Tannic acid attenuate AKT phosphorylation to inhibit UMUC3 bladder cancer cell proliferation.

Urothelial bladder cancer is rapidly spreading across Western countries, and therapy has shown little-to-moderate effects on bladder cancer. Thus, focusing on curbing cancer incidence has become crucial. The aim of the present study was to investigate the anticancer effects of Tannic acid (TA) in human bladder cancer. UMUC3 bladder cancer cells were treated with different concentrations of TA (0-100 µM) and tested for cell viability, colony formation, and apoptosis. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of TA was examined. TA treatment significantly inhibited the viability and increased percentage of apoptotic cells, thereby decreasing antiapoptotic proteins (BCL2, MCL-1, and BCL-XL) expression, resulting in the Caspase-3 activation. TA treatment decreased stem cell markers expression such as SOX2, OCT4, and NANOG. Additionally, TA treatment significantly reduced the phosphorylation levels of Akt in bladder cancer cells. Our study demonstrates the growth inhibitory effects of TA in bladder cancer cells, and highlights its potential as an anticancer agent for bladder cancer.

Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses.

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

Low-dose rapamycin prevents Ang-II-induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR model.

Hypertension is a common chronic cardiovascular disease reported among both men and women. Hypertension in males affects the testis and reproduction function; however, the pathogenesis is poorly understood. Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high-doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low-dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low-dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin-converting enzyme-2 (ACE2) expression through AT1R, p-ERK, and MAS receptor in LC-540 Leydig cells in a dose-dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3ß-HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p-PKAc and p-PI3k in Ang II-treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2-mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang-II-induced testicular toxicity, suggesting low-dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.

Exploring the COVID-19 Pandemic as a Catalyst for Behavior Change Among Patient Health Record App Users in Taiwan: Development and Usability Study.

BACKGROUND: During the COVID-19 pandemic, personal health records (PHRs) have enabled patients to monitor and manage their medical data without visiting hospitals and, consequently, minimize their infection risk. Taiwan's National Health Insurance Administration (NHIA) launched the My Health Bank (MHB) service, a national PHR system through which insured individuals to access their cross-hospital medical data. Furthermore, in 2019, the NHIA released the MHB software development kit (SDK), which enables development of mobile apps with which insured individuals can retrieve their MHB data. However, the NHIA MHB service has its limitations, and the participation rate among insured individuals is low. OBJECTIVE: We aimed to integrate the MHB SDK with our developed blockchain-enabled PHR mobile app, which enables patients to access, store, and manage their cross-hospital PHR data. We also collected and analyzed the app's log data to examine patients' MHB use during the COVID-19 pandemic. METHODS: We integrated our existing blockchain-enabled mobile app with the MHB SDK to enable NHIA MHB data retrieval. The app utilizes blockchain technology to encrypt the downloaded NHIA MHB data. Existing and new indexes can be synchronized between the app and blockchain nodes, and high security can be achieved for PHR management. Finally, we analyzed the app's access logs to compare patients' activities during high and low COVID-19 infection periods. RESULTS: We successfully integrated the MHB SDK into our mobile app, thereby enabling patients to retrieve their cross-hospital medical data, particularly those related to COVID-19 rapid and polymerase chain reaction testing and vaccination information and progress. We retrospectively collected the app's log data for the period of July 2019 to June 2021. From January 2020, the preliminary results revealed a steady increase in the number of people who applied to create a blockchain account for access to their medical data and the number of app subscribers among patients who visited the outpatient department (OPD) and emergency department (ED). Notably, for patients who visited the OPD and ED, the peak proportions with respect to the use of the app for OPD and ED notes and laboratory test results also increased year by year. The highest proportions were 52.40% for ED notes in June 2021, 88.10% for ED laboratory test reports in May 2021, 34.61% for OPD notes in June 2021, and 41.87% for OPD laboratory test reports in June 2021. These peaks coincided with Taiwan's local COVID-19 outbreak lasting from May to June 2021. CONCLUSIONS: This study developed a blockchain-enabled mobile app, which can periodically retrieve and integrate PHRs from the NHIA MHB's cross-hospital data and the investigated hospital's self-pay medical data. Analysis of users' access logs revealed that the COVID-19 pandemic substantially increased individuals' use of PHRs and their health awareness with respect to COVID-19 prevention.

Protective effects of CHIP overexpression and Wharton's jelly mesenchymal-derived stem cell treatment against streptozotocin-induced neurotoxicity in rats.

Diabetic neuropathy is a common complication of diabetes mellitus, posing a challenge in treatment. Previous studies have indicated the protective role of mesenchymal stem cells against several disorders. Although they can repair nerve injury, their key limitation is that they reduce viability under stress conditions. We recently observed that overactivation of the carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP) considerably rescued cell viability under hyperglycemic stress and played an essential role in promoting the beneficial effects of Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Thus, the present study was designed to unveil the protective effects of CHIP-overexpressing WJMSCs against neurodegeneration using in vivo animal model based study. In this study, western blotting observed that CHIP-overexpressing WJMSCs could rescue nerve damage observed in streptozotocin-induced diabetic rats by activating the AMPKα/AKT and PGC1α/SIRT1 signaling pathway. In contrast, these signaling pathways were downregulated upon silencing CHIP. Furthermore, CHIP-overexpressing WJMSCs inhibited inflammation induced in the brains of diabetic rats by suppressing the NF-κB, its downstream iNOS and cytokines signaling nexus and enhancing the antioxidant enzyme system. Moreover, TUNEL assay demonstrated that CHIP carrying WJMSCs suppressed the apoptotic cell death induced in STZ-induced diabetic group. Collectively, our findings suggests that CHIP-overexpressing WJMSCs might exerts beneficial effects, which may be considered as a therapeutic strategy against diabetic neuropathy complications.

Calycosin alleviates H2 O2 -induced astrocyte injury by restricting oxidative stress through the Akt/Nrf2/HO-1 signaling pathway.

Oxidative stress-induced brain cell damage is a crucial factor in the pathogenesis of reactive oxygen species (ROS)-associated neurological diseases. Further, studies show that astrocytes are an important immunocompetent cell in the brain and play a potentially significant role in various neurological diseases. Therefore, elimination of ROS overproduction might be a potential strategy for preventing and treating neurological diseases. Accumulating evidence indicates that calycosin, a main active ingredient in the Chinese herbal medicine Huangqi (Radix Astragali Mongolici), is a potential therapeutic candidate with anti-inflammation and/or anticancer effects. Here, we investigated the protective effect of calycosin in brain astrocytes by mimicking in vitro oxidative stress using H2 O2 . The results revealed that H2 O2 significantly induced ROS and inflammatory factor (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) production, whereas post-treatment with calycosin dramatically and concentration-dependently suppressed H2 O2 -induced damage by enhancing cell viability, repressing ROS and inflammatory factor production, and increasing superoxide dismutase (SOD) expression. Additionally, we found that calycosin facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of antioxidant molecules (heme oxygenase [HO]-1 and SOD) following H2 O2 treatment. Moreover, calycosin did not attenuated H2 O2 -induced astrocyte damage and ROS production in the presence of the ML385 (a Nrf2-specific inhibitor) and following Nrf2 silencing. Furthermore, calycosin failed to increase Akt phosphorylation and mitigate H2 O2 -induced astrocyte damage in the presence of the LY294002 (a selective phosphatidylinositol 3-kinase inhibitor), indicating that calycosin-mediated regulation of oxidative-stress homeostasis involved Akt/Nrf2/HO-1 signaling. These findings demonstrated that calycosin protects against oxidative injury in brain astrocytes by regulating oxidative stress through the AKT/Nrf2/HO-1 signaling pathway.

Edible folic acid and medicinal folinic acid produce cardioprotective effects in late-stage triple-transgenic Alzheimer's disease model mice by suppressing cardiac hypertrophy and fibrosis.

Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.

Isoliquiritigenin ameliorates advanced glycation end-products toxicity on renal proximal tubular epithelial cells.

Diabetic nephropathy is a serious chronic complication affecting at least 25% of diabetic patients. Hyperglycemia associated advanced glycation end-products (AGEs) increase tubular epithelial-myofibroblast transdifferentiation (TEMT) and extracellular matrix synthesis and thereby causes renal fibrosis. The chalcone isoliquiritigenin, found in many herbs of Glycyrrhiza family, is known for potential health-promoting effects. However, their effects on AGE-associated renal proximal tubular fibrosis are not known yet. In this study, the effect of isoliquiritigenin on AGE-induced renal proximal tubular fibrosis was determined in cultured HK-2 cell line. The results show that 200 µg/mL of AGE-induced TEMT and the formed myofibroblasts synthesized collagen to increase extracellular matrix formation thereby lead to renal tubular fibrosis. However, treatment with 200 nM of isoliquiritigenin considerably inhibited the TEMT and suppressed the TGFß/STAT3 mechanism to inhibit collagen secretion. Therefore, isoliquiritigenin effectively suppressed AGE-induced renal tubular fibrosis.

A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

Naphthalimide derivatives have multiple biological activities, including antitumour and anti-inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. The data revealed that compound 5 (5-10 µM) inhibited collagen- and convulxin- but not thrombin- or U46619-mediated platelet aggregation, suggesting that compound 5 is more sensitive to the inhibition of glycoprotein VI (GPVI) signalling. Indeed, compound 5 could inhibit the phosphorylation of signalling molecules downstream of GPVI, followed by the inhibition of calcium mobilization, granule release and GPIIb/IIIa activation. Moreover, compound 5 prevented pulmonary embolism and prolonged the occlusion time, but tended to prolong the bleeding time, indicating that it can prevent thrombus formation but may increase bleeding risk. This study is the first to demonstrate that the naphthalimide derivative compound 5 exerts antiplatelet and antithrombotic effects. Future studies should modify compound 5 to synthesize more potent and efficient antiplatelet agents while minimizing bleeding risk, which may offer a therapeutic potential for cardiovascular diseases.

miR-145-5p targets paxillin to attenuate angiotensin II-induced pathological cardiac hypertrophy via downregulation of Rac 1, pJNK, p-c-Jun, NFATc3, ANP and by Sirt-1 upregulation.

Pathological cardiac hypertrophy is associated with many diseases including hypertension. Recent studies have identified important roles for microRNAs (miRNAs) in many cardiac pathophysiological processes, including the regulation of cardiomyocyte hypertrophy. However, the role of miR-145-5p in the cardiac setting is still unclear. In this study, H9C2 cells were overexpressed with microRNA-145-5p, and then treated with Ang-II for 24 h, to study the effect of miR-145-5p on Ang-II-induced myocardial hypertrophy in vitro. Results showed that Ang-II treatment down-regulated miR-145-5p expression were revered after miR-145-5p overexpression. Based on results of bioinformatics algorithms, paxillin was predicted as a candidate target gene of miR-145-5p, luciferase activity assay revealed that the luciferase activity of cells was substantial downregulated the following co-transfection with wild paxillin 3'UTR and miR-145-5p compared to that in scramble control, while the inhibitory effect of miR-145-5p was abolished after transfection of mutant paxillin 3'UTR. Additionally, overexpression of miR-145-5p markedly inhibited activation of Rac-1/ JNK /c-jun/ NFATc3 and ANP expression and induced SIRT1 expression in Ang-II treated H9c2 cells. Jointly, our study suggested that miR-145-5p inhibited cardiac hypertrophy by targeting paxillin and through modulating Rac-1/ JNK /c-jun/ NFATc3/ ANP / Sirt1 signaling, therefore proving novel downstream molecular pathway of miR-145-5p in cardiac hypertrophy.

Exercise renovates H2S and Nrf2-related antioxidant pathways to suppress apoptosis in the natural ageing process of male rat cortex.

Ageing is a complex biological process that increases the probability of disease and death, which affects the organs of all species. The accumulation of oxidative damage in the brain contributes to a progressive loss of cognitive functions or even declined the energy metabolism. In this study, we tested the effects of exercise training on the apoptosis, survival, and antioxidant signaling pathways in the cerebral cortex of three age groups of male rats; 3, 12, and 18 months. We observed that H2S and the expression of Nrf2-related antioxidant pathways declined with age and increased after exercise training. IGF1R survival pathway was less increased in middle-aged rats; however, significantly increased after exercise training. The expression of mitochondrial-dependent apoptotic pathway components, such as Bak, cytochrome C, and caspase 3 in the ageing control group, were much higher than those of the exercise training groups. This study demonstrated that exercise training could reduce the apoptosis and oxidative stress that accrues throughout ageing, which causes brain damage.

Bioactive dipeptide from potato protein hydrolysate combined with swimming exercise prevents high fat diet induced hepatocyte apoptosis by activating PI3K/Akt in SAMP8 mouse.

Obesity in aged population have surges the occurrence of various metabolic disorders including Nonalcoholic fatty liver disease (NAFLD). Apoptosis in the liver is one of the causative factors for NAFLD-induced liver damage. Plants derived bioactive peptides have been shown as an alternative treatment approach for the treating NAFLD due to its less toxicity. Moderate exercise has been reported to improve cellular physiological function prevent age associated metabolic disorders. In the present study, we evaluate the effects of bioactive dipeptide (IF) derived from alcalase potato-protein hydrolysates and swimming exercise in preventing High Fat Diet (HFD)-induced liver damage in senescence accelerated mouse-prone 8 (SAMP8) mice model. Mouse were fed with HFD for 6 weeks followed by oral IF administration or swimming exercise and both for 8 weeks. HFD induces significant structural changes in liver of HFD fed SAMP8 mouse. Both IF administration and exercise prevent the structural abnormalities induced by HFD, however, combined IF treatment and exercise offer better protection. Combined IF treatment and exercise activate PI3K/Akt cell survival protein and effectively inhibit Fas-FADD-induced apoptosis in HFD fed aged mouse. Oral supplementation of bioactive peptide IF combined with moderate swimming exercise effectively alleviate HFD-induced hepatic injury in aged mice.

Correction: A COVID-19 Pandemic Artificial Intelligence-Based System With Deep Learning Forecasting and Automatic Statistical Data Acquisition: Development and Implementation Study.

[This corrects the article DOI: 10.2196/27806.].

A COVID-19 Pandemic Artificial Intelligence-Based System With Deep Learning Forecasting and Automatic Statistical Data Acquisition: Development and Implementation Study.

BACKGROUND: More than 79.2 million confirmed COVID-19 cases and 1.7 million deaths were caused by SARS-CoV-2; the disease was named COVID-19 by the World Health Organization. Control of the COVID-19 epidemic has become a crucial issue around the globe, but there are limited studies that investigate the global trend of the COVID-19 pandemic together with each country's policy measures. OBJECTIVE: We aimed to develop an online artificial intelligence (AI) system to analyze the dynamic trend of the COVID-19 pandemic, facilitate forecasting and predictive modeling, and produce a heat map visualization of policy measures in 171 countries. METHODS: The COVID-19 Pandemic AI System (CPAIS) integrated two data sets: the data set from the Oxford COVID-19 Government Response Tracker from the Blavatnik School of Government, which is maintained by the University of Oxford, and the data set from the COVID-19 Data Repository, which was established by the Johns Hopkins University Center for Systems Science and Engineering. This study utilized four statistical and deep learning techniques for forecasting: autoregressive integrated moving average (ARIMA), feedforward neural network (FNN), multilayer perceptron (MLP) neural network, and long short-term memory (LSTM). With regard to 1-year records (ie, whole time series data), records from the last 14 days served as the validation set to evaluate the performance of the forecast, whereas earlier records served as the training set. RESULTS: A total of 171 countries that featured in both databases were included in the online system. The CPAIS was developed to explore variations, trends, and forecasts related to the COVID-19 pandemic across several counties. For instance, the number of confirmed monthly cases in the United States reached a local peak in July 2020 and another peak of 6,368,591 in December 2020. A dynamic heat map with policy measures depicts changes in COVID-19 measures for each country. A total of 19 measures were embedded within the three sections presented on the website, and only 4 of the 19 measures were continuous measures related to financial support or investment. Deep learning models were used to enable COVID-19 forecasting; the performances of ARIMA, FNN, and the MLP neural network were not stable because their forecast accuracy was only better than LSTM for a few countries. LSTM demonstrated the best forecast accuracy for Canada, as the root mean square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) were 2272.551, 1501.248, and 0.2723075, respectively. ARIMA (RMSE=317.53169; MAPE=0.4641688) and FNN (RMSE=181.29894; MAPE=0.2708482) demonstrated better performance for South Korea. CONCLUSIONS: The CPAIS collects and summarizes information about the COVID-19 pandemic and offers data visualization and deep learning-based prediction. It might be a useful reference for predicting a serious outbreak or epidemic. Moreover, the system undergoes daily updates and includes the latest information on vaccination, which may change the dynamics of the pandemic.

Cardioprotective potential of amygdalin against angiotensin II induced cardiac hypertrophy, oxidative stress and inflammatory responses through modulation of Nrf2 and NF-κB activation.

Heart failure (HF) and cardiac hypertrophy is an unfavorable outcome of pathological cardiac remodeling and represents the most important contributing factor for HF and cardiac hypertrophy. Amygdalin (AMG) is a cyanogenic glycoside derived from bitter almonds. Accumulating evidences have highlighted their pharmacological potentials against various diseases. However, there is no report delineating the potential of AMG against angiotensin (Ang II) induced cardiac injuries. Thus, the present study was performed to explore whether AMG could ameliorate Ang II induced cardiomyopathies and thereby ascertain the underlying mechanisms thereof. To this end, H9c2 cells were treated with Ang II and thereafter treated with various concentration of AMG and finally the cardio-protective effects of AMG were analyzed through Western blotting, immunofluorescence, and insilico analysis. Our results showed that the cardiomyocyte cell size, inflammatory markers and cytokines(pNF-κB, TNF-α, iNOS and COX-2) were markedly increased following Ang II treatment; nevertheless, treatment with AMG led to considerable decrement in the Ang II induced enlargement of the cardiomyocytes, and attenuate the expression of hypertrophic markers(ANP, BNP and MHC-7), inflammatory markers and cytokines. Additionally, oxidative stress related proteins (Nrf2, catalase, SOD-2, and GPX-4) were markedly increased following AMG treatment. Molecular docking reveals the interaction of AMG with Nrf2 possessing good binding affinity. Cumulatively, our study highlights the cardio-protective role of AMG against Ang II induced cardiomyopathies, including oxidative stress and inflammation effects. The intriguing in vitro results warrants the need of further animal studies to truly ascertain their potentialities.

Epimedium promotes steroidogenesis by CREB activation-mediated mitochondrial fusion in endosulfan treated leydig cells.

Epimedium, is used traditionally in Chinese medicine to treat infertility problems. In this study, we establish the cell model to elucidate the protective effect of epimedium against ES by analyzing the molecular relationship between mitochondrial dynamics and steroidogenesis and to explore the molecular mechanism focusing on mitochondria function relating to fertility. ES induced ROS accumulation in mitochondria and the epimedium treatment significantly reduced the ROS accumulation. Furthermore, mitochondria morphology was restored to elongated shape following epimedium treatment. Epimedium treatment promoted dynamin-associated protein 1 (Drp1)-mediated steroidogenesis pathway by upregulating PKA, CREB, Drp1, and StAR protein expression in response to ES exposure in Leydig cells. Moreover, it was also identified that, CREB plays an important role in epimedium activation in Drp1-mediated steroidogenesis signaling pathway by increasing, phospho-CREB expression in nucleus. Testosterone level is decreased in ES-exposed cells; however, the testosterone level was increased after epimedium treatment. In conclusion, epimedium treatment improved mitochondria function in ES-exposed Leydig cells and activated downstream Drp1-dependent steroidogenesis by CREB mediated signaling pathway.

Leu27 IGF-II-induced hypertrophy in H9c2 cardiomyoblasts is ameliorated by saffron by regulation of calcineurin/NFAT and CaMKIIδ signaling.

The insulin-like growth factor II receptor (IGF-IIR) induces myocardial hypertrophy under various pathological conditions like diabetes and hypertension via G protein receptors like Gαq or Gαs. Increased expression of the ligand IGF II and IGF-IIR induces pathological hypertrophy through downstream signaling mediators such as calcineurin, nuclear factor of activated T cells 3 and calcium-calmodulin (CaM)-dependent kinase II (CaMKII)-histone deacetylase 4 (HDAC4). The dried stigma of Crocus sativus L. (saffron) has a long repute as a traditional medicine against various disorders. In the present study, we have investigated whether C. sativus extract (CSE) canameliorate Leu27 IGF-II triggered hypertrophy and have elucidated the underlying mechanism of protection. Additionally, the effects of oleic acid (OA), an activator of calcineurin and CaMKII was investigated thereof. The results demonstrate that CSE can ameliorate Leu27 IGF-II-induced hypertrophy seemingly through regulation of calcineurin-NFAT3 and CaMKII-HDAC4 signaling cascade.

Arecoline induces heart injure via Fas/Fas ligand apoptotic pathway in heart of Sprague-Dawley rat.

Habitual chewing of areca nut increases the risk of cardiovascular disease mortality, but less report demonstrate the toxic mechanism of areca nut on heart. To investigate toxicity of areca nut on cardiomyocytes, we induced the heart injury with arecoline to evaluate the acute damage of areca nut on heart. Different concentrations of are coline (lowdosage: 5 mg/kg/day and high dosage 50 mg/kg/day) were injected into Sprague-Dawley rat via intra-peritoneal method for 21 days to create negative effects of arecoline on cardiomyocyte. Themyocardial architecture of the rat heart was observed. The arecoline-induced apoptotic proteins were analysed via western blotting. The myocardialarchitecture of heart was injured with arecoline and TUNEL stain was also shown are coline-induced cardiac apoptosis. Arecoline promoted the protein expression of both Fas dependent snd mitochondrial dependent apoptosis. In summary, arecoline induces cardiac toxicity and apoptosis by inducing both death receptor and mitochondria-dependent apoptotic pathways on heart.

Cardioprotective effects of transplanted adipose-derived stem cells under Ang II stress with Danggui administration augments cardiac function through upregulation of insulin-like growth factor 1 receptor in late-stage hypertension rats.

In aging hypertensive conditions, deterioration of insulin-like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose-derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late-stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose-derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui-treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine-phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC-MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR-D-ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late-stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR-D-ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late-stage SHR rats.

Influence of Vincristine, Clinically Used in Cancer Therapy and Immune Thrombocytopenia, on the Function of Human Platelets.

Vincristine is a clinically used antimicrotubule drug for treating patients with lymphoma. Due to its property of increasing platelet counts, vincristine is also used to treat patients with immune thrombocytopenia. Moreover, antiplatelet agents were reported to be beneficial in thrombotic thrombocytopenic purpura (TTP). Therefore, we investigated the detailed mechanisms underlying the antiplatelet effect of vincristine. Our results revealed that vincristine inhibited platelet aggregation induced by collagen, but not by thrombin, arachidonic acid, and the thromboxane A2 analog U46619, suggesting that vincristine exerts higher inhibitory effects on collagen-mediated platelet aggregation. Vincristine also reduced collagen-mediated platelet granule release and calcium mobilization. In addition, vincristine inhibited glycoprotein VI (GPVI) signaling, including Syk, phospholipase Cγ2, protein kinase C, Akt, and mitogen-activated protein kinases. In addition, the in vitro PFA-100 assay revealed that vincristine did not prolong the closure time, and the in vivo study tail bleeding assay showed that vincristine did not prolong the tail bleeding time; both findings suggested that vincristine may not affect normal hemostasis. In conclusion, we demonstrated that vincristine exerts antiplatelet effects at least in part through the suppression of GPVI signaling. Moreover, this property of antiplatelet activity of vincristine may provide additional benefits in the treatment of TTP.