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Prostate cancer is the most commonly diagnosed and frequently occurred cancer in the males globally. The current treatment strategies available to treat prostate cancer are not much effective and express various adverse effects. Hence, there is an urgent need to identify novel treatment that can improve patient outcome. From times immemorial, natural products are highly recognized for novel drug development for various diseases including cancer. Cancer cells generally maintain higher basal levels of reactive oxygen species (ROS) when compared to normal cells due to its high metabolic rate. However, initiation of excess intracellular ROS production can not be tolerated by the cancer cells and induce several cell death signals which are in contrast to normal cells. Therefore, small molecules of natural origin that induce ROS can potentially kill cancer cells in specific and provide a better opportunity to develop a novel drug therapy. In this review, we elaborated various classes of medicinal compounds and their mechanism of killing prostate cancer cells through direct or indirect ROS generation. This can generate a novel thought to develop promising drug candidate to treat prostate cancer patients.

Proper regulation of cellular protein quality control is crucial for cellular health. It appears that the protein quality control machinery is subjected to distinct regulation in different cellular contexts such as in somatic cells and in germ cells. Heat shock factors (HSFs) play critical role in the control of quality of cellular proteins through controlling expression of many genes encoding different proteins including those for inducible protein chaperones. Mammalian cells exert distinct mechanism of cellular functions through maintenance of tissue-specific HSFs. Here, we have discussed different HSFs and their functions including those during spermatogenesis. We have also discussed the different heat shock proteins induced by the HSFs and their activities in those contexts. We have also identified several small molecule activators and inhibitors of HSFs from different sources reported so far.

BackgroundEsculetin is a natural coumarin derivative from various plants with multiple pharmacological effects. Hence, the present study was undertaken to explore the cardio protective potential of esculetin against isoproterenol induced myocardial toxicity in rats. Methods The treatment schedule was fixed for 28 days and the rats were divided into five groups of six each. Rats of group I received the normal saline and served as normal control, group II was received ISO (100mg/kg body weight) for last two consecutive days of the study and served as disease control. Groups III and IV received esculetin 10 and 20 mg/kg body weight respectively once a day per oral for 28 days along with ISO for last two consecutive days of the study. Cardiac biomarkers such as CK-MB and LDH, membrane bound Na+ /K+ ATPases activity, myocardial lysosomal enzymes activity and tissue antioxidants status were estimated in the heart tissue samples. The histopathological changes in the myocardium were also assessed. Further, DPPH assay was done to evaluate the free radicals scavenging potential of esculetin. Cytoxicity assay, intracellular ROS levels by DCFDA assay and m-RNA expression of TNF-α, IL-6 and NF-κB by quantitative RT-PCR in H9c2 cell lines.ResultsThe increased levels of CK-MB, LDH, LPO, myocardial lysosomal enzymes and membrane bound Na+ /K+ ATPase levels by ISO administration was significantly increased with concomitant decrease in tissue antioxidant enzymes such as GSH, Catalase, and SOD. Pre-treatment with esculetin for 28 days has significantly decreased the levels of cardiac bio-markers, lysosomal enzymes, membrane bound Na+ /K+ ATPase levels as well as Lipid peroxides which is in contrary to the ISO group. Amelioration of the antioxidant levels were also found in esculetin treated groups. Histopathological examination of heart reveals that myocardial degeneration, mononuclear cell infiltration was noticed in ISO treated rats, whereas the same was restored with esculetin treatment. In H9C2 cell lines esculetin could effectively reduced intracellular ROS inhibition and m-RNA expression of pro-inflammatory cytokines including TNF-α, IL-6 and NF-κB to prevent apoptosis or cell necrosis. Conclusion The study provides the evidence of cardioprotective potentials of esculetin against isoproterenol induced myocardial infarction by antioxidant and myocardial membrane stabilization along with in vitro protection from arsenic induced ROS cell necrosis or apoptosis in H9C2 cells.

Prostate cancer (PCa) is a major cause of morbidity and mortality in men worldwide. A geographic variation on the burden of the disease suggested that the environment, genetic makeup, lifestyle, and food habits modulate one's susceptibility to the disease. Although it has been generally thought to be an older age disease, and awareness and timely execution of screening programs have managed to contain the disease in the older population over the last decades, the incidence is still increasing in the population younger than 50. Existing treatment is efficient for PCa that is localized and responsive to androgen. However, the androgen resistant and metastatic PCa are challenging to treat. Conventional radiation and chemotherapies are associated with severe side effects in addition to being exorbitantly expensive. Many isolated phytochemicals and extracts of plants used in traditional medicine are known for their safety and diverse healing properties, including many with varying levels of anti-PCa activities. Many of the phytochemicals discussed here, as shown by many laboratories, inhibit tumor cell growth and proliferation by interfering with the components in the pathways responsible for the enhanced proliferation, metabolism, angiogenesis, invasion, and metastasis in the prostate cells while upregulating the mechanisms of cell death and cell cycle arrest. Notably, many of these agents simultaneously target multiple cellular pathways. We analyzed the available literature and provided an update on this issue in this review article., Graphical abstract Image 1, Highlights • Prostate cancer in a major cause of death in older population worldwide. • Efficacies of current treatment options are limited in many cases. • Phytochemicals and extracts isolated from plants show anti-prostate cancer activity with unique mechanisms. • Certain phytochemicals alone or in combination with current chemotherapy show therapeutic promise.

BackgroundsColon cancer is the third most deadly and one of the most diagnosed diseases in the world. Although routine screening and early detection during last decades has improved the survival, colon cancer still claims hundreds of thousands lives each year worldwide. Surgery and chemotherapy is mainstay of current treatment, nevertheless toxicity associated with this treatment underscores the urgency of demand of a better therapeutics. Close to 50% of current chemotherapeutic drugs are direct or indirect descendants compounds isolated from medicinal plants, which indicate plants are great potential sources of novel therapeutics. In our literature review we foundEclipta albato posses many pharmacological activities, including those with anticancer potentials. However, no study on anticancer activity of this kind has been reported.MethodsPhytochemicals were extracted by maceration method from shade dried whole plant ofEclipta albausing methanol as a solvent. The anticancer effect of extract was investigated on various cancer cell lines like human colorectal carcinoma (HCT-116), human prostate cancer (PC-3), Michigan cancer foundation-breast cancer (MCF-7) and renal cell carcinoma (RCC-45). We have also studied the effects on normal human embryonic lung fibroblast cell (WI-38) using MTT (methyl thiazoldiphenyltetrazolium bromide) assay, clonogenic (colony formation) and migration assay. Finally obtained results were analyzed using ANNOVA and Dunnett’s test.ResultsResults obtained from MTT assay revealed that the methanolic extract ofEclipta albacarried significant (p ConclusionThis is a unique finding of its kind because the specific anticancer effect with minimal toxicity on normal cells has not been reported onEclipta albaextract. Finally this finding opens up a great possibility to develop a novel antitumor drug candidate against deadly colon cancer in the future.

Background Heat shock response (HSR), a component of cellular protein quality control mechanisms, is defective in different neurodegenerative conditions such as Parkinson's disease (PD). Forced upregulation of heat shock factor 1 (HSF1), an HSR master regulator, showed therapeutic promise in PD models. Many of the reported small-molecule HSF1 activators have limited functions. Therefore, identification and understanding the molecular bases of action of new HSF1 activating molecules is necessary. Method We used a cell-based reporter system to screen Andrographis paniculata leaf extract to isolate andrographolide as an inducer of HSF1 activity. The andrographolide activity was characterized by analyzing its role in different protein quality control mechanisms. Result We find that besides ameliorating the PD in MPTP-treated mice, andrographolide upregulated different machineries controlled by HSF1 and NRF2 in both cell and mouse brain. Andrographolide achieves these functions through mTORC1 activated via p38 MAPK and ERK pathways. NRF2 activation is reflected in the upregulation of proteasome as well as autophagy pathways. We further show that NRF2 activation is mediated through mTORC1 driven phosphorylation of p62/sequestosome 1. Studies with different cell types suggested that andrographolide-mediated induction of ROS level underlies all these activities in agreement with the upregulation of mTORC1 and NRF2-antioxidant pathway in mice. Conclusion Andrographolide through upregulating HSF1 activity ameliorates protein aggregation induced cellular toxicity. General significance Our results provide a reasonable basis for use of andrographolide in the therapy regimen for the treatment of PD.

Ethnopharmacological relevance Ervatamia coronaria, a popular garden plant in India and some other parts of the world is known traditionally for its anti-inflammatory and anti-cancer properties. The molecular bases of these functions remain poorly understood. Aim of the study Efficacies of the existing therapies for colorectal cancer (CRC) are limited by their life-threatening side effects and unaffordability. Therefore, identifying a safer, efficient, and affordable therapeutic is urgent. We studied the anti-CRC activity of an alkaloid-rich fraction of E. coronaria leaf extracts (AFE) and associated underlying mechanism. Materials and methods Activity guided solvant fractionation was adopted to identify the activity in AFE. Different cell lines, and tumor grown in syngeneic mice were used to understand the anti-CRC effect. Methodologies such as LCMS, MTT, RT-qPCR, immunoblot, immunohistochemistry were employed to understand the molecular basis of its activity. Results We showed that AFE, which carries about six major compounds, is highly toxic to colorectal cancer (CRC) cells. AFE induced cell cycle arrest at G1 phase and p21 and p27 genes, while those of CDK2, CDK-4, cyclin-D, and cyclin-E genes were downregulated in HCT116 cells. It predominantly induced apoptosis in HCT116p53+/+ cells while the HCT116p53-/- cells under the same treatment condition died by autophagy. Notably, AFE induced upregulation of AMPK phosphorylation, and inhibition of both of the mTOR complexes as indicated by inhibition of phosphorylation of S6K1, 4EBP1, and AKT. Furthermore, AFE inhibited mTOR-driven conversion of cells from reversible cell cycle arrest to senescence (geroconversion) as well as ERK activity. AFE activity was independent of ROS produced, and did not primarily target the cellular DNA or cytoskeleton. AFE also efficiently regressed CT26-derived solid tumor in Balb/c mice acting alone or in synergy with 5FU through inducing autophagy as a major mechanism of action as indicated by upregulation of Beclin 1 and phospho-AMPK, and inhibition of phospho-S6K1 levels in the tumor tissue lysates. Conclusion AFE induced CRC death through activation of both apoptotic and autophagy pathways without affecting the normal cells. This study provided a logical basis for consideration of AFE in future therapy regimen to overcome the limitations associated with existing anti-CRC chemotherapy.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only HSF1 (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD.

Lysosomal membrane damage suggests that it would be the major contributing factor of myocardial infarction followed by necrosis. The present investigation was carried out on the defensive effect of ethanolic extract of Rosa damascena Mill. L. extract on alterations in myocardial lysosomal enzyme activity and membrane bound Na+/K+ ATPases against isoproterenol induced myocardial infarction in rats. On treatment with isoproterenol (100 mg/kg body weight) for two consecutive days, animals have shown a significant increase in serum creatinine kinase-MB, lactate dehydrogenase and lysosomal enzyme activity; whereas membrane bound Na+/K+ ATPases and tissue antioxidants were decreased. Pre-treatment with Rosa damascena Mill. L. extracts 200 and 400 mg/kg body weight respectively, for 28 days, significantly prevented the alterations and restored the CK-MB, LDH, tissue antioxidants and lysosomal enzyme activity to near-normal status in rats. These findings demonstrate that Rosa damascena could preserve lysosomal integrity through increasing the antioxidant enzyme levels and membrane bound Na+/K+ ATPases integrity. The cardio protective activity of Rosa damascena was further supported by histopathological examination of heart sections. Hence all these findings confirm cardio protective potential of ethanolic extract of Rosa damascena.

// Vinod K. Nelson 1,7,* , Asif Ali 1,* , Naibedya Dutta 1 , Suvranil Ghosh 1 , Manas Jana 1 , Arnab Ganguli 2 , Andrei Komarov 3 , Soumyadip Paul 1 , Vibha Dwivedi 4 , Subhrangsu Chatterjee 5 , Nihar R. Jana 6 , Subhash C. Lakhotia 4 , Gopal Chakrabarti 2 , Anup K. Misra 1 , Subhash C. Mandal 7 and Mahadeb Pal 1 1 Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India 2 Dr. B. C. Guha Center for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, West Bengal, India 3 Cellecta Inc, Mountain View, California, United States of America 4 Department of Zoology, Cytogenetics Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh, India 5 Department of Biophysics, Bose Institute, Kolkata, West Bengal, India 6 Cellular and Molecular Neuroscience Laboratory, National Brain Research Institute, Manesar, Gurgaon, Haryana, India 7 Department of Pharmaceutical Technology, Pharmacognosy and Phytotherapy Laboratory, Jadavpur University, Jadavpur, West Bengal, India * These authors have contributed equally to this work Correspondence to: Mahadeb Pal, email: // Keywords : heat shock factor 1, HSF1, neurodegenerative diseases, small molecule, azadiradione, Gerotarget Received : June 27, 2016 Accepted : August 21, 2016 Published : October 26, 2016 Abstract Aggregation of proteins with the expansion of polyglutamine tracts in the brain underlies progressive genetic neurodegenerative diseases (NDs) like Huntington’s disease and spinocerebellar ataxias (SCA). An insensitive cellular proteotoxic stress response to non-native protein oligomers is common in such conditions. Indeed, upregulation of heat shock factor 1 (HSF1) function and its target protein chaperone expression has shown promising results in animal models of NDs. Using an HSF1 sensitive cell based reporter screening, we have isolated azadiradione (AZD) from the methanolic extract of seeds of Azadirachta indica, a plant known for its multifarious medicinal properties. We show that AZD ameliorates toxicity due to protein aggregation in cell and fly models of polyglutamine expansion diseases to a great extent. All these effects are correlated with activation of HSF1 function and expression of its target protein chaperone genes. Notably, HSF1 activation by AZD is independent of cellular HSP90 or proteasome function. Furthermore, we show that AZD directly interacts with purified human HSF1 with high specificity, and facilitates binding of HSF1 to its recognition sequence with higher affinity. These unique findings qualify AZD as an ideal lead molecule for consideration for drug development against NDs that affect millions worldwide.

Chronic alcoholism is one of the most common causes of liver diseases worldwide. Nitric oxide (NO) has been proposed to have potential for clinical application against chronic hepatocellular injuries. However, mechanisms underlying hepatoprotective functions of NO in ethanol-induced apoptosis are largely unknown. Sprauge–Dawley rats were exposed to ethanol for 8 weeks. Half of the ethanol-fed animals received 14-deoxyandrographolide (14-DAG) treatment for the last 4 weeks of study. Preventive effect of 14-DAG against ethanol-induced hepatotoxicity involved constitutive nitric oxide synthase (cNOS) activation followed by up-regulation of γ-glutamylcysteine synthetase activity and reduced oxidative stress. Enhanced interaction of cNOS with caveolin-1 caused down-regulation of enzyme activity and led to depletion of NO in the hepatocytes of ethanol-fed animals. 14-DAG acted as activator of adenylate cyclase and modulated cyclic AMP (cAMP) mediated expression of caveolin-1 and calmodulin. This eventually favored activation of cNOS through inhibition of cNOS-caveolin-1 interaction. Our results suggest that, protective effect of 14-DAG against ethanol-induced hepatic injury is based on its ability to reduce oxidative stress through cNOS dependent improvement of redox status. 14-DAG mediated activation of adenylate cyclase-cAMP signaling leading to up-regulation of cNOS may provide a promising approach in the prevention of liver diseases during chronic alcoholism.