Disease burden of breast cancer and risk factors in Europe 44 countries, 1990-2019: findings of the global burden of disease study 2019.

Background: Breast cancer (BC) represents a significant health challenge in Europe due to its elevated prevalence and heterogeneity. Despite notable progress in diagnostic and treatment methods, the region continues to grapple with rising BC burdens, with comprehensive investigations into this matter notably lacking. This study explores BC burden and potential contributing risk factors in 44 European countries from 1990 to 2019. The aim is to furnish evidence supporting the development of strategies for managing BC effectively. Methods: Disease burden estimates related to breast cancer from the Global Burden of Disease 2019(GBD2019) across Eastern, Central, and Western Europe were examined using Joinpoint regression for trends from 1990 to 2019. Linear regression models examined relationships between BC burden and Socio-demographic Index (SDI), healthcare access and quality (HAQ), and BC prevalence. We utilized disability-adjusted life year(DALY) proportions for each risk factor to depict BC risks. Results: In Europe, the BC burden was 463.2 cases per 100,000 people in 2019, 1.7 times the global burden. BC burden in women was significantly higher and increased with age. Age-standardized mortality and DALY rates of BC in Europe in 2019 decreased by 23.1%(average annual percent change: AAPC -0.92) and 25.9%(AAPC -1.02), respectively, compared to 1990, in line with global trends. From 1990 to 2019, age-standardized DALY declined faster in Western Europe (-34.8%, AAPC -1.49) than in Eastern Europe (-9.4%, AAPC -0.25) and Central Europe (-15.0%, AAPC -0.56). Monaco, Serbia, and Montenegro had the highest BC burden in Europe in 2019. BC burden was negatively correlated with HAQ. In addition, Alcohol use and Tobacco were significant risk factors for DALY. High fasting plasma glucose and obesity were also crucial risk factors that cannot be ignored in DALY. Conclusion: The burden of BC in Europe remains a significant health challenge, with regional variations despite an overall downward trend. Addressing the burden of BC in different regions of Europe and the increase of DALY caused by different risk factors, targeted prevention measures should be taken, especially the management of alcohol and tobacco should be strengthened, and screening services for BC should be popularized, and medical resources and technology allocation should be optimized.

Efficacy and safety of natural killer cells injection combined with XELOX chemotherapy in postoperative patients with stage III colorectal cancer in China: a prospective randomised controlled clinical trial study protocol.

BACKGROUND: Colorectal cancer (CRC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in China. However, resistance to multiple chemotherapeutics after surgery leads to failure of the main therapy to CRC. Natural killer (NK) cells are innate cytotoxic lymphocytes that exhibit strong cytotoxic activity against tumour cells. NK cell-based therapy, either alone or in combination with chemotherapy, has achieved favourable results and holds promise for addressing recurrence and metastasis in CRC patients after surgery. METHODS AND ANALYSIS: This is a prospective, randomised controlled clinical trial to evaluate efficacy and safety of interleukin 2 activated NK cells injection combined with XELOX (capecitabine plus oxaliplatin)-based chemotherapy for postoperative CRC patients. Participants will be randomly divided into treatment group and control group, and every group includes 40 patients. The treatment group will also receive NK cells (5×109) with+XELOX-based chemotherapy, while the control group will receive only XELOX-based chemotherapy. This treatment will be repeated for eight cycles (6 months). The follow-up period lasts about 3 years, during which CEA, CA19-9, CA125, enhancement CT and colonoscopy will be conducted. The primary endpoints of this study are progression-free survival and overall survival, while the secondary endpoint is safety (number and severity of adverse events). Additionally, we aim to identify cancer stem cells in peripheral blood and predictive biomarkers (cytokines secreted by NK cells and activated markers of NK cells) that indicate patients who achieve an effective response. ETHICS AND DISSEMINATION: The study has been approved by the Clinical Research Ethics Committee of our hospital (approval number 2023LLSC006) and the Chinese Clinical Trials. It will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The study findings will be submitted to peer-reviewed journals for publication. TRIAL REGISTRATION NUMBER: Chinese Clinical Trials Registry (ChiCTR2300075861).

Canagliflozin combined with aerobic exercise protects against chronic heart failure in rats.

To determine the efficacy and potential protective mechanism of canagliflozin combined with aerobic exercise in treating chronic heart failure (CHF). Isoproterenol was injected into rats to create CHF models. The rats were then subsequently divided into saline, canagliflozin (3 mg/kg/d), aerobic exercise training, and canagliflozin combined with aerobic exercise training. Compared to the CHF group, the canagliflozin combined with the aerobic exercise group had superior ventricular remodeling and cardiac function. In rats treated with canagliflozin combined with aerobic exercise, the expression of cytochrome P450 (CYP) 4A3, CYP4A8, COL1A1, COL3A1, and FN1 was reduced, while the expression of CYP26B1, ALDH1A2, and CYP1A1 increased significantly. Additionally, canagliflozin combined with aerobic exercise decreased the phosphorylation of AKT and ERK1/2. Canagliflozin combined with aerobic exercise has a positive effect on the development of CHF via the regulation of retinol metabolism and the AKT/ERK signaling pathway.

Efficacy of polyethylene glycol loxenatide for type 2 diabetes mellitus patients: a systematic review and meta-analysis.

Objective: Some studies have proved that polyethylene glycol loxenatide (PEG-Loxe) has significant effects on controlling blood glucose and body weight in patients with type 2 diabetes mellitus (T2DM), but there is still some controversy over the improvement of blood lipid profiles (BLP) and blood pressure (BP), and more evidences are needed to verify such effects. Therefore, this study was conducted to provide a comprehensive evaluation of the efficacy of PEG-Loxe in improving blood glucose (BG), BLP, BP, body mass index (BMI), and body weight (BW) in patients with T2DM for clinical reference. Methods: Randomized controlled trials (RCT) in which PEG-Loxe was applied to treat T2DM were retrieved by searching PubMed, Cochrane Library, Embase, Medline, Scopus, Web of Science, China National Knowledge Infrastructure, China Scientific Journal, Wanfang Data, and SinoMed databases. Outcome measures included BG, BLP, BP, BMI, and BW. RevMan 5.3 software was used to perform data analysis. Results: Eighteen trials were identified involving 2,166 patients. In experimental group 1,260 patients received PEG-Loxe alone or with other hypoglycemic agents, while in control group 906 patients received placebo or other hypoglycemic agents. In the overall analysis, PEG-Loxe significantly reduced the levels of glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2-h PBG), BMI, and BW compared with control group. However, it had no obvious effect on total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusion: PEG-Loxe has better hypoglycemic effects compared with placebo in patients with T2DM, but could not significantly improved TG, LDL-C, HDL-C, SBP, and DBP. And the combination of conventional hypoglycemic drugs (CHD) and PEG-Loxe could more effectively improve the levels of HbA1c, FPG, 2-h PBG, TC, TG, BMI, and BW compared with CHD in T2DM patients. Systematic Review Registration: www.inplasy.com, identifier INPLASY202350106.

Serum levels of Vanin-2 increase with obesity in relation to inflammation of adipose tissue and may be a predictor of bariatric surgery outcomes.

Objective: Excessive obesity can lead to dysfunction in adipose tissue, which contributes to the development of comorbidities associated with obesity, such as type 2 diabetes (T2D), cardiovascular and cerebrovascular disease, among others. Previous research has mainly focused on the Vanin family in systemic inflammatory diseases or predicting its role in tumor prognosis, while neglecting its role as a secretory protein in adipose tissue inflammation and metabolism. The objective of this study was to compare the changes in Vanin-2 levels in the circulating blood of normal and obese individuals, and to assess its correlation with inflammatory factors in vivo. Furthermore, the study aimed to systematically evaluate its effectiveness in human weight loss surgery. Methods: Serum concentrations of Vanin-2 and inflammatory indicators were measured in 518 volunteers. Furthermore, the concentrations of Vanin-2 were measured both before and after weight loss through a dietetic program or laparoscopic sleeve gastrectomy (LSG). Additionally, we assessed the levels of insulin, adiponectin, and inflammation-related factors. The hormonal profile and changes in body weight were evaluated at baseline and 3 months after surgery. Results: Serum levels of Vanin-2 were found to be significantly increased in individuals with overweight/obesity (OW/OB) group (controls 438.98 ± 72.44, OW/OB 530.89 ± 79.39 ug/L; p < 0.001). These increased levels were associated with IL-18, BMI, FAT%, and HOMA-IR. However, levels of Vanin-2 remained unchanged after conventional dietary treatment. On the other hand, weight loss induced by LSG resulted in a significant decrease in Vanin-2 concentrations from 586.44 ± 48.84 to 477.67 ± 30.27 ug/L (p < 0.001), and this decrease was associated with the Vanin-2 concentrations observed before the operation. Conclusion: Serum Vanin-2 is a highly effective biomarker for assessing adipose tissue inflammation in obesity and has the potential to serve as a predictor of bariatric surgery outcomes.

Effects of once-weekly glucagon-like peptide-1 receptor agonists on type 2 diabetes mellitus complicated with coronary artery disease: Potential role of the renin-angiotensin system.

AIM: To investigate the potential mechanism of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). METHODS: We searched both Chinese and English databases for randomized controlled trials related to once-weekly GLP-1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP-1 RA. The underlying mechanism was analysed by network pharmacology. RESULTS: In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non-fatal stroke (p < .00). Levels of cardiovascular risk factors were significantly reduced in the once-weekly GLP-1 RA group compared with the conventional treatment group (glycated haemoglobin: p < .00; fasting blood glucose: p < .00; weight: p < .00; systolic blood pressure: p < .00; total cholesterol: p < .00; low-density lipoprotein cholesterol: p < .00). Network pharmacology results were enriched to the renin-angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. CONCLUSIONS: Our study suggests that once-weekly GLP-1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin-angiotensin system. However, further research is needed to confirm these findings and determine cause and effect.

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) patients who recur at different times are associated with distinct biological characteristics and prognoses. Research on rapid-relapse TNBC (RR-TNBC) is sparse. In this study, we aimed to describe the characteristics of recurrence, predictors for relapse, and prognosis in rrTNBC patients. Methods: Clinicopathological data of 1584 TNBC patients from 2014 to 2016 were retrospectively reviewed. The characteristics of recurrence were compared between patients with RR-TNBC and slow relapse TNBC(SR-TNBC). All TNBC patients were randomly divided into a training set and a validation set to find predictors for rapid relapse. The multivariate logistic regression model was used to analyze the data of the training set. C-index and brier score analysis for predicting rapid relapse in the validation set was used to evaluate the discrimination and accuracy of the multivariate logistic model. Prognostic measurements were analyzed in all TNBC patients. Results: Compared with SR-TNBC patients, RR-TNBC patients tended to have a higher T staging, N staging, TNM staging, and low expression of stromal tumor-infiltrating lymphocytes (sTILs). The recurring characteristics were prone to appear as distant metastasis at the first relapse. The first metastatic site was apt to visceral metastasis and less likely to have chest wall or regional lymph node metastasis. Six predictors (postmenopausal status, metaplastic breast cancer,≥pT3 staging,≥pN1 staging, sTIL intermediate/high expression, and Her2 [1+]) were used to construct the predictive model of rapid relapse in TNBC patients. The C-index and brier score in the validation set was 0.861 and 0.095, respectively. This suggested that the predictive model had high discrimination and accuracy. The prognostic data for all TNBC patients showed that RR-TNBC patients had the worst prognosis, followed by SR-TNBC patients. Conclusion: RR-TNBC patients were associated with unique biological characteristics and worse outcomes compared to non-RR-TNBC patients.

Calcium dobesilate efficiency in the treatment of diabetic kidney disease through suppressing MAPK and chemokine signaling pathways based on clinical evaluation and network pharmacology.

Aims: To evaluate the effectiveness and potential mechanism of calcium dobesilate (CaD) in diabetic kidney disease (DKD) patients. Methods: We searched for available randomized controlled studies on DKD patients' treatment with CaD through open databases. Continuous variables were expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). The putative targets and possible pathways of CaD on DKD were analyzed by network pharmacology. Molecular docking was employed to verify the match between CaD and the target genes. Results: In the meta-analysis, 42 trials were included, involving 3,671 DKD patients, of which 1,839 received CaD treatment in addition to conventional treatment, while 1,832 received conventional treatment. Compared with routine therapy, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) significantly decreased in the CaD treatment (early stage of DKD, Scr: p < 0.00001; BUN: p < 0.0001; clinical stage of DKD, Scr: p < 0.00001; BUN: p < 0.00001; kidney failure stage, Scr: p = 0.001; BUN: p = 0.004). The levels of serum cystatin C (Cys-C), urine levels of molecules reflecting kidney function (urinary albumin excretion rate (UAER) and micro glycoprotein), and inflammatory factors [hypersensitive c-reactive protein (hs-CRP)] were reduced compared with control groups, while glomerular filtration rate (GFR) was increased in patients treated with CaD for 12 weeks. CaD also showed a better effect on improving endothelial function. Network pharmacology results showed that the interaction pathway between CaD and DKD was mainly enriched in MAPK and chemokine signaling pathways. AKT1, CASP3, IGF1, MAPK8, and CCL5 might be the key targets for CaD in treating DKD. Conclusion: Combination with CaD is effective and safe in patients with DKD. Inhibition of MAPK and chemokine signaling pathways might be vital in treating CaD in DKD patients.

Exploration of the main active components and pharmacological mechanism of Yerba Mate based on network pharmacology.

INTRODUCTION: Yerba mate is widely consumed in South American countries and is gaining popularity around the world. Long-term consumption of yerba mate has been proven to have health-care functions and therapeutic effects on many diseases; however, its underlying mechanism has not been clearly elucidated. In this research, we explored the pharmacological mechanism of yerba mate through a network pharmacological approach. MATERIAL AND METHODS: The bioactive components of yerba mate were screened from published literature and the Traditional Chinese Medicine System Pharmacology Database (TCMSP), and the targets and related diseases were retrieved by TCMSP. Furthermore, the component-target-disease network an protein-protein interaction (PPI) network were constructed, and combined with gene ontology (GO) functional analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the pharmacological mechanism of yerba mate. RESULTS: As a result, 16 bioactive components of yerba mate were identified, which acted on 229 targets in total. Yerba mate can be used to treat 305 diseases, such as breast cancer, asthma, Alzheimer's disease, osteoarthritis, diabetes mellitus, atherosclerosis, and obesity. Protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), transcription factor AP-1 (JUN), cellular tumour antigen (p53) TP53, tumour necrosis factor (TNF), transcription factor p65 (RELA), interleukin-6 (IL6), amyloid-beta precursor protein (APP), and vascular endothelial growth factor A (VEGFA) were identified as the key targets of yerba mate playing pharmacological roles. The signalling pathways identified by KEGG pathway enrichment analysis that were most closely related to the effects of yerba mate included pathways in cancer, fluid shear stress and atherosclerosis, and human cytomegalovirus infection. CONCLUSION: the results of our study preliminarily verify the basic pharmacological action and possible mechanism of yerba mate and provide a reference for the further development of its medicinal value.

Angiotensin II receptor blocker irbesartan attenuates sleep apnea-induced cardiac apoptosis and enhances cardiac survival and Sirtuin 1 upregulation.

BACKGROUND: The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. METHODS: Sprague-Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle. RESULTS: Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. CONCLUSIONS: Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.

Cerebral Cortex Apoptosis in Early Aged Hypertension: Effects of Epigallocatechin-3-Gallate.

This study aimed to investigate cerebral cortex apoptosis on the early aged hypertension and the effects of green tea flavonoid epigallocatechin-3-gallate (EGCG). Twenty-four rats were divided into three groups: a control Wistar-Kyoto group (WKY, n = 8), a spontaneously early aged hypertensive group (SHR, n = 8), and an early aged hypertension with EGCG treatment group (SHR-EGCG, n = 8; daily oral EGCG 200 mg/kg-94%, 12 weeks). At 48 weeks old, blood pressures (BPs) were evaluated and cerebral cortexes were isolated for TUNEL assay and Western blotting. Systolic, diastolic, and mean blood pressure levels in the SHR-EGCG were reduced compared to the SHR. The percentage of neural cell deaths, the levels of cytosolic Endonuclease G, cytosolic AIF (Caspase-independent apoptotic pathway), Fas, Fas Ligand, FADD, Caspase-8 (Fas-mediated apoptotic pathway), t-Bid, Bax/Bcl-2, Bak/Bcl-xL, cytosolic Cytochrome C, Apaf-1, Caspase-9 (Mitochondrial-mediated apoptotic pathway), and Caspase-3 (Fas-mediated and Mitochondria-mediated apoptotic pathways) were increased in the SHR relative to WKY and reduced in SHR-EGCG relative to SHR. In contrast, the levels of Bcl-2, Bcl-xL, p-Bad, 14-3-3, Bcl-2/Bax, Bcl-xL/Bak, and p-Bad/Bad (Bcl-2 family-related pro-survival pathway), as well as Sirt1, p-PI3K/PI3K and p-AKT/AKT (Sirt1/PI3K/AKT-related pro-survival pathway), were reduced in SHR relative WKY and enhanced in SHR-EGCG relative to SHR. In conclusion, green tea flavonoid epigallocatechin-3-gallate (EGCG) might prevent neural apoptotic pathways and activate neural survival pathways, providing therapeutic effects on early aged hypertension-induced neural apoptosis.

Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway.

Clinical studies have shown that dapagliflozin can reduce cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM), but the exact mechanism is unclear. In this study, we used the molecular docking and network pharmacology methods to explore the potential mechanism of dapagliflozin on T2DM complicated with cardiovascular diseases (CVD). Dapagliflozin's potential targets were predicted via the Swiss Target Prediction platform. The pathogenic targets of T2DM and CVD were screened by the Online Mendelian Inheritance in Man (OMIM) and Gene Cards databases. The common targets of dapagliflozin, T2DM and CVD were used to establish a protein-protein interaction (PPI) network; the potential protein functional modules in the PPI network were found out by MCODE. Metascape tool was used for Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A potential protein functional module with the best score was obtained from the PPI network and 9 targets in the protein functional module all showed good binding properties when docking with dapagliflozin. The results of KEGG pathway enrichment analysis showed that the underlying mechanism mainly involved AGE-RAGE signalling pathway in diabetic complications, TNF signalling pathway and MAPK signalling pathway. Significantly, the MAPK signalling pathway was considered as the key pathway. In conclusion, we speculated that dapagliflozin played a therapeutic role in T2DM complicated with CVD mainly through MAPK signalling pathway. This study preliminarily reveals the possible mechanism of dapagliflozin in the treatment of T2DM complicated with CVD and provides a theoretical basis for future clinical research.

The effect of dance-based mind-motor activities on the quality of life in the patients recovering from COVID-19: A protocol for systematic review and meta-analysis.

BACKGROUND: Since the outbreak of coronavirus disease 2019 (COVID-19), with the improvement of diagnosis and treatment level in various countries, more and more patients have been discharged after systematic treatment. In order to effectively promote the overall recovery of patients' physical and mental function and quality of life (QOL), the focus of clinical work should be gradually shifted to rehabilitation treatment. Dance-based mind-motor activities were defined as coordinated upright mind-motor movements that emphasize dynamic balance, structured through music or an inner rhythm (e.g., breathing) and distinctive instructions or choreography, and that involve social interaction. It has positive effects on motor function, lung function, psychological mood and other aspects, so it can be used as a safe alternative therapy for patients recovering from COVID-19. At present, there are no relevant articles for systematic review. METHODS: From its inception until March 2021, we will conduct a comprehensive electronic search, including Cochrane Library, MEDLINE, PubMed, Springer, EMBASE, Chinese Science Citation Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, Wan-fang database. Two independent researchers will conduct article retrieval, screening, quality assessment, and data analysis through the Review Manager (V. 5.3.5). RESULTS: The results of this study will evaluate the effectiveness and safety of dance-based mind-motor activities for the improvement of QOL in COVID-19 patients during the recovery period. CONCLUSION: The conclusion of the study will provide an evidence to judge whether dance-based mind-motor activities is effective and safe for COVID-19 in recovery period. ETHICS AND DISSEMINATION: This protocol will not evaluate individual patient information or infringe patient rights and therefore does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42021232995.

Voluntary exercise training attenuated the middle-aged maturity-induced cardiac apoptosis.

AIMS: Voluntary exercise training has cardioprotective effects in humans, but the underlying mechanism is unknown. This research was done to estimate the effect of voluntary exercise training to attenuate middle-aged maturity-induced cardiac apoptosis. MATERIALS AND METHODS: The study was designed to divide 64 male mice randomly into four groups, consisting of a 9-month sedentary pre-middle-aged group (9M), 15-month sedentary middle-aged group (15M), and two exercise groups using a voluntary wheel running respectively (9M+EX, 15M+EX). After 3 months, the condition of cardiac apoptosis in different groups was measured by HE dying, TUNEL and DAPI staining, and Western Blot analysis. KEY FINDINGS: TUNEL-positive cells were increased in 15M group compared with 9M group, while decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. Protein levels of AIF, Endo G, TNF-α, TNFR1, TRAF2, TRADD, Fas, FasL, FADD, activated caspase 8, 3, 9, Bax/Bcl2, Bak/BclxL, and tBid were decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. The protein levels of pBad/Bad, 14-3-3, IGF1, IGFR1, pPI3K/PI3K, and pAKT/AKT were more activated in the 9M+EX and 15M+EX groups than those in their control groups respectively. Significant differences were found between 9M group and 15M group for the protein levels of TRAF2, FADD, Bax/Bcl2, tBid and pAKT/AKT. SIGNIFICANCE: Voluntary exercise training as an important lifestyle modification may prevent cardiac widely dispersed apoptosis and enhance cardiac survival at middle-aged maturity.

Anti-Apoptotic Effects of Diosgenin in D-Galactose-Induced Aging Brain.

The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.

Neuroprotective Effect of Rhodiola crenulata in D-Galactose-Induced Aging Model.

The medicinal plant Rhodiola crenulata grows at high altitudes in the Arctic and mountainous regions and is commonly used in phytotherapy in Eastern European and Asian countries. In the present study, we investigated the anti-apoptotic effect of Rhodiola crenulata and its neuroprotective mechanism of action in a rat model of D-galactose-induced aging. Two groups of twelve-week-old male Wistar rats received a daily injection of D-galactose (150mg/kg/day, i.p.) and orally administered Rhodiola crenulata (0, 248mg/kg/day) for eight weeks, while a control group received a saline injection (1ml/kg/day, i.p.). We examined apoptosis in the cortex and hippocampus of three groups of rats based on a terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL) positive assay. The expression levels of apoptotic and anti-apoptotic proteins in excised brains were analyzed by Western blotting. Our findings indicated that D-galactose caused marked neuronal apoptosis via activation of both extrinsic-dependent and mitochondrial-dependent apoptotic pathways. When compared to the control group, the protein levels of Fas receptor, Fas ligand, Fas-associated death domain (FADD), and activated caspase-8 (Fas-dependent apoptotic pathways), as well as those of t-Bid, Bax, cytochrome c, activated caspase-9, and activated caspase-3 (mitochondrial-dependent apoptotic pathways), were significantly increased in the D-galactose treated group. In addition, D-galactose impaired the phosphorylation of PI3K/Akt, an important survival signaling event in neurons. Rhodiola crenulata, however, protected against all these neurotoxicities in aging brains. The present study suggests that neuronal survival promoted by Rhodiola crenulata may be a potentially effective method to enhance the resistance of neurons to age-related disorders.

Antiapoptotic and mitochondrial biogenetic effects of exercise training on ovariectomized hypertensive rat hearts.

This study was to investigate the effects of exercise training on antiapoptotic pathways and mitochondrial biogenesis in ovariectomized hypertensive rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from female spontaneously hypertensive rats (SHR), which were divided into a sham-operated sedentary hypertensive (SHR-S), a sedentary hypertensive ovariectomized (SHR-O), and hypertensive ovariectomized rats that underwent treadmill exercise training (SHR-OT; 60 min/day, 5 days/wk) for 8 wk, along with normotensive Wistar Kyoto rats (WKY). When compared with the WKY group, the SHR-S group exhibited decreased protein levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial OPA-1 (mitochondrial biogenesis) and decreased further in the SHR-O group. The protein levels of p-PI3K, p-Akt, Bcl-2, Bcl-xL (prosurvival pathways), and the protein levels of PGC-1α and mitochondrial OPA1 (mitochondrial biogenesis) were increased in the SHR-OT group, but estrogen receptor (ER)α and ERß were not changed when compared with the SHR-O group. The protein levels of t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3 (mitochondria-dependent apoptotic pathways), as well as Fas ligand, TNF-α, Fas receptors, Fas-associated death domain, activated caspase 8 (Fas receptor-dependent apoptotic pathways) were decreased in the SHR-OT group, when compared with the SHR-O group. Exercise training protection on the coexistence of hypertension and ovariectomy-induced cardiac mitochondria-dependent and Fas receptor-dependent apoptotic pathways by enhancing the Bcl2-related and mitochondrial biogenetic prosurvival pathways might provide a new therapeutic effect on cardiac protection in oophorectomized early postmenopausal hypertensive women. NEW & NOTEWORTHY Widely dispersed cardiac apoptosis was found in the coexistence of hypertension and ovariectomy. Exercise training on a treadmill could prevent ovariectomized hypertension-induced widely dispersed cardiac apoptosis via mitochondria-dependent apoptotic pathway (t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) and Fas receptor-dependent apoptotic pathway (Fas ligand, tumor necrosis factor-α, Fas receptors, Fas-associated death domain, activated caspase 8, and activated caspase 3) through enhancing the Bcl2-related (p-PI3K, p-Akt, Bcl-2, Bcl-xL) and mitochondrial biogenetic (PGC-1α and mitochondrial optic atrophy 1) prosurvival pathways.

Adoptive transfer of natural killer cells promotes the anti-tumor efficacy of T cells.

The density of NK cells in tumors correlates positively with prognosis in many types of cancers. The average number of infiltrating NK cells is, however, quite modest (approximately 30 NK cells/sq.mm), even in tumors deemed to have a "high" density of infiltrating NK cells. It is unclear how such low numbers of tumor-infiltrating NK cells can influence outcome. Here, we used ovalbumin-expressing tumor cell lines and TCR transgenic, OVA-specific cytotoxic T lymphocytes (OT-I-CTLs) to determine whether the simultaneous attack by anti-tumor CTLs and IL-2-activated NK (A-NK) cells synergistically increases the overall tumor cell kill and whether upregulation of tumor MHC class-I by NK cell-derived interferon-gamma (IFNγ) improves tumor-recognition and kill by anti-tumor CTLs. At equal E:T ratios, A-NK cells killed OVA-expressing tumor cells better than OT-I-CTLs. The cytotoxicity against OVA-expressing tumor cells increased by combining OT-I-CTLs and A-NK cells, but the increase was additive rather than synergistic. A-NK cells adenovirally-transduced to produce IL-12 (A-NKIL-12) produced high amounts of IFNγ. The addition of a low number of A-NKIL-12 cells to OT-I-CTLs resulted in a synergistic, albeit modest, increase in overall cytotoxicity. Pre-treatment of tumor cells with NK cell-conditioned medium increased tumor MHC expression and sensitivity to CTL-mediated killing. Pre-treatment of CTLs with NK cell-conditioned medium had no effect on CTL cytotoxicity. In vivo, MHC class-I expression by OVA-expressing B16 melanoma lung metastases increased significantly within 24-48h after adoptive transfer of A-NKIL-12 cells. OT-I-CTLs and A-NKIL-12 cells localized selectively and equally well into OVA-expressing B16 lung metastases and treatment of mice bearing 7-days-old OVA-B16 lung metastases with both A-NKIL-12 cells and OT-I-CTLs lead to a significant prolongation of survival. Thus, an important function of tumor-infiltrating NK cells may be to increase tumor cell expression of MHC class-I through secretion of IFNγ, to prepare them for recognition by tumor-specific CTLs.

Yerba mate (Ilex paraguariensis) improves microcirculation of volunteers with high blood viscosity: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Elevated blood viscosity is a risk factor for atherosclerosis, thrombosis and other cardiovascular events. Our previous studies have suggested that consumption of Yerba mate tea (Ilex paraguariensis) has strong antioxidant and lipid-lowering properties in animals. The in vivo effects of Yerba mate on blood viscosity in humans, however, have not been studied. OBJECTIVE: This study aims to investigate the effect of Yerba mate tea on the reduction of blood viscosity and the improvement of microcirculatory parameters commonly regarded as risk factors for serious cardio and cerebrovascular disorders. METHODS: 142 subjects with high blood viscosity were recruited in this randomized, double-blind, placebo-controlled study. Yerba mate tea or placebo (5 g/day) was administered to different groups for 6 weeks. After treatment, results of hemorheological indexes, nailfold microcirculation, 6-keto-PGF1α and TXB2 and lipid profiles of subjects in the Yerba mate tea group were compared with those in the placebo-receiving group. RESULTS: Parameters of blood viscosity and microcirculation were improved in the subjects from the Yerba mate tea group but not in placebo-receiving patients. After treatment, whole blood viscosity, plasma viscosity and the Equation K value of erythrocyte sedimentation rate (ESRK) decreased significantly in the Yerba mate group. Meanwhile, shape, flow state and nailfold microcirculation appeared positively changed. Specifically, blood flow speeds accelerated gradually and nailfold weighted integral values decreased significantly. Moreover, the vasodilator 6-keto PGF1α increased while the thromboxane TXB2 decreased in serum samples of subjects in the Yerba mate-receiving group. Overall, Yerba mate tea-receiving subjects saw nearly all measured values improve to levels comparable to those characteristic of patients with normal microcirculation. CONCLUSIONS: These results indicate the therapeutic capacity of Yerba mate tea in the treatment of high blood viscosity. Here, Yerba mate tea played a role in the regulation of various indexes of hemorheology, nailfold microcirculation, and the platelet aggregating factors 6-keto-PGF1a and TXB2. The regulation of these might be correlated with reduced blood viscosity and accelerating blood flow. Thus, Yerba mate tea may reduce some key risk-factors of cardiovascular disease. Daily consumption of Yerba mate tea may be a better-tolerated option for individuals with high blood viscosity and microcirculatory disturbance and as such, a novel preventative strategy for patients at-risk for vascular disease.

[An experimental study of recombinant adenovirus microsphere carrying antisense multidrug resistance-associated protein gene for reversing MRP of hepatocellular carcinoma in vitro].

OBJECTIVE: To conduct an in vitro study on the effect of recombinant adenovirus microsphere encapusulated antisense MRP (as-mrp) for use in the gene therapy to overcome drug resistance in hepatocellular carcinoma. METHODS: Recombinant adenovirus microsphere encapusulated as-mrp was transfected into hepatocellular carcinoma multidrug resistance cells HepG2/ADM, the fluorescence intensity of transfected cells were observed at 48 hours and 120 hours after transfection. in vitro drug sensitivity was measured by MTT assay; the resistant index of andromycin resistant variants was determined by drawing the cell dosage reaction curves. The levels of MRP mRNA expression were detected by RT-PCR and the ratio of MRP mRNA/beta-actin was detected. Intracelluar rubidomycin (DNR) concertration was examined by flow cytometry (FCM). RESULTS: More than 90% of the HepG2/ADM cells could be transfected when microspheres being 10 mg. Adv microsphere inhibited the expression of mRNA in HepG2/ADM and enhanced the sensitivity of HepG2/ADM to chemotherapeutic drug. CONCLUSION: Recombinant adenovirus microsphere encapusulated as-mrp could effectively reverse HepG2/ADM cells, which would provide an experimental basis for the methods of reversing the multidrug resistance in human hepatocellular carcinoma.