Panax quinquefolius saponins and panax notoginseng saponins attenuate myocardial hypoxia-reoxygenation injury by reducing excessive mitophagy.

OBJECTIVE: Panax quinquefolius saponins (PQS) and Panax notoginseng saponins (PNS) are key bioactive compounds in Panax quinquefolius L. and Panax notoginseng, commonly used in the treatment of clinical ischemic heart disease. However, their potential in mitigating myocardial ischemia-reperfusion injury remains uncertain. This study aims to evaluate the protective effects of combined PQS and PNS administration in myocardial hypoxia/reoxygenation (H/R) injury and explore the underlying mechanisms. METHODS: To investigate the involvement of HIF-1α/BNIP3 mitophagy pathway in the myocardial protection conferred by PNS and PQS, we employed small interfering BNIP3 (siBNIP3) to silence key proteins of the pathway. H9C2 cells were categorized into four groups: control, H/R, H/R + PQS + PNS, and H/R + PQS + PNS+siBNIP3. Cell viability was assessed by Cell Counting Kit-8, apoptosis rates determined via flow cytometry, mitochondrial membrane potential assessed with the JC-1 fluorescent probes, intracellular reactive oxygen species detected with 2',7'-dichlorodihydrofluorescein diacetate, mitochondrial superoxide production quantified with MitoSOX Red, and autophagic flux monitored with mRFP-GFP-LC3 adenoviral vectors. Autophagosomes and their ultrastructure were visualized through transmission electron microscopy. Moreover, mRNA and protein levels were analyzed via real-time PCR and Western blotting. RESULTS: PQS + PNS administration significantly increased cell viability, reduced apoptosis, lowered reactive oxygen species levels and mitochondrial superoxide production, mitigated mitochondrial dysfunction, and induced autophagic flux. Notably, siBNIP3 intervention did not counteract the cardioprotective effect of PQS + PNS. The PQS + PNS group showed downregulated mRNA expression of HIF-1α and BNIP3, along with reduced HIF-1α protein expression compared to the H/R group. CONCLUSIONS: PQS + PNS protects against myocardial H/R injury, potentially by downregulating mitophagy through the HIF-1α/BNIP3 pathway.

Tongxinluo capsule in combination with conventional therapies for stable angina pectoris: A meta-analysis and systematic review.

BACKGROUND: This study aimed to assess the efficacy and safety of Tongxinluo capsule (TXLC) in combination with conventional therapies for treating stable angina pectoris (SAP) through a comprehensive meta-analysis and systematic review. METHODS: We conducted a systematic search of the China National Knowledge Infrastructure, Wanfang, VIP, PubMed, Embase, and CENTRAL databases for randomized controlled trials investigating the use of TXLC as adjuvant therapy for SAP published up to June 2023. The Cochrane Handbook was used to evaluate the risk of bias. Meta-analysis was performed using Review Manager 5.4.1, and publication bias was assessed using Begg test and Egger test in the Stata SE 12.0 software. GRADEpro was used to assess the quality of the evidence. RESULTS: This meta-analysis included 26 randomized controlled trials with a total of 2352 patients. TXLC co-administration demonstrated significant reduction in angina attack frequency (mean difference (MD) -0.91, 95% confidence interval (CI) -0.97 to -0.84, P < .00001) and duration (MD -1.71, 95% CI -2.24 to -1.19, P < .00001), decreased use of nitroglycerin tablets (MD -6.28, 95% CI -7.16 to -5.41, P < .00001), lowered C-reactive protein (MD -1.19, 95% CI -1.35 to -1.03, P < .00001) and low-density lipoprotein cholesterol levels (MD -0.68, 95% CI -0.86 to -0.51, P < .00001). TXLC co-administration did not increase gastrointestinal reactions (RR 1.17, 95% CI 0.38 to 3.57, P = .78). The Begg test and Egger test results indicated no publication bias. The evidence quality was rated as very low for frequency of angina attack, duration of angina attack, and nitroglycerin usage, and low for C-reactive protein, low-density lipoprotein cholesterol levels, and gastrointestinal reaction events. CONCLUSION: This meta-analysis supports TXLC as a beneficial adjunct treatment for SAP.

Impact of time-to-treatment initiation on survival in single primary non-small cell lung Cancer: A population-based study.

Background: Understanding the effects of a delayed time-to-treatment initiation(TTI) for non-small cell lung cancer (NSCLC) is vital. Methods: We analyzed NSCLC data from the Surveillance, Epidemiology, and End Results database, focusing on lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). TTI was studied as both continuous and dichotomous variables. Restricted cubic splines were employed to identify potential nonlinear dependency between the hazard ratio (HR) and TTI. Propensity score matching was used to ensure a balanced patient allocation, and then survival differences between groups were assessed using Kaplan-Meier analysis and competing risk models. We used overall survival (OS) as the primary outcome and cancer-specific cumulative mortality (CSCM) as a complementary indicator. Finally, sensitivity analyses were performed on censored data. Results: A total of 80,020 with NSCLC were analyzed. TTI was assessed as a continuous variable, showing a noticeable increase in the HR for stage I to II NSCLC with TTI >1 month. Conversely, the trend for stage III to IV NSCLC was the opposite. In stage I LUAD, the 'early' group demonstrated a higher OS compared to the 'delayed' group (Log-rank P = 0.002), while there was no significant difference in CSCM (Fine-gray P = 0.321). In stage I LUSC, there was no significant difference in OS(Log-rank P = 0.260), but the 'early' group had a lower CSCM (Fine-gray P = 0.018). For stage II-IV NSCLC, the 'delayed' group did not exhibit a negative impact on OS or CSCM. The sensitivity analysis further supported the results of the main analysis. Conclusion: Prolongation of TTI ≥31 days has a negative impact on OS or CSCM in stage I NSCLC only. Further exploration and validation are needed to determine whether these results can be used as evidence for a 'safe' TTI threshold setting for future NSCLC.

Role of Mitophagy in Myocardial Ischemia/Reperfusion Injury and Chinese Medicine Treatment.

Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury (MIRI). Moderate mitophagy can remove damaged mitochondria, inhibit excessive reactive oxygen species accumulation, and protect mitochondria from damage. However, excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival, and aggravates cell death. How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane, which mainly include phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced kinase 1/Parkin, hypoxia-inducible factor-1 α/Bcl-2 and adenovirus e1b19k Da interacting protein 3, FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on. In this review, the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI, and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine, thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.

Pre-clinical Evidence: Berberine as a Promising Cardioprotective Candidate for Myocardial Ischemia/Reperfusion Injury, a Systematic Review, and Meta-Analysis.

Objective: Myocardial ischemia/reperfusion (I/R) injury is one of the causes of most cardiomyocyte injuries and deaths. Berberine (BBR) has been suggested a potential to exert protective effects against myocardial I/R injury. This systematic review aims to determine the intrinsic mechanisms of BBR's protective effects in myocardial I/R injury. Methods: Seven databases were searched for studies performed from inception to July 2020. Methodological quality was assessed by SYRCLE's-RoB tool. Results: Ten studies including a total of 270 animals were included in this study. The methodology quality scores of the included studies ranged from 5 to 7 points. The meta-analysis we conducted demonstrated that BBR significantly reduced myocardial infarct size and the incidence of ventricular arrhythmia, compared to control groups (P < 0.00001). Cardiac function of animals in the BBR treatment group was also markedly increased (P < 0.00001). The index of myocardial apoptosis and the levels of biomarkers of myocardial infarction (LDH and CK) were also decreased in the BBR treatment groups compared to the control groups (P < 0.00001). Conclusions: The pre-clinical evidence, according to our study, showed that BBR is a promising therapeutic agent for myocardial I/R injury. However, this conclusion should be further investigated in clinical studies.

Randomized controlled clinical study on Yiqi Liangxue Shengji prescription for intervention cardiac function of acute myocardial infarction with ischemia-reperfusion injury.

INTRODUCTION: The morbidity and mortality of acute myocardial infarction patients still remains high after percutaneous coronary intervention (PCI). Myocardial ischemia-reperfusion (MIR) injury is one of the important reasons. Although the phenomenon of MIR injury can paradoxically reduce the beneficial effects of myocardial reperfusion, there currently remains no effective therapeutic agent for preventing MIR. Previous studies have shown that Yiqi Liangxue Shengji prescription (YLS) is effective in improving clinical symptoms and ameliorating the major adverse cardiovascular events of coronary heart disease patients undergoing PCI. This study aims to evaluate the effectiveness and safety of YLS in patients with acute myocardial infarction (AMI) after PCI. METHODS: This study is a randomized, double-blinded, placebo-controlled, single-central clinical trial. A total of 140 participants are randomly allocated to 2 groups: the intervention group and the placebo group. Based on routine medications, the intervention group will be treated with YLS and the placebo group will be treated with YLS placebo. All participants will receive a 8-week treatment and then be followed up for another 12 months. The primary outcome measures are N terminal pro B type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction. Secondary outcomes are plasma levels of microRNA-145, plasma cardiac enzyme, and Troponin I levels in blood samples, changes in ST-segment in ECG, Seattle Angina Questionnaire, the efficacy of angina symptoms, and occurrence of major adverse cardiac events. All the data will be recorded in case report forms and analyzed by SPSS V.17.0. DISCUSSION: The trial will investigate whether the postoperative administration of YLS in patients with AMI after PCI will improve cardiac function. And it explores microRNAs (miRNA)-145 as detection of blood-based biomarkers for AMI by evaluating the relation between miRNAs in plasma and cardiac function. TRIAL REGISTRATION: Chinese Clinical Trials Registry identifier ChiCTR2000038816. Registered on October 10, 2020.

[Inherited paternal antigens induce pregnancy thrombocytopenia].

Objective of this study was to investigate the correlation of body-carried inherited paternal antigens (IPA) in one mother after delivery with pregnancy thrombocytopenia. The changes of platelet (Plt) count in the mother who delivered 2 years ago and her child who is now one year's old were detected, routine tests included Helicobacter pylori, CMV, EBV, parvovirus and other herpes virus's infection were carried out. Eight insertion or deletion sites (InDel) SNP with strong polymorphisms in Chinese population was selected to detect IPA from a genomic library, then primers were designed, the nested PCR and real-time quantitative PCR were used to detect 54 healthy mother-child pairs, the obtained average value was taken as the control, finally two InDel polymorphism sites between mother and child were used to identify the mother/child microchimerism. The IPA of the mother were examined at 4 time points. The results showed that the Plt level of the mother who had suffered thrombocytopenia since 20 weeks after pregnancy reduced to 10 × 10(9)/L. After using gamma globulin, the Plt count increased gradually, but the Plt count decreased rapidly when withdrawal. This patient did not have the infections of virus and Helicobacter pylori. IPA average value of 54 cases were from 10(-5) to 10(-4). At 67 d after delivery, the Plt count of the mother was 14 × 10(9)/L, IPA was 3.45 × 10(-3), which was 30 times higher than the normal. In one month after treatment the IPA was 1.3 × 10(-4) (Plt 256 × 10(9)/L), 5 months later it was 1.2 × 10(-4) (Plt 158 × 10(9)/L), and 6 months later it was 1.5 × 10(-4) (Plt 325 × 10(9)/L). When IPA reached the normal level, the Plt count returned to normal. Her child suffered thrombocytopenia (4 × 10(9)/L) one month after he was born, then recovered after high-dose gamma globulin therapy. It is concluded that abnormal high level IPA may lead to pregnancy thrombocytopenia.

[Relationship between V617F mutation and 46/1 haplotype in JAK2 gene in patients with chronic myeloproliferative diseases and frequencies of 46/1 haplotype in different Chinese nationalities].

Somatic gene V617F mutation in JAK2 is a critical molecular and biological indicator to diagnosis of chronic myeloproliferative disease (MPD). This study was aimed to investigate the genetic background of V617F mutation in 46/1 gene haplotype in Chinese MPD patients, and the frequencies of 46/1 gene haplotype and V617F mutation in three nationalities of Chinese populations. Peripheral blood or bone marrow samples of 150 V617F mutation positive MPD patients, 123 V617F mutation negative MPD patients, 124 healthy Han individuals, 395 healthy Tibetan individuals and 315 healthy Yugu individuals were collected. The allele-specific multiplex PCR method was established, the presence or absence of V617F mutation, the presence or absence of 46/1 haplotype, and the relationship between V617F and 46/1 haplotype were easily identified by agarose gel image. The results showed that the V617F mutation located in the 46/1 haplotype of 88 cases (58.67) among 150 V617F-positive MPD cases. In 814 Chinese healthy individuals including Han, Tibetan, Yugu nationalities, the frequency of the 46/1 gene haplotype was 38.37 without difference in the frequency among different nationalities, and no V617F mutation was found in Chinese healthy populations, The frequency of the 46/1 gene haplotype was 43.09 in V617F mutation negative MPD patients and was 69.33 in V617F mutation positive MPD patients, the latter was obviously higher than former and than that in healthy Han individuals. In conclusion, a multiplex PCR method has been developed that is simple and useful to identify V617F mutation in JAK2 gene and its relationship to the 46/1 haplotype. In more than half of Chinese V617F-positive MPD patients, the V617F mutation locates in 46/1 haplotype in JAK2. The frequencies of 46/1 haplotype are statistically insignificant among Han, Tibetan and Yugu nationality populations.

[Immunogenetic diagnosis of large granular lymphocytic leukemia and therapy by sirolimus].

This study was aimed to investigate the immunogenetic diagnosis of large granular lymphocytic leukemia (LGLL) and therapeutic efficacy of sirolimus, and to analysis 256 cases of LGLL reported at home and abroad within 2000 - 2010. Besides the routine examination of peripheral blood and classification of bone marrow cell morphology, the expression of T cell receptor variable region of ß-chain (TCR BV), CD3, CD4 and CD8, as well as TCRαß, TCRγδ were detected by flow cytometry; the RT-PCR was used to amplify and determine the TCR gene spectrotypes, and to analyze the clonality of abnormal cells. Sirolimus was first given to patients who did not gain efficacy from common agents. The results showed that lymphocytosis happened in all LGLL patients, but patients from West countries always displayed neutropenia while Chinese patients always displayed anemia. In 2 out of 4 patients from our hospital, the large granular lymphocytes (LGL) were difficult to be distinguished. In all 4 patients, almost all lymphocytes were CD3(+), CD8(+), and TCRα/ß(+). TCR BV 24 gene family clones showed monoclonal TRBV 23, TRBV 20, TRBV 13.6, and TRBV 13.6, respectively. FCM results were consistent with those of RT-PCR. When 4 patients had been given sirolimus (6 mg first dose, 2 mg once a day) for about 1 week, hemoglobin level and reticulocyte count increased significantly without any serious side effects. It is concluded that the detection of specific lymphocyte monoclonal TCR BV 24 gene family by FCM contributes to the diagnosis of LGLL. Sirolimus is an effective agent without serious side effect for LGLL patients, especially for patients who cannot tolerate common drugs.