the effects of TQPs on depression among patients with HF. METHODS: Randomized controlled trials (RCTs) that examined the effect of TQPs on depression in patients with HF were searched by five databases (PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, CINAHL, and China National Knowledge Infrastructure (CNKI)). With standardized mean difference (SMD) and 95% confidence intervals (95% CI), random-effects meta-analyses of the effect of TQPs on depressive symptoms were performed. RESULTS: Of eight included RCTs, seven (481 patients) provided data for the meta-analysis. The pooling revealed that TQPs contribute to depression remission in HF (SMD -0.66; 95% CI -0.98 to -0.33, P < 0.0001; I 2 = 64%). Its antidepressive effect was not influenced by intervention duration or exercise setting, but rather by ejection fraction subtype, depressive severity, and depression instruments. The beneficial effects were preserved when the study with the largest effect was removed. CONCLUSION: This study suggests that TQPs might be a good strategy for alleviating depressive symptoms in patients with HF. And rigorous-design RCTs, which focus on the identified research gaps, are needed to further establish the therapeutic effects of TQPs for depression in HF.

Chemical profile and potential mechanisms of Huo-Tan-Chu-Shi decoction in the treatment of coronary heart disease by UHPLC-Q/TOF-MS in combination with network pharmacology analysis and experimental verification.

Huo-Tan-Chu-Shi Decoction (HTCSD), a traditional Chinese medicine (TCM) prescription within Guangdong Provincial TCM Hospital (the largest TCM hospital in China), is used for effective clinical treatment of coronary heart disease (CHD) caused by phlegm-dampness syndrome with high incidence in the hot and humid climate of Lingnan region. However, its chemical components responsible for the therapeutic effects remain unclear, which restricts its application and further development. Hence, a detailed workflow, combing with UHPLC-Q/TOF-MS, network pharmacology analysis and experimental verification, was proposed and applied to characterize the chemical profile and potential mechanism of HTCSD against CHD. As a result, a total of 130 components from all six composed herbal medicines were characterized in a rapid and sensitive manner through UHPLC-Q/TOF-MS, of which 33 compounds were unambiguously confirmed with reference standards. Consequently, based on the integrated pharmacology network of "herbs-chemicals-targets-pathways-therapeutic effects", four chemicals (magnoflorine, menisperine, 13-hydroxyberberine, luteolin) with four CHD related targets (SRC, MAPK1, EGFR and AKT1) were considered as the key components and targets of HTCSD in the treatment of CHD. Furthermore, the effect of HTCSD was confirmed in animal experiments by enhancing the phosphorylation of MAPK, and the published literature and molecular binding results suggested that magnoflorine and luteolin tended to be the critical compounds involved in the process. Taken together, the characterization of chemical profile combined with network pharmacology analysis and experimental verification not only provided an efficient insight into the overall chemical profile of HTCSD but also revealed the potential pharmacological components and mechanisms of HTCSD against CHD, which laid a necessary chemical and biological basis for the discovery of in vivo bioactive components and the further revelation of functionary mechanism.

Berberine Promotes Induction of Immunological Tolerance to an Allograft via Downregulating Memory CD8+ T-Cells Through Altering the Gut Microbiota.

Emerging evidence has linked the gut microbiota dysbiosis to transplant rejection while memory T-cells pose a threat to long-term transplant survival. However, it's unclear if the gut microbiome alters the formation and function of alloreactive memory T-cells. Here we studied the effects of berberine, a narrow-spectrum antibiotic that is barely absorbed when orally administered, on the gut microbiota, memory T-cells, and allograft survival. In this study, C57BL/6 mice transplanted with islets or a heart from BALB/c mice were treated orally with berberine. Allograft survival was observed, while spleen, and lymph node T-cells from recipient mice were analyzed using a flow cytometer. High-throughput sequencing and qPCR were performed to analyze the gut microbiota. CD8+ T-cells from recipients were cultured with the bacteria to determine potential T-cell memory cross-reactivity to a specific pathogen. We found that berberine suppressed islet allograft rejection, reduced effector CD8+CD44highCD62Llow and central memory CD8+CD44highCD62Lhigh T-cells (TCM), altered the gut microbiota composition and specifically lowered Bacillus cereus abundance. Further, berberine promoted long-term islet allograft survival induced by conventional costimulatory blockade and induced cardiac allograft tolerance as well. Re-colonization of B. cereus upregulated CD8+ TCM cells and reversed long-term islet allograft survival induced by berberine plus the conventional costimulatory blockade. Finally, alloantigen-experienced memory CD8+ T-cells from transplanted recipients rapidly responded to B. cereus in vitro. Thus, berberine prolonged allograft survival by repressing CD8+ TCM through regulating the gut microbiota. We have provided the first evidence that donor-specific memory T-cell generation is linked to a specific microbe and uncovered a novel mechanism underlying the therapeutic effects of berberine. This study may be implicated for suppressing human transplant rejection since berberine is already used in clinic to treat intestinal infections.

Analysis of transcriptome in the relationship between expression of PRC1 protein and prognosis of patients with cholangiocarcinoma.

OBJECTIVE: To investigate whether protein regulator of cytokinesis 1 (PRC1), which is involved in the regulation of human carcinogenesis, contributes to poor prognosis in patients with cholangiocarcinoma (CCA). METHODS: Data and tissues from patients with CCA were retrospectively studied. Immunohistochemical staining and western blotting were used to evaluate and contrast the PRC1 expression profile at the protein level in CCA tumour and pericarcinomatous tissues from the same study population. Relationships between clinical characteristics and patient survival were observed using univariate and multivariate analyses. Correlations between PRC1 expression and clinical characteristics were analysed by logistic regression. RESULTS: A total of 45 patients were included. PRC1 expression was found to be upregulated in CCA cancer tissues versus pericarcinomatous tissues. Overexpression of PRC1 was shown to be related to tumour differentiation, tumour node metastasis staging and lymph node metastasis, and was also revealed to be an independent marker of poor CCA prognosis. CONCLUSIONS: The present results suggest that PRC1 may be a prognostic and therapeutic biomarker for patients with CCA.