Polygonum Cuspidatum Alcohol Extract Exerts Analgesic Effects via the MAPK/ERK Signaling Pathway.

Objective: Traditional Chinese medicine Polygonum cuspidatum (PC) has significant effects on reducing pain. In this study, we investigated the analgesic effects of the alcohol extract of PC on three types of inflammatory pain and explored its mechanism. Methods: Potential targets for the analgesic effects of the main active components of PC alcohol extract were screened by network pharmacology and molecular docking. Three different inflammatory pain mouse models (acetic acid twisting, formalin foot swelling, and xylene ear swelling) were used to study the analgesic effects of PC. The expression of latent signaling pathways in L4-6 spinal cord tissues in formalin foot swelling mice was evaluated using real-time qPCR (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC) analyses. Results: Network pharmacology analysis shows that PC analgesic mechanism is related to the MAPK/ERK signaling pathway. The five main active components of PC have good docking ability with JNK and p38. PC alcohol extract significantly reduced the pain behavior and alleviated inflammatory reactions in three mouse models, inhibited the mRNA and protein phosphorylation levels of JNK, ERK, p38, and CREB in spinal cord tissues. Conclusion: PC alcohol extract can inhibit inflammation and alleviate pain, which is related to its inhibition of the MAPK/ERK signaling pathway in spinal cord. Thus, PC alcohol extract is a promising candidate for pain treatment.

Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.

Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling.

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism.

Polydatin has attracted much attention as a potential cardioprotective agent against ischemic heart disease and diabetic cardiomyopathy. However, the effect and mechanism of polydatin supplementation on alcoholic cardiomyopathy (ACM) are still unknown. This study aimed to determine the therapeutic effect of polydatin against ACM and to explore the molecular mechanisms with a focus on SIRT6-AMP-activated protein kinase (AMPK) signaling and mitochondrial function. The ACM model was established by feeding C57/BL6 mice with an ethanol Lieber-DeCarli diet for 12 weeks. The mice received polydatin (20 mg kg-1) or vehicle treatment. We showed that polydatin treatment not only improved cardiac function but also reduced myocardial fibrosis and dynamin-related protein 1 (Drp-1)-mediated mitochondrial fission, and enhanced PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent mitophagy in alcohol-treated myocardium. Importantly, these beneficial effects were mimicked by SIRT6 overexpression but abolished by the infection of recombinant serotype 9 adeno-associated virus (AAV9) carrying SIRT6-specific small hairpin RNA. Mechanistically, alcohol consumption induced a gradual decrease in the myocardial SIRT6 level, while polydatin effectively activated SIRT6-AMPK signaling and modulated mitochondrial dynamics and mitophagy, thus reducing oxidative stress damage and preserving mitochondrial function. In summary, these data present new information regarding the therapeutic actions of polydatin, suggesting that the activation of SIRT6 signaling may represent a new approach for tackling ACM-related cardiac dysfunction.

Activation of PKG-CREB-KLF15 by melatonin attenuates Angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism.

Mitochondrial reactive oxygen species (ROS) damage and atrial remodeling serve as the crucial substrates for the genesis of atrial fibrillation (AF). Branched-chain amino acids (BCAAs) catabolic defect plays critical roles in multiple cardiovascular diseases. However, the alteration of atrial BCAA catabolism and its role in AF remain largely unknown. This study aimed to explore the role of BCAA catabolism in the pathogenesis of AF and to further evaluate the therapeutic effect of melatonin with a focus on protein kinase G (PKG)-cAMP response element binding protein (CREB)-Krüppel-like factor 15 (KLF15) signaling. We found that angiotensin II-treated atria exhibited significantly elevated BCAA level, reduced BCAA catabolic enzyme activity, increased AF vulnerability, aggravated atrial electrical and structural remodeling, and enhanced mitochondrial ROS damage. These deleterious effects were attenuated by melatonin co-administration while exacerbated by BCAA oral supplementation. Melatonin treatment ameliorated BCAA-induced atrial damage and reversed BCAA-induced down-regulation of atrial PKGIα expression, CREB phosphorylation as well as KLF15 expression. However, inhibition of PKG partly abolished melatonin-induced beneficial actions. In summary, these data demonstrated that atrial BCAA catabolic defect contributed to the pathogenesis of AF by aggravating tissue fibrosis and mitochondrial ROS damage. Melatonin treatment ameliorated Ang II-induced atrial structural as well as electrical remodeling by activating PKG-CREB-KLF15. The present study reveals additional mechanisms contributing to AF genesis and highlights the opportunity of a novel therapy for AF by targeting BCAA catabolism. Melatonin may serve as a potential therapeutic agent for AF intervention.

Radiotherapy after mastectomy has significant survival benefits for inflammatory breast cancer: a SEER population-based retrospective study.

OBJECTIVES: The survival benefit of postmastectomy radiotherapy (PMRT) has not been fully proven in inflammatory breast cancer (IBC). Thus, in the present research, we aimed at elucidating the effects of PMRT on the survival of IBC patients. METHODS: Eligible patients were collected from the Surveillance, Epidemiology, and End Results (SEER) dataset between 2010 and 2013. The Kaplan-Meier method along with the log-rank test was utilized for the comparison of both the overall survival (OS) andthe cancer-specific survival (CSS) in patients undergoing PMRT or not. Additionally, multivariate survival analysis of CSS and OS were performed using the Cox proportional hazard model. RESULTS: In total, 293 eligible cases were identified, with the median follow-up time of 27 months (range: 5-59 months). After propensity score matching (PSM), 188 patients (94 for each) were classified intothe No-PMRT and the PMRT group. Consequently, significantly higher OS rates were detected in the PMRT group compared with the No-PMRT group prior to PSM (P = 0.034), and significantly higher CSS (P = 0.013) and OS (P = 0.0063) rates were observed following PSM. Furthermore, multivariate analysis revealed thatPMRT [CSS (HR: 0.519, 95% CI [0.287-0.939], P = 0.030); OS (HR: 0.480, 95% CI [0.269-0.859], P = 0.013)], as well as Her2+/HR+ subtype, was independent favorable prognostic factors.Besides, black ethnicity, AJCC stage IV and triple-negative subtype were independent unfavorable prognostic factors. Further subgroup analysis revealed that most of the study population could benefit from PMRT, no matter OS or CSS. CONCLUSIONS: Our findings support that PMRT could improve the survival of IBC patients.

The Role of Spirituality in Patients Undergoing Hematopoietic Stem Cell Transplantation: a Systematic Mixed Studies Review.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has become the standard treatment for many diseases, but it is an intense and distinctive experience for patients. HSCT-related mortality is present throughout the whole process of transplantation, from pretransplantation to recovery. Long-term rehabilitation and the uncertain risk of death evoke feelings of vulnerability, helplessness, and intense fear. Zimmermann et al. proposed that spiritual well-being is an important dimension of quality of life and that patients at the end stage of life require spiritual support in addition to physical care, psychological care, and social support. Therefore, the purpose of this review is to examine the role of spirituality in the process of HSCT. METHOD: A systematic mixed studies review (SMSR) was based on Pluye and Hong's framework to understand the role of spirituality in patients' experiences while undergoing HSCT. We use the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement to report the results of integration. RESULTS: Fifteen original qualitative studies, 19 quantitative studies, and one mixed method study were included in the systematic mixed studies review. The evidence from the review revealed the following three themes: the spiritual experiences of HSCT patients, the spiritual coping styles of HSCT patients, and the spiritual need changes brought about by HSCT. DISCUSSION: Few medical institutions currently offer spiritual healing, although HSCT patients with different cultural backgrounds may have different spiritual experiences and spiritual coping styles. Psychotherapists or nurses should be considered to provide spiritual care for patients undergoing HSCT, to help patients cope with disease pressures, promote HSCT patients' comfort, and improve their quality of life.

Extent of breast cancer type 1 promoter methylation correlates with clinicopathological features in breast cancers.

AIM OF STUDY: The current meta-analysis investigated the correlation between breast cancer type 1 (BRCA1) promoter methylation and the clinicopathological features of breast cancer (BC). MATERIALS AND METHODS: An electronic literature search was performed to identify and select cohort studies, by employing stringent inclusion and exclusion criteria, for data relevant to promoter methylation of BRCA1 and BC. Statistical analysis of the extracted data was performed using comprehensive meta-analysis 2.0 software (CMA 2.0) (Biostat Inc., Englewood, New Jersey, USA). RESULTS: A total of 125 published studies were retrieved from the literature search, and finally, 18 cohort studies meeting our inclusion criteria were incorporated into our meta-analysis. The 18 studies contained a total of 3213 BC patients. Meta-analysis results revealed that BRCA1 promoter methylation in BC patients with high and moderately differentiated tumors (I-II) was significantly lower than patients with poorly-differentiation tumors (III) (odds ratio [OR] =0.450, 95% confidence interval [95% CI] =0.241-0.838, P = 0.012). BRCA1 promoter methylation in BC patients with lymph node (LN) metastasis was significantly higher than patients without LN metastasis (OR = 2.244, 95% CI = 1.278-3.940, P = 0.005). The results of ethnicity-based subgroup analysis showed a significant difference in histological grade of BC on Asians, LN metastasis of BC in Asians and Caucasians, subtypes of BC in Caucasians, and age at diagnosis of BC patients in Caucasians (all P < 0.05). CONCLUSIONS: Our meta-analysis revealed that BRCA1 promoter methylation status is linked to tumor grade and LN metastasis of BC.

An enzymatic mechanism for balancing the stoichiometry of nitrogen and phosphorus in a shallow Chinese eutrophic lake.

The over-enrichment of lake waters with nitrogen (N) and phosphorus (P) has become a serious environmental problem, but modes of change in stoichiometry and enzymatic regeneration along trophic gradients are largely unknown. Seasonal variations in the kinetics of extracellular aminopeptidase (LAP) and alkaline phosphatase (AP), together with the composition of phytoplankton and concentrations of N and P, were examined from Jun 2013 to September 2014 in a Chinese shallow lake in which two basins had contrasting trophic states. The turbid basin had a significantly higher concentration of chlorophyll a and lower ratios of N to P. In parallel, the turnover time of organic N mediated by LAP (LAPT) was significantly shorter, and its maximum velocity (Vmax) was significantly higher compared to those in the clear basin. Considering data from both basins, there were linear decreases in N/P and the ratios between dissolved inorganic N and total N with an increasing trophic state index, coupled with a significantly positive relationship between N/P and LAPT. Additionally, with decreasing TN/TP, the Michaelis constant (Km) of the AP increased linearly, reducing the efficiency of P regeneration. In contrast, the Km value of LAP decreased, and Vmax increased, which enhanced N mineralization by simultaneously increasing the reaction velocity and improving the affinity for substrate. Additionally, the Km value of LAP was significantly related to that of AP and the ammonium concentration. Thus, substrate affinity acted as a key factor modifying the pathways of enzymatic degradation of organic N and P according to their stoichiometry in the water column. Phytoplankton composition was directly linked to LAPT. Overall, this study seemed to be the first to connect a stoichiometric shift of N and P with kinetics of extracellular enzymes responsible for their regeneration along trophic gradients, presenting an additional pathway to overcome nitrogen deficiency in eutrophic lakes.

Evaluation of Outpatient Antibiotic Use in Beijing General Hospitals in 2015.

BACKGROUND: Medical misuse of antibiotics is associated with the acquisition and spread of antibiotic resistance, resulting in a lack of effective drugs and increased health-care cost. Nevertheless, inappropriate antibiotic use in China remains common and the situation requires urgent improvement. Here, we analyzed the prescriptions of antibiotics and evaluated the rationality of antibiotic use among outpatients in Beijing general hospitals during 2015. METHODS: We collected basic medical insurance claim data from January 1, 2015 to December 31, 2015 in 507 general hospitals of Beijing. A descriptive analysis of outpatient antibiotic prescribing was performed. The Anatomical Therapeutic Chemical Classification/defined daily doses system was used to evaluate the rationality of antibiotic use. RESULTS: Over the study, an estimated 721,930, 613,520, and 822,480 antibiotics were dispensed in primary, secondary, and tertiary general hospitals corresponding to 5.09%, 5.06%, and 2.53% of all prescriptions, respectively. Antibiotic combinations represented 2.95%, 7.74%, and 10.18% of the total antibiotic prescriptions, respectively. Expenditure for the top twenty antibiotics in primary, secondary, and tertiary general hospitals was RMB 42.92, 65.89, and 83.26 million Yuan, respectively. Cephalosporins were the most frequently prescribed class of antibiotic in clinical practice. The antibiotics used inappropriately included azithromycin enteric-coated capsules, compound cefaclor tablets and nifuratel nysfungin vaginal soft capsules in primary hospitals, amoxicillin and clavulanate potassium dispersible tablets (7:1) and cefonicid sodium for injection in secondary hospitals, cefminox sodium for injection and amoxicillin sodium and sulbactam sodium for injection in tertiary hospitals. CONCLUSIONS: Antibiotic use in Beijing general hospitals is generally low; however, inappropriate antibiotic use still exists. Inappropriately used antibiotics should be subject to rigorous control and management, and public policy initiatives are required to promote the judicious use of antibiotics.

Standardization of Type 2 Diabetes Outpatient Expenditure with Bundled Payment Method in China.

BACKGROUND: In recent years, the prevalence of type 2 diabetes among Chinese population has been increasing by years, directly leading to an average annual growth rate of 19.90% of medical expenditure. Therefore, it is urgent to work on strategies to control the growth of medical expenditure on type 2 diabetes on the basis of the reality of China. Therefore, in this study, we explored the feasibility of implementing bundled payment in China through analyzing bundled payment standards of type 2 diabetes outpatient services. METHODS: This study analyzed the outpatient expenditure on type 2 diabetes with Beijing Urban Employee's Basic Medical Insurance from 2010 to 2012. Based on the analysis of outpatient expenditure and its influential factors, we adopted decision tree approach to conduct a case-mix analysis. In the end, we built a case-mix model to calculate the standard expenditure and the upper limit of each combination. RESULTS: We found that age, job status, and whether with complication were significant factors that influence outpatient expenditure for type 2 diabetes. Through the analysis of the decision tree, we used six variables (complication, age, diabetic foot, diabetic nephropathy, cardiac-cerebrovascular disease, and neuropathy) to group the cases, and obtained 11 case-mix groups. CONCLUSIONS: We argued that it is feasible to implement bundled payment on type 2 diabetes outpatient services. Bundled payment is effective to control the increase of outpatient expenditure. Further improvements are needed for the implementation of bundled payment reimbursement standards, together with relevant policies and measures.

Comparative Study of Three Commonly Used Methods for Hospital Efficiency Analysis in Beijing Tertiary Public Hospitals, China.

BACKGROUND: Tertiary hospitals serve as the medical service center within the region and play an important role in the medical and health service system. They are also the key targets of public hospital reform in the new era in China. Through the reform of health system, the public hospital efficiency has changed remarkably. Therefore, this study aimed to provide some advice for efficiency assessment of public hospitals in China by comparing and analyzing the consistency of results obtained by three commonly used methods for examining hospital efficiency, that is, ratio analysis (RA), stochastic frontier analysis (SFA), and data envelopment analysis (DEA). METHODS: The theoretical basis, operational processes, and the application status of RA, SFA, and DEA were learned through literature analysis. Then, the empirical analysis was conducted based on measured data from 51 tertiary public hospitals in Beijing from 2009 to 2011. RESULTS: The average values of hospital efficiency calculated by SFA with index screening and principal component analysis (PCA) results and those calculated by DEA with index screening results were relatively stable. The efficiency of specialized hospitals was higher than that of general hospitals and that of traditional Chinese medicine hospitals. The results obtained by SFA with index screening results and the results obtained by SFA with PCA results showed a relatively high correlation (r-value in 2009, 2010, and 2011 were 0.869, 0.753, and 0.842, respectively, P < 0.01). The correlation between results obtained by DEA with index screening results and PCA results and results obtained by other methods showed statistical significance, but the correlation between results obtained by DEA with index screening results and PCA results was lower than that between results obtained by SFA with index screening results and PCA results. CONCLUSIONS: RA is not suitable for multi-index evaluation of hospital efficiency. In the given conditions, SFA is a stable efficiency analysis method. In the evaluation of hospital efficiency, DEA combined with PCA should be adopted with caution due to its poor stability.

Effect and cost of perioperative use of antibiotics in coronary artery bypass grafting: a randomized controlled study.

BACKGROUND: Bacterial infections remain a serious complication following coronary artery bypass grafting (CABG). The objective of the study was to determine the effectiveness of a guideline for the appropriate use of antibiotics in CABG during the perioperative period. METHODS: Six hundred and fourteen hospitalized patients who had undergone CABG from January to June 2006 were randomly allocated to an intervention group and a control group. The data on the hospital stay, days of antibiotic used, types of prophylactic antibiotics used, surgical wound infection and pulmonary infection and antibiotic costs for the patients were compared. RESULTS: The postoperative hospitalization days of the intervention group were significantly fewer than that for the control group (P < 0.05). The time of antibiotic use and post-infection treatment time were also significantly less in the intervention group than in the control group (P < 0.05). The average hospital daily cost and total cost of antibiotics were less in the intervention group than in the control group (P < 0.05). Compared with the control group, prophylactic antibiotic use in the intervention group was more reasonable. CONCLUSIONS: The guideline for the appropriate use of antibiotics in CABG during the perioperative period is effective strategies for reducing antibiotic costs, the time of antibiotic use and post-infection treatment time without compromising the patients' clinical outcome.