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Glioblastoma is the malignant tumor affecting the central nervous system. Despite the advancement in treatment modalities, presence of blood-brain barrier, recurrence after surgical removal, resistance to radiotherapy and chemotherapy remain the major obstacles for long term survival of the patients. In this context, finding suitable therapeutics which have anticancer potential and are nontoxic might be useful to improve the overall survival of GBM. Plant products are safer, nontoxic and cheaper when compared to the chemotherapeutic drugs in trend which are expensive and highly toxic, owing to their systemic effects. Bacoside A (BA) is one such plant constituent isolated from Bacopa monnieri which offers neuroprotection and possesses anticancer potential. The present investigation elucidates the specific interaction of BA with various cell surface receptors, signal transduction proteins, effector proteins and transcription factors involved in glioblastoma signalling such as EGFR/Ras/Raf/MAPK pathway, Notch signalling and Wnt-beta catenin signalling through molecular docking studies. The interaction between BA and the target proteins of glioblastoma were analysed through the Glide module (Version 6.5) of Schrodinger Suite (2015) software. According to the results of molecular docking, jagged-1 ligands interact with BA with stronger affinity and Frizzled receptors interact with least affinity in terms of glide score. The results indicate that BA interacts well with the polar amino acids such as Asn, Trp, Arg, Ser, Thr, Tyr, Gln, Asp, Lys and Glu. The ligand also showed interactions with specific hydrophobic amino acids such as Val, Ala and Leu in all the protein targets studied. The in vitro cytotoxicity studies reveal the cytotoxic potential of BA on the U87MG glioblastoma cell line. This study warrants further investigation to elucidate modulations on cell signalling pathways resulting from the specific BA-target interactions in glioblastoma.

Doxorubicin (Dox) causes the generation of intracellular reactive oxygen species (ROS) and inactivates insulin-like growth factor 1 (IGF1) signaling, leading to cardiomyocyte apoptosis. IGF-binding protein 3 (IGFBP3) is the most abundant circulating IGF1 carrier protein with high affinity, which has been reported to mediate ROS-induced apoptosis. Hypoxia-inducible factor 1α (HIF1A), an upstream protein of IGFBP3 is regulated by prolyl hydroxylase domain (PHD) through hydroxylation. In this study, we investigated the role of IGFBP3, HIF1A, and PHD in Dox-induced cardiac apoptosis. Cells challenged with 1 μM Dox for 24 h increased ROS generation, augmented intracellular and secreted IGFBP3 levels, and reduced IGF1 signaling. Further, we showed that Dox enhanced the extracellular association of IGF1 with IGFBP3. Moreover, echocardiography parameters, especially ejection fraction (EF) and fractional shortening (FS) were significantly reduced in ventricle tissue of Dox challenged rats. Notably, siRNA approach against IGFBP3 or an anti-IGFBP3 antibody rescued Dox-induced cardiac apoptosis, mitochondrial ROS, and the decrease in the IGF1 signaling activity. Furthermore, silencing HIF1A either using siRNA or inhibitor downregulated intracellular IGFBP3, rescued apoptosis, mitochondrial generation, and reduction in IGF1 signaling. Finally, western blot data revealed that ROS scavenger reversed Dox-induced cardiac apoptosis, increased levels of HIF1A and secreted IGFBP3, and decreased IGF1 survival signaling and PHD expression. These findings suggest that Dox-induced ROS generation suppressed PHD, which might stabilize nuclear HIF1A protein, leading to increased IGFBP3 expression and secretion. This in turn results in enhanced extracellular association of the latter with IGF1 and blocks IGF1 pro-survival signaling and may result in inducing cardiac apoptosis.

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.

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.

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.

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.

Oxidative stress is a major cause of aging related skin injuries. Hydrogen peroxide related ROS accumulation triggers increase in matrix metalloproteinases and elevated collagen degradation, which is a characteristic of skin aging. In this study, we investigated the protective effect of Poria cocos, used widely in the treatment of inflammatory diseases, against H2 O2 induced oxidative stress. The aqueous extract of dried P. cocos was obtained by heating 10 g in 500 ml of distilled water. The mixture was evaporated up to 400 ml and the remaining 100 ml was filtered through muslin cloth repeatedly to obtain a clear aqueous extract of the P. cocos. Hs68 human dermal fibroblast cells were challenged with 100 μM of H2 O2 for 24 h. Following H2 O2 challenge, the cells were treated with increasing concentration of P. cocos extract (100-400 μg/ml) for 24 h. P. cocos extract hindered the H2 O2 induced cell death significantly that was correlated with reduction in ROS accumulation. Western blot analysis show that P. cocos extract suppressed the expression of metallomatrix proteinases, inflammatory markers and skin aging markers, but increased TGF-β1 levels and antioxidant related proteins. These data suggest that P. cocos is effective in attenuating oxidative stress associated skin aging effects and may be a potential agent in cosmetics products.

Doxorubicin (DOX), an anthracycline antineoplastic candidate is used to treat various malignancies. Around 41% of patients undergoing DOX treatment develop acute cardiotoxicity. Preventing DOX-induced cardiac fibrosis and hypertrophy helps in evading cardiac remodeling leading to cardiomyopathy and heart failure. Neferine, an alkaloid from the lotus has numerous pharmacological activities. The present study was designed to evaluate the protective effect of neferine on DOX-mediated fibrosis and hypertrophy. DOX-induced fibrosis involves activation of transforming growth factor-β1 (TGF-β1), matrix metalloproteinase 2 (MMP-2), and MMP-9 with concomitant downregulation of tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 expressions in H9c2 cardiomyoblasts. Furthermore, DOX treatment also resulted in hypertrophy with the increased cell volume and overexpression of hypertrophy markers calcineurin, brain natriuretic peptide, and atrial natriuretic peptide. Finally, DOX treatment resulted in apoptosis through activation of p53. Pretreatment with neferine markedly activated SIRT1 expression and modulated the expression levels of TGF-β1 and p53, thereby significantly reducing DOX-induced fibrosis, hypertrophy, and apoptosis in H9c2 cardiomyoblasts.

Cisplatin chemotherapy to the colorectal cancer cells (CRCs) is accompanied by dose-limiting adverse effects along with the acquisition of drug resistance implicating low therapeutic outcomes. The present study is aimed to evaluate the chemosensitizing efficacy of neferine/isoliensinine or combinatorial regimen of neferine/isoliensinine with cisplatin against CSCs (cisplatin resistant colon stem cells). CSCs were developed using pulse exposure of cisplatin to parental HCT-15 cells. Neferine/isoliensinine or combinatorial regimens of Neferine/isoliensinine and cisplatin exhibited a stronger cytotoxic activity against CSCs compared to control. IC

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 H

It has been reported that 80% of diabetic patients die due to cardiovascular diseases. We previously demonstrated that activated hypoxia-inducible factor-1α (HIF-1 α)/insulin-like growth factor binding protein-3 (IGFBP-3) signaling by reactive oxygen species (ROS)-regulated prolyl hydroxylase domain-containing protein (PHD) is involved in high-glucose (HG)-induced cardiac apoptosis. Diallyl trisulfide (DATS), a garlic component, shows the strongest inhibitory effect on diabetic cardiomyopathy. In this study, we investigated whether HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes. It was observed that significantly increased levels of cell apoptosis and decreased Akt phosphorylation were reversed by DATS in HG-exposed cardiac cells. H2O2 and PHD small interfering RNA treatments increased HIF-1α and IGFBP-3 protein levels, which were decreased by DATS treatment. Overexpression of HIF-1α and IGFBP-3 increased HG-induced cell apoptosis, which was suppressed by DATS. The coimmunoprecipitation assay results showed that DATS not only increased the IGF-1 level and reduced IGFBP-3 level but also suppressed their extracellular association for cardiac cells exposed to HG. Experiments using neonatal cardiomyocytes and hearts showed similar results. These findings indicate that the effect of ROS-regulated PHD on the activation of HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes.

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. In this study, we examined the effects of tannic acid, a polyphenol with anti-fungal and anti-cancer effects, on UMUC3 bladder cancer cells. UMUC3 cells were exposed to tannic acid for 24 hours, following which we observed significant inhibition of cell proliferation. Additionally, flow cytometry and TUNEL assay revealed that tannic acid induces apoptosis in UMUC3 cells in a dose-dependent manner. Furthermore, tannic acid treatment upregulated the expression of cleaved caspase-3 which further confirmed induction of apoptosis in UMUC3 cells by treatment with tannic acid. TA treatment decreased stem cell markers expression such as SOX2, OCT4, and NANOG. Together, these results showed that tannic acid can promote apoptosis; therefore, it may have potential as treatment for bladder cancer.

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.

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 Leu

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.

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.

Oxidative stress has been implicated in the pathogenesis of atherosclerotic cardiovascular diseases. Dietary supplementation of anti-oxidants has been reported to have beneficial effects on the prevention of atherogenic diseases. Luteolin (a natural flavonoid) has been shown to possess antimutagenic, antitumorigenic, anti-oxidant and anti-inflammatory properties. However, the effects and underlying molecular mechanisms of luteolin on cardiovascular systems are poorly explored. Therefore, the aim of the present study was to test whether luteolin could protect against oxidative stress-induced endothelial cell injury and explore the underlying mechanisms. In this study, human umbilical vein endothelial cells (HUVECs) were pre-treated with luteolin followed by hydrogen peroxide induction (H2O2). Our results showed that luteolin protected against H2O2-induced oxidative stress and ameliorated ROS and superoxide generation. In addition, we found that luteolin treatment inhibited the H2O2-induced membrane assembly of NADPH oxidase subunits, which was further confirmed by specifically inhibiting NADPH oxidase using DPI treatment. Furthermore, pAMPK protein expression was enhanced and p-PKC isoforms were significantly down-regulated by luteolin treatment in a dose-dependent manner, and a similar effect was observed upon DPI treatment. However, co-treatment with the specific inhibitor of AMPK (Compound C) restored p-PKC levels suggesting the role of AMPK signaling in regulating p-PKC expression under oxidative stress condition in HUVECs. Finally, we confirmed using siRNAs and specific inhibitor and/or activator of AMPK (AICAR) that luteolin treatment induced AMPK is a key player and regulator of activated expression of PKC isoforms and thereby confers protection against H2O2-induced oxidative stress in HUVECs.

Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-induced oxidative stress is mediated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status. Thus, treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased gene expression of NF-κB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR and significantly decreased the gene expression of p53, Bax, caspase-9 and caspase-3. Neferine treatment restored the DEN- induced alteration of these gene expression levels. Further, blotting analysis also revealed increased expression of NF-κB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase-3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN- induced lung carcinogenesis.

Fisetin, a naturally occurring flavonoid in fruits, nuts and vegetables possess antioxidant and anti-inflammatory properties. This study shows that fisetin exerts preventive and therapeutic effects on hypertension associated cardiac abnormalities in H9c2 cells and Spontaneously Hypertensive Rats (SHRs). For In vitro analysis, H9c2 cells were challenged with AngII and Fisetin (50 µM/mL) was administered either before 2 h or after 12 h of AngII challenge. For In vivo studies, SHRs received oral fisetin (10 mg/kg, twice a week for 6 weeks) and their cardiac function was analyzed by echocardiography. Histological studies and Western blotting were performed to assess the severity and the mechanism of the underlying cardiac abnormality. Fisetin effectively suppressed calcineurin-NFATC3 involved cellular hypertrophic effects as observed in H9c2 cells and in SHR hearts. Fisetin also enhanced cardiac function and restored cardiac morphology and therefore, fisetin is a potential agent against hypertension associated hypertrophy and cardiac deterioration.

Recent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated. In this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased Carboxyl terminus of Hsc70 interacting protein (CHIP) expression promoted phosphatase and tensin homolog (PTEN) degradation via the ubiquitin-proteasome system and shortened its half-life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP-mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Coculturing CHIP overexpressed WJMSCs suppressed HG-induced apoptosis and oxidative stress in embryo derived cardiac cell lines. CHIP overexpressing and PTEN silenced WJMSCs ameliorated diabetic effects in streptozotocin (STZ) induced diabetic rats and further improved their body weight and heart weight, and rescued from hyperglycemia-induced cardiac injury. Considering these, the current study suggests that CHIP confers resistance to apoptosis and acts as a potentiation factor in WJMSCs to provide protection from degenerative effects of diabetes.

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 H

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

It has been reported that two sets of blot figures in Figure 3A,C looked identical in the original published paper [...]

Background Cardiovascular diseases are caused by multitudes of stress factors like hypertension and their outcomes are associated with high mortality and morbidity worldwide. Nerolidol, a naturally occurring sesquiterpene found in several plant species, embodies various pharmacological benefits against numerous health disorders. However, their effects on hypertension induced cardiac complications are not completely understood. Purpose The present study is to elucidate the efficacy of nerolidol against hypertension related cardiac hypertrophy in spontaneously hypertensive rats (SHRs). Study Design For preliminary in vitro studies, H9c2 cardiomyoblasts cells were challenged with 200 nM Angiotensin-II (AngII) for 12 h and were then treated with nerolidol for 24 h. The hypertrophic effect in H9c2 cells were analyzed by actin staining and the modulations in hypertrophic protein markers and mediators were determined by Western blotting analysis. For in vivo experiments, sixteen week-old male Wistar Kyoto (WKY) and SHRs were segregated into five groups (n = 9): Control WKY, hypertensive SHRs, SHRs with low dose (75 mg/kg b.w/day) nerolidol, SHRs with high dose (150 mg/kg b.w/day) nerolidol and SHR rats treated with an anti-hypertensive drug captopril (50 mg/kg b.w/day). Nerolidol treatment was given orally for 8 weeks and were analysed through Echocardiography. After euthanasia, hematoxylin and eosin staining, Immunohistochemical analysis and Western blotting was performed on left ventricle tissue. Results Western blotting analysis revealed that nerolidol significantly attenuates AngII induced expression of hypertrophic markers ANP and BNP in H9c2 cardiomyoblasts. In addition, actin staining further ascertained the potential of nerolidol to ameliorate AngII induced cardiac hypertrophy. Moreover, nerolidol administration suppressed the hypertrophic signalling mediators like calcineurin, GATA4, Mel-18, HSF-2 and IGFIIR in a dose-dependent fashion. In silico studies also ascertained the role of Mel-18 in the ameliorative effects of nerolidol. Further, these intriguing in vitro results were further confirmed in in vivo SHR model. Oral neraolidol in SHRs efficiently reduced blood pressure and ameliorated hypertension induced cardiac hypertrophic effects by effectively reducing the levels of proteins involved in cardiac MeL-18-HSF2-IGF-IIR signalling. Conclusion Collectively, the data reveals that the cardioprotective effect of nerolidol against hypertension induced hypertrophy involves reduction in blood pressure and regulation of the cardiac Mel-18-IGFIIR signalling cascade.

Leukotrienes are one of the major eicosanoid lipid mediators produced due to an oxidative transformation of arachidonic acid. Subsequently, they get converted into various cellular signaling hormones by a series of enzymes of myeloid origin to mediate or debilitate inflammation. Interestingly, the available literature demonstrates the pivotal role of eicosanoids in neurodegenerative, obesity, diabetes, cardiovascular diseases, and cancers as well. The aberrant metabolism of arachidonic acid by the LOX pathway is a common feature of epithelial-derived malignancies and suggests the contributory role of dietary fats in carcinogenesis. The enzymes and receptors of the LOX pathway play a significant role in cell proliferation, differentiation and regulation of apoptosis through multiple signaling pathways and have been reported to be involved in various cancers, including prostate, colon, lung and pancreatic cancers. So far, leukotriene receptor antagonists and 5-LOX inhibitors have reached up to the clinical trials for treating various diseases. Keeping its various roles in cancer, the review highlights the components of the leukotriene synthesizing machinery, emerging opportunities for pharmacological intervention, and the probability of considering lipoxygenases and leukotriene receptors as good candidates for clinical chemoprevention studies.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson&rsquo, s disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases &alpha, synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

Ethnopharmacological relevance The prevalence of cardiovascular diseases (CVDs) has been increasing worldwide. Despite significant improvements in therapeutics and on-going developments of novel targeted-treatment regimens, cardiac diseases lack effective preventive and curative therapies with minimal side effects. Therefore, there is an urgent need to identify and propagate alternative and complementary therapies against cardiovascular diseases. Some traditional Chinese medicines can contribute to the prevention and treatment of CVDs and other chronic diseases, with few side effects. Hirudo, a medicinal leech, has been acclaimed for improving blood circulation and overcoming blood stagnation; however, the precise molecular mechanisms of leech extract treatment against pathological cardiac remodeling remain elusive. In this study, we aimed to delineate the molecular mechanisms of medicinal leech extract in the treatment of cardiac hypertrophy and fibrosis, using both in vitro and in vivo assessments. Materials and methods We conducted in vitro and in vivo animal experiments, including cell-viability assays, fluorescence microscopy, immunoblotting, immunohistochemistry, and Masson’s trichrome staining. Results Pre-treatment with leech extract conferred a survival benefit to spontaneously-hypertensive rats (SHRs) and significantly reduced angiotensin II (ANG II)-induced cardiac hypertrophy and fibrosis. ANG II-stimulated cardiac hypertrophy markers were attenuated by leech extract treatment, versus controls. Translational expression of stress-associated mitogen-activated protein kinases (MAPKs) was also repressed. In vivo, leech extract treatment significantly ameliorated the cardiac hypertrophy phenotype in SHRs and diminished interstitial fibrosis, accompanied with reduced fibrosis markers. Conclusion Leech extract treatment under a hypertensive condition exerted significant cardio-protective benefits by reducing the expression of cardiac hypertrophy-related transcription factors, stress-associated MAPKs, and fibrosis mediators. Our findings imply that medicinal leach extract may be effective against hypertension-induced cardiac hypertrophy and fibrosis.

Cancer stem cells (CSCs) exist in colon cancer and exhibit characteristics of stem cells which are due to lineages of tissues where they arise. Epithelial to mesenchymal transition (EMT)-undergoing cancer cells display CSC properties and therapeutic resistance. Cancer and stromal cells comprise of a tumor microenvironment. One way the two populations communicate with each other is to secret CXC ligands (CXCLs). CXCLs are capable of causing chemotaxis of specific types of stromal cells and control angiogenesis. Double immunofluorescence, western blot analysis, and colony-formation assay were carried out to compare parental and CPT-11-resistant LoVo cells. CPT-11-R LoVo colon cancer cells showed increased expression of CXCL1, CXCL2, CXCL3, and CXCL8. They displayed significantly increased intracellular protein levels of CXCL2 and CXCR2. CPT-11-R LoVo cells showed significantly elevated expression in aldehyde dehydrogenase 1 (ALDH1), cluster of differentiation 24 (CD24), cluster of differentiation 44 (CD44), and epithelial cell adhesion molecule (EpCAM). CXCL2 knockdown by short hairpin RNA resulted in reduced expression of CSC proteins, cyclins, EMT markers, G proteins, and matrix metalloproteinases (MMPs). Finally, Gαi-2 was found to promote expression of CSC genes and tumorigenesis which were more apparent in the resistant cells. In addition, Gαq/11 showed a similar pattern with exceptions of EpCAM and MMP9. Therefore, CXCL2-CXCR2 axis mediates through Gαi-2 and Gαq/11 to promote tumorigenesis and contributes to CSC properties of CPT-11-R LoVo cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are easily accessible and are attractive mesenchymal stem cells for use in regenerative medicine; however their application is frequently restricted due to various challenges present in the environment they are administered. Therefore ADMSCs are preferably preconditioned with various stimulating factors to overcome the barriers developed in any pathological conditions. Here we used ADMSCs from rat adipose based on the abundance of positive markers and preconditioned the cells with extracts from Alpinate Oxyphyllae Fructus (AOF), a traditional Chinese herb used for antiaging, associated various health benefits. The preconditioned stem cells were tested for their potential to drive H9c2 from doxorubicin (Dox)-induced aging. The AOF-treated stem cells enriched stemness in ADMSCs with respect to their stem cells' positive marker, and enhanced their longevity mechanism and elevated the stem cell homing-associated C-X-C chemokine receptor type 7 (CXCR7). The AOF preconditioned stem cells, when cocultured with H9c2 cells, showed effective protection to Dox-induced senescence and stem cell homing to damaged H9c2 cells. The presence of AOF provided greater protective effects in the Dox environment. In addition, AOF-pretreated ADMSCs showed enhanced migration than those treated with AOF in Dox environment. Therefore, our results show that administration of AOF preconditioned stem cells is potentially an effective strategy in the management of aging-associated cardiac disorders.

Aim The current study was designed to investigate the effect of berbamine (BBM) on isoproterenol (ISO) induced changes in cardiac marker enzymes, myocardial oxidative stress, lipid profile and expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in male Wistar rats. Rats were pretreated with BBM (25 mg/kg) through intraperitoneal injection for 7 days followed by induction of myocardial infarction (MI) by subcutaneous injection of ISO (85 mg/kg) for last two days. Key findings: In the present study, the histopathological findings of the heart tissue showed that BBM treatment significantly minimized the damage induced by ISO. BBM pretreatment showed a significant decrease in heart weight, serum marker enzymes, lipid peroxidation and significant increase in cardiac endogenous enzymatic and non-enzymatic antioxidants compared to the ISO-treated group. In addition, we observed significantly upregulated eNOS expression and downregulated iNOS expression in BBM pretreated group. Thus, BBM protected the rat’s heart from ISO-induced myocardial infarction by its antioxidant, and antilipidemic properties. Significance: The results of the present investigation suggested that BBM efficiently ameliorated the ISO-induced myocardial infarction in rats.