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Parkinson's disease (PD) is a common neurodegenerative disorder associated with striatal dopaminergic neuronal loss in the Substantia nigra. Oxidative stress plays a significant role in several neurodegenerative diseases. Paraquat (PQ) is considered a potential neurotoxin that affects the brain leading to the death of dopaminergic neurons mimicking the PD phenotype. Various scientific reports have proven that cryptotanshinone possesses antioxidant and anti-inflammatory properties. We hypothesized that cryptotanshinone could extend its neuroprotective activity by exerting antioxidant effects. This study was designed to evaluate the effects of cryptotanshinone in both cellular and animal models of PQ-induced PD. Annexin V-PI double staining and immunoblotting were used to detect apoptosis and oxidative stress proteins, respectively. Reactive oxygen species kits were used to evaluate oxidative stress in cells. For in vivo studies, 18 B6 mice were divided into three groups. The rotarod data revealed the motor function and immunostaining showed the survival of TH+ neurons in SNpc region. Our study showed that cryptotanshinone attenuated paraquat-induced oxidative stress by upregulating anti-oxidant markers in vitro, and restored behavioral deficits and survival of dopaminergic neurons in vivo, demonstrating its therapeutic potential.

This study investigated the effect of the moringa (Moringa oleifera) leaf extract and Lactobacillus acidophilus individually or combined on growth performance, enzyme activity, intestinal and hepatopancreatic histology, intestinal microbiota, immune response, and resistance against Vibrio alginolyticus and Vibrio parahaemolyticus in whiteleg shrimp (Penaeus vannamei). Six diets were formulated: three diets without L. acidophilus containining 0 (control, ME0), 2.5 (ME2.5), and 5.0 g/kg of moringa (ME5.0) and the same three diets containing L. acidophilus at 1 × 10

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.

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.

Colorectal cancer (CRC) is a leading cause of cancer-related death globally. Although surgery is still the major method for CRC therapy, the adoption of alternative treatments, such as traditional Chinese medicine (TCM), for CRC treatment is increasing. Our previous study has indicated the anti-breast cancer activity of T33 (a TCM formula). Interestingly, a major ingredient in T33, Baishao (Paeoniae Radix Alba), was reported to have antiproliferative effects on CRC cells. Therefore, this study further validated the influences of T33 on HT-29 and Caco2 cells both in vitro and in vivo. Viability and migration assays were performed to analyze the influences of T33 on proliferation and migratory activity of HT-29 and Caco2 cells. Immunofluorescence (IF) staining and immunoblotting were performed to confirm T33-induced autophagy in HT-29 and Caco2 cells. Xenograft HT-29 tumors were generated to test the effects of T33 in vivo. Significantly reduced survival and migratory activity were observed in both HT-29 and Caco2 cells treated with T33 along with apparently increased LC3-II protein. Significantly decreased p62/SQSTM1 protein, increased LC3-II/LC3-I ratio, and elevated amounts of Atg7, Atg5, and Beclin-1 proteins were detected in both HT-29 and Caco2 cells treated with T33. Moreover, the volume of xenograft HT-29 tumors was significantly lower in mice receiving 200 or 600 mg/kg T33 than in control-treated mice. These findings indicate that T33 exerts anti-CRC activity by inducing autophagy and suggest the potential of T33 for CRC treatment.

Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.

Advanced glycation end products (AGEs), which are highly reactive molecules resulting from persistent high-glucose levels, can lead to the generation of oxidative stress and cardiac complications. The carboxyl terminus of HSP70 interacting protein (CHIP) has been demonstrated to have a protective role in several diseases, including cardiac complications; however, the role in preventing AGE-induced cardiac damages remains poorly understood. Here, we found that elevated AGE levels impaired cardiac CHIP expression in streptozotocin-induced diabetes and high-fat diet-administered animals, representing AGE exposure models. We used the TUNEL assay, hematoxylin and eosin, Masson's trichrome staining, and western blotting to prove that cardiac injuries were induced in diabetic animals and AGE-treated cardiac cells. Interestingly, our results collectively indicated that CHIP overexpression significantly rescued the AGE-induced cardiac injuries and promoted cell survival. Moreover, CHIP knockdown-mediated stabilization of nuclear factor κB (NFκB) was attenuated by overexpressing CHIP in the cells. Furthermore, co-immunoprecipitation and immunoblot assay revealed that CHIP promotes the ubiquitination and proteasomal degradation of AGE-induced NFκB. Importantly, fluorescence microscopy, a luciferase reporter assay, electrophoretic mobility shift assay, and subcellular fractionation further demonstrated that CHIP overexpression inhibits AGE-induced NFκB nuclear translocation, reduced its binding ability with the promoter sequences of the receptor of AGE, consequently inhibiting the translocation of the receptor AGE to the cell membrane for its proper function. Overall, our current study findings suggest that CHIP can target NFκB for ubiquitin-mediated proteasomal degradation, and thereby potentially rescue AGE-induced cardiac damages.

Different stress condition stimulates the expression level of insulin-like growth factor receptor II (IGF-IIR) in cardiomyoblasts that lead to apoptosis. Tanshinone IIA (TSN), a pharmacologically active component from Danshen, has been shown cardioprotective effects against cardiac apoptosis induced by several stress conditions. Therefore, this study was conducted to assess the cardioprotective effects of TSN IIA mediated through the estrogen receptor (ER) in order to inhibit the Leu27IGF-II-enhanced IGF-IIR-mediated cardiac apoptosis. The estrogenic activity of TSN IIA was examined after myocardial cells were pretreated with the ER antagonist, and inhibited the phospho-inositide-3 kinase (PI3K). Here, we found that TSN IIA significantly induced ER that phosphorylated Akt. Further, Akt activation considerably suppressed the Leu27IGF-II induced IGF-IIR expression level and the downstream effectors, including Gαq and calcineurin as well as mitochondrial dependent apoptosis proteins including Bad, cytochrome c, and active caspase-3 that result in cardiac apoptosis resistance. However, the western blot analysis, JC-1 staining, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay revealed that TSN IIA attenuated Leu27IGF-II-induced IGF-IIR mediated cardiac apoptosis was reversed by an ER antagonist such as ICI 182780, and PI3K inhibition. All these findings demonstrate that TSN IIA exerts estrogenic activity, which can activate PI3K-Akt pathway, and thereby inhibits Leu27IGFII induced IGF-IIR mediated cardiac apoptosis. Thus, TSN IIA can be considered as an effective therapeutic strategy against IGF-IIR signaling cascade to suppress cardiac apoptosis.

Hyperglycemia results in the formation of reactive oxygen species which in turn causes advanced glycation end products (AGEs) formation, leading to diabetic cardiomyopathy. Our previous study showed that AGE-induced reactive oxygen species-dependent apoptosis is mediated via protein kinase C delta (PKCδ)-enhanced mitochondrial damage in cardiomyocytes. By using microRNA (miRNA) database, miRNA-210 was predicted to target c-Jun N-terminal kinase (JNK), which were previously identified as downstream of PKCδ in regulating mitochondrial function. Therefore, we hypothesized that miR-210 mediates PKCδ-dependent upregulation of JNK to cause cardiac mitochondrial damage and apoptosis following AGE exposure. AGE-exposed cells showed activated cardiac JNK, PKCδ, and apoptosis, which were reversed by treatment with a JNK inhibitor and PKCδ-KD (deficient kinase). Cardiac miR-210 and mitochondrial function were downregulated following AGE exposure. Furthermore, JNK was upregulated and involved in AGE-induced mitochondrial damage. Interestingly, luciferase activity of the miR-210 mimic plus JNK WT-3'-untranslated region overexpressed group was significantly lower than that of miR-210 mimic plus JNK MT-3'UTR group, indicating that JNK is a target of miR-210. Moreover, JNK activation induced by AGEs was reduced by treatment with the miR-210 mimic and reversed by treatment with the miR-210 inhibitor, indicating the regulatory function of miR-210 in JNK activation following AGE exposure. Additionally, JNK-dependent mitochondrial dysfunction and apoptosis were reversed following treatment with the miR-210 mimic, while the miR-210 inhibitor showed no effect on JNK-induced mitochondrial dysfunction and apoptosis in AGE-exposed cardiac cells. Taken together, our study showed that PKCδ-enhanced JNK-dependent mitochondrial damage is mediated through the reduction of miR-210 in cardiomyocytes following AGE exposure.

Background: Several pharmacological therapeutic interventions are being used as therapeutic agents against myocardial infarction/ischemia (MI) but their usage is constrained by toxicity and nonselective pharmacological actions. Our preliminary report depicted the cardioprotective effect of piperine against isoproterenol (ISO)-induced MI. Aim: Current study determined the protective efficacy of piperine by modulating mitochondrial function in rat models of isoproterenol (ISO)-induced myocardial ischemia. Methods: The above aim was achieved by analyzing mitochondrial antioxidant status, mitochondrial calcium, mitochondrial enzyme activity, ATP level, and apoptosis. Ultra-structural alterations in heart tissue were determined by TEM analysis. RT-PCR studies and Western blotting were executed to determine apoptotic and proapoptotic gene expression, and apoptotic protein expression, respectively. Results: The results elucidate that piperine pre-treatment prevents ISO induced alterations in the mitochondrial antioxidant status, Krebs cycle as well as mitochondrial respiratory chain enzyme activities (MRCEs). ISO induced ultrastructural changes of heart mitochondria were significantly reduced in the group that received piperine pretreatment followed by ISO injection. Piperine maintains mitochondrial calcium homeostasis and inhibits ISO-induced myocardial apoptosis. A significant increase in the expression levels of proapoptotic genes such as Bax, caspases (caspase 9, caspase 3), and cytochrome-c with a concomitant decrease in Bcl-2 expression (anti-apoptotic gene) was observed in ISO injected group compared to the control group. The group that received the piperine pretreatment followed by ISO administration showed a significant decrease in the expression profile of proapoptotic genes with a concomitant increase in the anti-apoptotic gene expression than the ISO injected group. Apoptotic protein expressions including Bax, cytochrome-c, caspase-3, and cleaved PARP were upregulated & Bcl-2 was downregulated with ISO treatment, whereas piperine pre-treatment prevented these changes in apoptotic protein expressions during ISO-induced myocardial cell damage. Conclusion: Current results demonstrate the efficacy of piperine for attenuating ISO-induced myocardial ischemia by enhancing mitochondria function. This study described that piperine could be used as a nutritional intervention against ISO-induced myocardial ischemia.

Accumulating studies have demonstrated the protective roles of mesenchymal stem cells against several disorders. However, one of their crucial limitations is reduced viability under stress conditions, including the hyperglycemia induced by diabetes. The molecular mechanisms involved in diabetes-induced kidney injuries are not fully elucidated. In this study, we found that high glucose (HG) reduced human proximal tubular epithelial cell viability. Further, hyperglycemia induced oxidative stress-mediated apoptosis and fibrosis in HK-2 cells via activation of the mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinase JNK and p38 kinase. Carboxyl terminus of HSP70 interacting protein (CHIP) overactivation considerably rescued cell viability under HG stress. Moreover, Western blot analysis, flow cytometry, and MitoSOX staining revealed that hyperglycemia-induced mitochondrial oxidative stress production and apoptosis were attenuated in CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Co-culture with CHIP-expressing WJMSCs maintained HK-2 cell viability, and inhibited apoptosis and fibrosis by attenuating HG-induced ROS-mediated MAPK activation. CHIP-overexpressing WJMSCs also rescued the decreased kidney weight and hyperglycemia-induced kidney damage observed in streptozotocin-induced diabetic rats. Cumulatively, the current research findings demonstrate that CHIP suppresses hyperglycemia-induced oxidative stress and confers resistance to MAPK-induced apoptosis and fibrosis, and suggests that CHIP protects WJMSCs and the high quality WJMSCs have therapeutic effects against diabetes-induced kidney injuries.

Hypertension is a severe public health risk factor worldwide. Elevated angiotensin II (Ang II) produced by the renin-angiotensin-aldosterone system can lead to hypertension and its complications.In this study, we addressed the cardiac-injury effects of Ang II and investigated the signaling mechanism induced by Ang II. Both H9c2 cardiomyoblast cells and neonatal rat cardiomyocytes were exposed to Ang II to observe hypertension-related cardiac apoptosis.The results of western blotting revealed that Ang II significantly attenuated the IGF1R-PI3K-AKT pathway via the Ang II-AT1 receptor axis and phosphatase and tensin homolog expression. Furthermore, real-time PCR showed that Ang II also activated miR-320-3p transcription to repress the PI3K-Akt pathway. In the heart tissue of spontaneously hypertensive rats, activation of the IGF1R survival pathway was also reduced compared with that in Wistar-Kyoto rats, especially in aged spontaneously hypertensive rats.Hence, we speculate that the Ang II-AT1 receptor axis induces both phosphatase and tensin homolog and miR-320-3p expression to downregulate the IGF1R-PI3K-AKT survival pathway and cause cell apoptosis in the heart.

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.

Although enormous achievements have been made in targeted molecular therapies against hepatocellular carcinoma (HCC), the treatments can only prolong the life of patients with extrahepatic metastases. We evaluated thymoquinone (TQ), a compound from Nigella sativa Linn., for its anti‐cancer effect on SK‐Hep1 cells and HCC‐xenograft nude mice. TQ effectively triggered cell death and activated p38 and extracellular signal‐regulated kinases (Erk) pathways up to 24 h after treatment in cells. TQ‐induced cell death was reversed by p38 inhibitor; however, it was enhanced by si‐Erk. The caspase3 activation and TUNEL assay revealed a stronger toxic effect upon co‐treatment with TQ and si‐Erk. Our study suggested that phosphorylation of p38 in SK‐Hep1 cells constituted the major factor leading to cell apoptosis, whereas phosphorylation of Erk led to drug resistance. Furthermore, TQ therapeutic effect was improved upon Erk inhibition in HCC‐xenograft nude mice. TQ could present excellent anti‐HCC potential under suitable p‐Erk inhibiting conditions.

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.

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.

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.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

Diabetes-induced cardiomyocyte apoptosis is one of the major causes of mortality in patients with diabetes. Numerous studies have indicated the beneficial effects of Lactobacillus reuteri GMNL-263. However, the protective effect of Lactobacillus reuteri GMNL-263 in cardiac damage associated with diabetes remains poorly understood. In this study, we aimed to investigate the protective effect of Lactobacillus reuteri GMNL-263 on cardiomyocytes in diabetic rats. Five-week-old male Wistar rats were categorized into normal control group, diabetes group (55 mg/kgw STZ-induced diabetes via intraperitoneal injection), and diabetic animals treated with Lactobacillus reuteri GMNL-263 (109 CFU/rat/day, oral administration for 4 weeks). The results were presented that oral administration of a high dose of Lactobacillus reuteri GMNL-263 in diabetic rats activated IGF1R cell survival pathways to decrease the Fas-dependent and mitochondrial-dependent apoptotic pathways induced by hyperglycemia. We found that GMNL-263 significantly attenuated cell apoptosis via the IGF1R survival pathway in diabetic rats. The findings of this study suggest that GMNL-263 treatment maybe an effective therapeutic approach for the prevention of cardiac apoptosis in patients with diabetes.

This study reports the effect of cardiac-specific insulin-like growth factor-II receptor α (IGF-IIRα) overexpression on the development of liver dysfunction in transgenic rats via STZ-induced diabetic hepatocyte damage. The cardio-hepatic syndrome comprises a number of heart and liver illnesses in which an acute or chronic disease in one organ can lead to acute or chronic disease in the other. However, the molecular mechanism involved in such a set of conditions is unclear. In this study, we developed a transgenic rat model with cardiac-specific overexpression of IGF-IIRα, which is a supplementary splicing variant of insulin-like growth factor-II receptor (IGF-IIR), expressed in pathological hearts, to investigate the relationship between late fetal gene expression in diabetic hearts and their influence on diabetic hepatopathy. STZ (55 mg/kg) was intraperitoneally delivered into IGF-IIR overexpressed transgenic (TG) and non-transgenic (NTG) animal models developed in Sprague-Dawley (SD) rats after an overnight fast. The relationship among IGF-IIRα overexpression and hepatocyte damages have been determined based on the complexity of damage in the liver. Our findings revealed that overexpression of the cardiac-specific IGF-IIRα enhances diabetes-induced morphological alterations and hepatic inflammation in the livers. The diabetic transgenic rats demonstrated the development of pathological conditions such as thick collagen fiber deposition, bridging fibrosis, and elevation of α-SMA and MMP1 related liver fibrosis mechanisms. Our data suggest that IGF-IIRα overexpression in the heart during a pathological state may worsen diabetic hepatopathy in rats.

This study investigated the effects of two probiotics, namely Lactobacillus paracasei and Bifidobacterium longum, as feed additives on growth performance, nonspecific immunity, immune-related gene expression, and disease resistance against Vibrio parahaemolyticus in Penaeus vannamei. The experimental diets were prepared using L. paracasei and B. longum at concentrations of 10

Neurodegenerative diseases have become increasingly prevalent in the aged population. Rheumatoid arthritis (RA) is an autoimmune disease that causes systemic inflammation, damaging the neurons. However, only a few treatment options can reduce RA-induced neurodegeneration. This study aimed to evaluate whether adipose-derived stem cells (ADSCs) pretreated with curcumin could ameliorate RA-induced neurodegenerative illness in an RA rat model. Wistar rats were randomly classified into the following four groups: control, RA, RA + ADSC (1 × 106 cells per rat), and RA + curcumin-pretreated ADSC (1 × 106 cells per rat). After treatment for two months, the effects were specifically evaluated in the brains collected from the rats. Our results demonstrated that the transplantation of curcumin-pretreated ADSCs substantially reduced inflammation and apoptosis in the cortices of RA rats compared to those of other groups. Thus, the combination of ADSCs and curcumin exerts a synergistic effect in enhancing neuronal protection in RA rats. In the future, this combination therapeutic strategy can potentially be used as a novel treatment method to reduce RA-induced neurodegenerative disorders.

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, 3β-hydroxysteroid dehydrogenase (3β-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 3β-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.

Adipose tissue-derived mesenchymal stem cells (ADSC) exert neuroprotective and anti-inflammatory effects. ADSCs are considered potential therapeutics for rheumatoid arthritis (RA), an inflammatory, multisystemic autoimmune disease. Epigallocatechin-3-gallate (EGCG), the major polyphenolic compound in green tea, has strong anti-inflammatory and antioxidant properties. This study aimed to investigate whether EGCG has a synergistic effect on the neuroprotective effects of ADSCs to protect the RA-damaged brain. Wistar rats were classified into four groups: sham, RA, RA + ADSCs (1 × 10

High-glucose (HG) suppresses mesenchymal stem cell (MSC) functions, resulting in a decrease in cardiac regenerative capability for MSC in diabetes mellitus (DM). Resveratrol enhances MSC functions under stress. This study explores if cardiac regenerative capability can be enhanced in MSCs pretreated with resveratrol in DM rats receiving MSCs. In vitro evidence confirms that HG decreases MSCs capability through suppression of survival markers, AMP-activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) axis, and expression of apoptotic markers. All of these markers are improved when MSCs are cocultured with resveratrol. Wistar male rats were randomly divided into Sham, DM (DM rats), DM rats with autologous transplantation of adipose-derived stem cells (DM + ADSC), and DM rats with resveratrol pretreated ADSC (DM + RSVL-ADSC). Compared to the Sham, DM induces pathological pathways (including fibrosis, hypertrophy, and apoptosis) and suppresses survival as well as the AMPK/Sirt1 axis in the DM group. DM + ADSC slightly improves the above pathways whereas DM + RSVL-ADSC significantly improves the above pathways when compared to the DM group. These results illustrate that resveratrol pretreated with MSCs may show clinical potential in the treatment of heart failure in patients with DM.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe neurotoxicity in patients. Diallyl trisulfide (DATS) is an organosulfur compound with established potent antioxidant and anti-inflammatory properties. Herein, we investigated the neuroprotective efficacy of DATS in preventing DOX-induced neurotoxicity in a rat model. Specifically, DATS (40 mg/kg) was administered to rats 24 h after DOX treatment, once a week for 8 weeks. Our results showed that DATS treatment led to a decrease in plasma levels of tumor necrosis factor-alpha (TNF-α) induced by DOX. DATS restored cerebral cortex and hippocampus histopathological architecture and neuronal loss. Immunohistochemical staining indicated that DATS decreased the expression of glial fibrillar acidic protein (GFAP) in DOX treated rats. Components of stress-related inflammatory proteins (TNF-α, phospho nuclear factor kappa B (NF-κB), inducible nitricoxide synthase (iNOS) and cyclooxygenase-2 (COX-2)) were all significantly increased in the DOX group, in comparison with the control group, whereas they were decreased after DATS treatment. In addition, the mRNA of antioxidant enzymes (superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1, 4 (GPx1 and GPx4)) and antioxidant proteins (heme oxygenase-1 (HO-1), superoxide dismutase 1, 2 (SOD1 and SOD2), Γ-glutamylcysteine synthase (Γ-GCSc)) were markedly increased in DOX group compared with the control group, which were significantly attenuated by DATS treatment. The upregulation of antioxidants enzymes in DOX group was probably a compensatory effect against elevated oxidative stress induced by DOX. DATS treatment could ameliorate this oxidative stress in brain. Our results suggested that DATS has potential clinical applications in the prevention of DOX-induced neurotoxicity by ameliorating inflammatory insults and oxidative stress.

It has been increasingly recognized that accelerated atherosclerosis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus, a multisystem autoimmune disease. In this study, we investigated the anti-apoptotic effects of heat-killed Lactobacillus reuteri GMNL-263 on the cardiac tissue of NZB/W F1 mice. The myocardial architecture of the mice heart was observed and evaluated using different staining techniques such as hematoxylin and eosin, TUNEL assay, Masson's trichrome, and fluorescent immunohistochemistry. Additionally, the probiotics-related pathway proteins were analyzed via western blot analysis. Our results showed prevention of enlarged interstitial spaces and abnormal myocardial structures in the hearts of NZB/W F1 mice with L. reuteri GMNL-263 feeding. Significant reduction in TUNEL-positive cells, Fas death receptor-related components, and apoptosis was also detected in the cardiac tissues of the NZB/W F1 mice after L. reuteri GMNL-263 feeding compared with the control group. These findings are the first to reveal the protective effects of L. reuteri GMNL-263 against cardiac abnormalities in NZB/W F1 mice and suggest the potential clinical applications of L. reuteri GMNL-263 in the treatment of SLE-related cardiovascular diseases.

Naturally occurring tumor in animals receiving high minerals from deep oceans (DOM: hardness 600 mg/L) from 6 months of age until natural death was firstly assessed in 200 Sprague Dawley rats, randomized into four groups: Control (C), DOM (D), Fructose (F), and Fructose + DOM (FD). Fructose drink contained 11% fructose. Tumor incidence (necropsy at death) in the D group was ~40% lower than that in the C group (P, Tumor incidence increases with advancing aging. Lifelong supplementation of deep ocean minerals significantly suppresses age‐associated tumorigenesis. This tumor‐suppressive action is associated with preventing weight gain and increasing spontaneous physical activity during the first two‐thirds period of life.

In this study, we used ICI 182 780 (ICI), an estrogen receptor (ER) antagonist, to investigate the estrogenic activity of Danshen, and to further explored whether Danshen extract can block Leu27IGF-II-induced hypertrophy in H9c2 cardiomyoblast cells. We first used an IGF-II analog Leu27IGF-II, which specifically activates IGF2R signaling cascades and induces H9c2 cardiomyoblast cell hypertrophy. However, Danshen extract completely inhibited Leu27IGF-II-induced cell size increase, ANP and BNP hypertrophic marker expression, and IGF2R induction. We also observed that Danshen extract inhibited calcineurin protein expression and NFAT3 nuclear translocation, leading to suppression of Leu27IGF-II-induced cardiac hypertrophy. Moreover, the anti-Leu27IGF-II-IGF2R signaling effect of Danshen was totally reversed by ICI, which suggest the cardio protective effect of Danshen is mediated through estrogen receptors. Our study suggests that, Danshen exerts estrogenic activity, and thus, it could be used as a selective ER modulator in IGFIIR induced hypertrophy model.

Hypertension (HTN) is one of the most prevalent chronic conditions; it can damage blood vessels and rupture blood vessels can trap in small vessels. This blockage can prevent blood flow and oxygen delivery to brain cells and can result in Alzheimer's disease (AD). HTN- and AD-mediated long-time memory loss and its treatment remain poorly understood. Plant-derived natural compounds are alternative solutions for effectively treating diseases without any side effects. This study revealed that bioactive peptides extracted from potato hydrolysis suppress HTN-mediated long-term memory (LTM) loss and cell apoptosis, thus improving memory formation and neuronal cell survival in the spontaneously hypertensive rat (SHR) rat model. SHR rats were treated with bioactive peptide IF (10 mg/kg orally) and angiotensin-converting enzyme inhibitors (5 mg/kg orally). In this study, we evaluated the molecular expression levels of BDNF-, GluR1-, and CREB-mediated markers protein expression in 24-week-old SHR rats. The study result showed that HTN-induced AD regulated long-term memory (LTM) loss and neuronal degeneration in the SHR animals. The bioactive peptide-treated animals showed an elevated level of survival proteins. Bioactive peptide IF activate CREB-mediated downstream proteins to regulate synaptic plasticity and neuronal survival in the SHR rat model.

Alcalase potato protein hydrolysate (APPH) might have a very important role in therapeutic effects. This study aims to examine the beneficial effects of bioactive peptides (DIKTNKPVIF [DI] and IF) from APPH supplement in the regulation of cardiac apoptosis, autophagy, and mitochondrial biogenesis pathway in spontaneously hypertensive rats (SHR). We have investigated ejection fraction, fractional shortening, Tunel assay, apoptosis, autophagy, and mitochondrial biogenesis pathway marker expression to show the efficacy of bioactive peptides in an SHR model. Bioactive peptides significantly upregulate ejection fraction and fractional shortening in SHR rats. SHR rats exhibited higher protein expression of apoptotic markers such as BAD, cytochrome c, and caspase 3. Finally, the bioactive peptides upregulate survival proteins (p-AKT/p-PI3K), autophagy (Beclin1/LC3B), and mitochondrial biogenesis (p-AMPKα/SIRT1/PGC1α/p-Foxo3a/Nrf2/CREB) marker expressions compared with the SHR groups. In summary, the bioactive peptides protect the heart tissues through the activation of autophagy and mitochondrial biogenesis pathway and thereby attenuate cardiac apoptosis in a spontaneously hypertensive rat model.

The potency of tumor-specific antigen (TSA) vaccines, such as neoantigen (neoAg)-based cancer vaccines, can be compromised by host immune checkpoint inhibitory mechanisms, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), that attenuate neoAg presentation on dendritic cells (DC) and hinder T cell–mediated cytotoxicity. To overcome PD-1/PD-L1 inhibition in DCs, we developed a novel adeno-associated virus (meAAV) neoAg vaccine, modified with TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA, which extend the persistence of meAAV and activate neoAg-specific T-cell responses in immune-competent colorectal and breast cancer murine models. Moreover, we found that in combination with radiotherapy, the meAAV-based neoAg cancer vaccine not only elicited higher antigen presentation ability, but also maintained neoAg-specific cytotoxic T lymphocyte (CTL) responses. These functional PD-1 traps and PD-L1 miRNAs overcome host PD-1/PD-L1 inhibitory mechanisms and boost the therapeutic efficacy of radiotherapy. More importantly, combined radiotherapy and meAAV neoAg cancer vaccines significantly enhanced neoAg-specific CTL responses, increased CTL infiltration in tumor microenvironment, and decreased tumor-associated immunosuppression. This process led to the complete elimination of colorectal cancer and delayed tumor growth of breast cancer in tumor-bearing mice. Taken together, our results demonstrated a novel strategy that combines neoAg cancer vaccine and radiotherapy to increase the therapeutic efficacy against colorectal and breast cancers.

Glucocorticoids (GCs) are the most common treatment for inflammatory skin disorders; however, they show several adverse side effects, including atrophy and collagen decrease following chronic treatment. In particular, transcription factors and p38 signaling for collagen synthesis have been shown to be suppressed by the active glucocorticoid receptor (GR). LY294002 (LY), a phosphoinositide 3-kinase (PI3K) inhibitor, has been reported to protect keratinocytes in epidermis against GC-induced hypoplasia; however, its protective effect in dermis remains unclear. Furthermore, clobetasol propionate (CP) is the most used commercial synthetic GC, yet studies on how CP causes side effects in dermal fibroblasts are limited. In this study, dermal atrophy was modeled using CP in human dermal fibroblasts (HDFs) and C57BL/6 mice. CP treatment significantly upregulated FK506 binding protein 5 (FKBP51), an atrophy marker (2.4 ± 0.25 and 3.3 ± 0.3 fold in

Common characteristics of aging include reduced somatic stem cell number, susceptibility to cardiac injuries, metabolic imbalances and increased risk for oncogenesis. In this study, Pleiotropic anti-aging effects of a decoction Jing Si herbal drink (JS) containing eight Traditional Chinese Medicine based herbs, with known effects against aging related disorders was evaluated. Adipose derived mesenchymal stem cells (ADMSCs) from 16 week old adult and 24 month old aging WKY rats were evaluated for the age-related changes in stem cell homeostasis. Effects of JS on self-renewal, klotho and Telomerase Reverse Transcriptase expression DNA damage response were determined by immunofluorescence staining. The effects were confirmed in senescence induced human ADMSCs and in addition, the potential of JS to maintain telomere length was evaluated by qPCR analysis in ADMSCs challenged for long term with doxorubicin. Further, the effects of JS on doxorubicin-induced hypertrophic effect and DNA damage in H9c2 cardiac cells; MPP+-induced damages in SH-SY5Y neuron cells were investigated. In addition, effects of JS in maintaining metabolic regulation, in terms of blood glucose regulation in type-II diabetes mice model, and their potential to suppress malignancy in different cancer cells were ascertained. The results show that JS maintains stem cell homeostasis and provides cytoprotection. In addition JS regulates blood glucose metabolism, enhances autophagic clearances in neurons and suppresses cancer growth and migration. The results show that JS acts on multiple targets and provides a cumulative protective effect against various age-associated disorders and therefore it is a candidate pleiotropic agent for healthy aging.

Growing evidences indicate that high glucose toxicity-associated fibrotic effects play a pivotal role in diabetic nephropathy (DN). Tubular epithelial-myofibroblast transdifferentiation is a major hallmark of renal fibrosis event under diabetic stress. Roots of Glycyrrhiza uralensis (Radix glycyrrhizae) used as a sweetener and traditional Chinese medicine possess high potential for renal protection. In this study, a cell model for high glucose (HG) injury with HK-2 renal proximal tubular epithelial cell line and a type-II-diabetes model with Apoe

Parkinson's disease (PD) is a neurodegenerative disorder involving the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Cellular clearance mechanisms, including the autophagy-lysosome pathway, are commonly affected in the pathogenesis of PD. The lysosomal CaThis study aims is to investigate the neuroprotective effects of A. argyi in promoting the TRPML1-mediated autophagy/mitophagy-enhancing effect METHODS: In this study, we used 1-methyl-4-phenyl-pyridinium (MPP+)-induced PD model established in an SH-SY5Y human neuroblastoma cell line as well as in a 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-induced PD model in C57BL/6 J mice. MTT assay was conducted to measure the cell viability and further MitoSoX and DCFDA assay were used to measure the ROS. Western blot analysis was used to access levels of TRPML1, p-DRP1 (ser616), p-AKT, PI3K, and β-catenin, Additionally, IF and IHC analysis to investigate the expression of TRPML1, LC3B, β-catenin, TH+, α-synuclein. Mitotracker stain was used to check mitophagy levels and a lysosomal intracellular activity kit was used to measure the lysosomal dysfunction. Behavioral studies were conducted by rotarod and grip strength experiments to check motor functions.In our in vitro study, A. argyi rescued the MPP+-induced loss of cell viability and reduced the accumulation of mitochondrial and total reactive oxygen species (ROS). Subsequently, it increased the expression of TRPML1 protein, thereby inducing autophagy, which facilitated the clearance of toxic accumulation of α-synuclein. Furthermore, A. argyi played a neuroprotective role by activating the PI3K/AKT/β-catenin cell survival pathway. MPP+-mediated mitochondrial damage was overcome by upregulation of mitophagy and downregulation of the mitochondrial fission regulator p-DRP1 (ser616) in SH-SY5Y cells. In the in vivo study, A. argyi ameliorated impaired motor function and rescued TH+ neurons in the SNpc region. Similar to the results of the in vitro study, TRPML1, LC3B, and β-catenin expression was enhanced in the SNpc region in the A. argyi-treated mice brain.Thus, our results first demonstrate that A. argyi can exert neuroprotective effects by stimulating TRPML1 and rescuing neuronal cells by boosting autophagy/mitophagy and upregulating a survival pathway, suggesting that A. argyi can further be exploited to slow the progression of PD.

UV radiation and H

Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might an have important role in anti-obesity activity. Recent studies from our lab indicated that APPH treatment had lipolysis stimulating activity and identified was an efficient anti-obesity diet ingredient. In this study we aim to investigate the beneficial effects of pure peptide amino acid sequences (DIKTNKPVIF (DI) and IF) from APPH supplement in the regulation of cardiac hypertrophy and fibrosis on spontaneously hypertensive rats (SHR). We examined hematoxylin and eosin staining, Masson's trichrome staining, echocardiographic parameters, serum parameters, hypertrophy, inflammation and fibrotic marker expression to demonstrate efficacy of bioactive peptides in a SHR model. There was a significant upregulation between SHR and bioactive peptides treated groups in left heart weight (LHW), LHW/WHW, LHW/Tibia, LVIDd, and LVd mass. In addition, the bioactive peptides repress the protein expression of hypertrophy markers (BNP, MYH7), inflammation (TLR-4, p-NFkB, TNF-α, IL-6), and fibrotic markers (uPA, MMP-2, TIMP1, CTGF). In summary, these results indicate that DI and IF bioactive peptides from APPH attenuate cardiac hypertrophy, inflammation and fibrosis in the SHR model. Keywords: Bioactive polypeptides, Fibrosis, Hypertrophy, SHR rats, Inflammation

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 (1[Formula: see text]mg/kg/day of saline, i.p.), DD0 (150[Formula: see text]mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose[Formula: see text] or 50[Formula: see text]mg/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 [Formula: see text], 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.

It has been well-documented that the consumption of deep sea water (DSW) has beneficial effects on myocardial hypertrophy and cardiac apoptosis induced by hypercholesterolemia. However, the molecular mechanisms for the anti-inflammatory effects of DSW on diabetic cardiomyopathy are still largely unclear. The main purpose of this present study was to test the hypothesis that DSW exerts anti-inflammatory effects through the suppression of the TNF-α-mediated signaling pathways. IP injection of streptozotocin (STZ) at the dose of 65 mg/kg was used to establish a diabetes rat model. DSW mineral extracts that diluted in desalinated water were prepared in three different dosages and administered to the rats through gavages for 4 weeks. These dosages are DSW-1X (equivalent to 37 mg Mg2+ /kg/day), 2X (equivalent to 74 mg Mg2+ /kg/day) and 3X (equivalent to 111 mg Mg2+ mg/kg/day). Immunofluorescence staining and Western blot showed that the protein expression level of TNF-α was markedly higher in the STZ-induced diabetic rat hearts than in the control group. Consequently, the phosphorylation levels of the TNF-α-modulated downstream signaling molecules and P38 mitogen-activated protein kinases (MAPKs) were notably elevated in heart tissues of STZ-induced diabetes. These higher phosphorylation levels subsequently upregulated NF-κB-modulated inflammatory mediators, such as cyclooxygenase (COX)-II and inducible nitric oxide synthase (iNOS). However, treatment with DSW as well as MgSO4 , the main mineral in DSW, significantly reversed all the alterations. These findings suggest that DSW has potential as a therapeutic agent for preventing diabetes-related cardiovascular diseases.

Stem cell therapy is a promising treatment for hepatopathy due to diabetes mellitus (DM); oral resveratrol treatment exhibits protective effects. We investigated whether protective effects could be produced in liver of diabetic rats receiving autologous adipose-derived stem cell transplantation (ADSC) plus oral resveratrol administration. Male rats were divided into four groups: sham group; streptozotocin induced DM group; DM + ADSC group, in which DM rats were treated with 10

We previously reported that deep sea water (DSW) prolongs the life span of streptozotocin (STZ)-induced diabetic rats by the compensatory augmentation of the insulin like growth factor (IGF)-I survival signaling and inhibition of apoptosis. Here, we investigated the effects of DSW on cardiac hypertrophy in diabetic rats. Cardiac hypertrophy was induced in rats by using STZ (65 mg/kg) administered via IP injection. DSW was prepared by mixing DSW mineral extracts and desalinated water. Different dosages of DSW-1X (equivalent to 37 mg Mg2+·kg−1·day−1), 2X (equivalent to 74 mg Mg2+·kg−1·day−1) and 3X (equivalent to 111 mg Mg2+·kg−1·day−1) were administered to the rats through gavage for 4 wk. Cardiac hypertrophy was evaluated by the heart weight-to-body weight ratio and the cardiac tissue cross-sectional area after hematoxylin and eosin staining. The protein levels of the cardiac hypertrophy signaling molecules were determined by Western blot. Our results showed that the suppressive effects of the DSW treatment on STZ-induced cardiac hypertrophy were comparable to those of MgSO4administration and that the hypertrophic marker brain natriuretic peptide (BNP) was decreased by DSW. In addition, DSW attenuated both the eccentric hypertrophy signaling pathway, IL-6-MEK-STAT3, and the concentric signaling pathway, IGF-II-PKCα-CaMKII, in DM rat hearts. The cardiac hypertrophy-associated activation of extracellular signal-regulated kinase (ERK) and the upregulation of the transcription factor GATA binding protein 4 (GATA4) were also negated by treatment with DSW. The results from this study suggest that DSW could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.NEW & NOTEWORTHY Deep sea water, containing high levels of minerals, improve cardiac hypertrophy in diabetic rats through attenuating the eccentric signaling pathway, IL-6-MEK5-STAT3, and concentric signaling pathway, IGF2-PKCα-CaMKII. The results from this study suggest that deep sea water could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.

Previous studies stated that stem cell functions are reduced under high glucose environment, leading to reduce stem cell capability of tissue regeneration. This study aimed to investigate if stem cells preconditioned with resveratrol show better therapeutic effect on the treatment of liver dysfunction in diabetic rats than stem cells without resveratrol precondition. Male Wistar rats were divided into four groups including sham, DM (diabetic rats), DM + ADSC (DM rats receiving autologous transplantation of adipose-derived stem cells), and DM + pre-R-ADSC (DM rats receiving ADSC preconditioned with resveratrol). Compared with sham group, experimental results showed that DM group induced suppression of survival, suppression of Sirt1, activation of apoptotic, and activation of fibrotic pathways, leading to liver dysfunction. Autologous transplantation of ADSC (DM + ADSC) improved above pathways except for fibrotic signaling. By contrast, transplantation of resveratrol preconditioned ADSC (DM + pre-R-ADSC) significantly improved above pathways including fibrosis. Supplemental evidences suggest that resveratrol precondition increases ADSC viability under high glucose stress via Sirt1 and IGF1R expressions. Furthermore, increased secretion of IGF1 via paracrine route also confirmed in ADSC preconditioned with resveratrol. The experimental results imply that ADSC preconditioned with resveratrol shows potential in the treatment of liver dysfunction in DM patients with liver dysfunction.

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.

Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin-like growth factor receptor type II α (IGF-IIRα) which is a novel stress-inducible protein was explored in doxorubicin-induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD-TG [IGF-IIRα]) overexpressing IGF-IIRα specifically in heart, we found that IGF-IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin-induced cardiac stress. Overexpression of IGF-IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p-Akt and estrogen receptor β/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin-I, and apoptosis-inducing agents such as p53, Bax, and cytochrome C, respectively. IGF-IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF-IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF-IIRα is a novel stress-induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin-induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy.

Clinical studies have shown that hyperglycemia can induce early-stage diabetic nephropathy (DN). Furthermore, oxidative stress, tubular epithelial-mesenchymal transition and extracellular matrix accumulation promote the progression of DN to chronic kidney disease and tubulointerstitial fibrosis. It is necessary to initiate treatment at the early stages of DN or even during the early stages of diabetes. In this work, rats with streptozotocin (STZ)-induced diabetes mellitus (DM) presented early DN symptoms within 45 days, and collagen accumulation in the glomerulus of the rats was primarily mediated through the RhoA/ROCK pathway instead of the TGF-β signaling pathway. Resveratrol (15 mg/kg/day) and ramipril (10 mg/kg/day) co-treatment of STZ-induced DN rats showed that glomerulosclerosis in early-stage DN was reversible (P < .05 compared with that in STZ-induced DM rats). The results of this study support early intervention in diabetes or DN as a more efficient therapeutic strategy.

Pancreatic damage results in insufficient insulin secretion, leading to type 1 diabetes. Stem cell-based therapy has recently shown potential in the treatment of type 1 diabetes. Resveratrol supplementation has demonstrated a beneficial effect in treating diabetes. This study investigates if adipose-derived stem cells (ADSC), preconditioned with resveratrol, show better effects on experimental diabetic animals. Wistar rats were randomly divided into four groups including sham (normal rats), DM (diabetic rats induced by SZT injection), DM+ADSC (DM rats with receiving autologous ADSC transplantation) and DM+R-ADSC (DM rats receiving resveratrol preconditioned ADSC). The experimental results show that SZT induced pancreatic damage (DM group), including reduction of islet size, fibrosis pathway activation, survival signaling suppression, and apoptotic pathway expression, lead to serum glucose elevation. Autologous ADSC (DM+ADSC group) transplantation shows improvement in the above observations in DM rats. Furthermore, ADSC precondition with resveratrol (DM+R-ADSC group) reveals significant improvement in the above pathological observations over both DM and DM+ADSC groups. We found that ADSC precondition with resveratrol increases the survival marker p-Akt expression, leading to enhanced ADSC viability. This study suggests that ADSC precondition with resveratrol shows potential in the treatment of patients with type 1 DM.

Background: Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet. Hypothesis The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR). Methods/study design The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24 h) for 2 h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10 mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting. Results Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-xL, p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models. Conclusion In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.

Oral Squamous Cell Carcinoma (OSSC) is a major life-threatening disease with high incidence in the Southeast Asian countries. Chronic exposure to arecoline causes genetic changes in the epithelial cells of the oral mucosa, induces proliferation through activation of the EGF receptor and promotes downstream COX-2 expression. Taiwanin C, a podophyllotoxin derived from Taiwania cryptomerioides Hayata is known to inhibit COX activity and to hinder PGE2 production in macrophages. In this study a tumor cell line T28 and a non-tumor cell line N28 derived from mice OSCC models were used to study the effect of Taiwanin C on PGE2 associated COX-2 expression and cell cycle regulators. Taiwanin C activated p21 protein expression, down-regulated cell cycle regulatory proteins, elevated apoptosis and down-regulated p-PI3K/p-Akt survival mechanism in T28 oral cancer cells. Our results therefore emphasize the therapeutic potential of Taiwanin C against arecoline-induced oral cancer.

The anti-apoptotic effects of diosgenin, a steroid saponin, on hearts in female with estrogen deficiency have been less studied. This study aimed to evaluate the anti-apoptotic effects of diosgenin on cardiac widely dispersed apoptosis in a bilateral ovariectomized animal model.A total of 60 female Wistar rats, aged 6-7 months, were divided into the sham-operated group (Sham), bilateral ovariectomized rats for 2 months, and ovariectomized rats administered with 0, 10, 50, or 100 mg/kg diosgenin daily (OVX, OVX 10, OVX 50, and OVX 100, respectively) in the second month. The excised hearts were analyzed by HE staining, TUNEL(+) assays and Western Blot.Cardiac TUNEL(+) apoptotic cells, the levels of Fas ligand, Fas death receptors, Fas-associated death domain, active caspase-8, and active caspase-3 (FasL/Fas-mediated pathways) as well as the levels of Bax, Bad, Bax/Bcl2, Bad/p-Bad, cytosolic Cytochrome c, active caspase-9, and active caspase-3 (mitochondria-initiated pathway) were increased in OVX compared with Sham group but those were decreased in OVX 50 compared with OVX.Diosgenin appeared to prevent or suppress ovariectomy-induced cardiac FasL/Fas-mediated and mitochondria-initiated apoptosis. These findings might provide one of the possible therapeutic approaches of diosgenin for potentially preventing cardiac apoptosis in women after bilateral ovariectomy or women with estrogen deficiency.