Survey of the present health & nutritional status of Shompen tribe of Great Nicobar Island.

BACKGROUND OBJECTIVES: Shompens are one of the two mongoloid tribes of Nicobar district. There is little information about their recent health status since the last survey which was conducted in 1998. Hence, a comprehensive health and nutritional survey was conducted in March 2017 to assess the changes. The survey was carried out by a joint team of various organizations including the ICMR-Regional Medical Research Centre and Tribal Welfare and Health Department both located in Port Blair. METHODS: A detailed health and nutrition survey of the Shompen community was planned by deputing a field research team. The survey included demographic data, anthropometric data, clinical examination, screening for the markers of infectious diseases, respiratory pathogens, tuberculosis and haemoglobinopathies. RESULTS: About half of the Shompen adults (both males and females) had a body mass index (BMI) of ≥23. However, Shompen children had a good nutritional status with no child suffering from undernutrition. As per BMI for age, none of the children <5 yr were under-nourished, while in the 5-17 yr group, 12 per cent of children were undernourished. Anaemia prevalence was about 48.3 per cent, with 54 per cent prevalence in females and 43.8 per cent in males. Fungal infection of the skin, acute respiratory infection and abdominal pain were the common morbidities observed. None had active pulmonary tuberculosis. Of 38 Shompens screened for IgG (immunoglobulin G) antibodies, 42.1 and 18.4 per cent were positive for measles and rubella, respectively. Seroprevalence of Leptospira was 35.5 per cent. The prevalence of hypertension was 13.2 per cent, whereas another 28.9 per cent were pre-hypertensive. INTERPRETATION CONCLUSIONS: The population structure of the Shompen is not skewed and under nutrition was not widely prevalent among the children of <5 yr. The other positive observations were the absence of malaria, filariasis and dengue. However, there was natural infection of measles and rubella. Fungal skin infection and intestinal parasitic infestations were widely prevalent. Although cardiovascular risk profile was low, there were signs of emerging risk of over-weight, hypertension and dyslipidaemia. These together with the high prevalence of smokeless tobacco use may have a serious effect on the cardiovascular disease susceptibility of the Shompen population in the future.

Targeting the complement system in pancreatic cancer drug resistance: a novel therapeutic approach.

Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030. The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma's rapid progression and metastasis, and development of drug resistance. Today, cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance. Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance, especially in pancreatic cancer. A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer, major ones including nuclear factor kappa B, signal transducer and activator of transcription 3, c-mesenchymal-epithelial transition factor, and phosphoinositide-3-kinase/protein kinase B. In addition, it has also been proven that the complement system has a very active role in establishing the tumor microenvironment, which would aid in promoting tumorigenesis, progression, metastasis, and recurrence. Interestingly, it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators, which in turn activate these chemo-resistant pathways. Therefore, targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance. In this review, we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.

Old drugs, new uses: Drug repurposing in hematological malignancies.

Discovery and development of novel anti-cancer drugs are expensive and time consuming. Systems biology approaches have revealed that a drug being developed for a non-cancer indication can hit other targets as well, which play critical roles in cancer progression. Since drugs for non-cancer indications would have already gone through the preclinical and partial or full clinical development, repurposing such drugs for hematological malignancies would cost much less, and drastically reduce the development time, which is evident in case of thalidomide. Here, we have reviewed some of the drugs for their potential to repurpose for treating the hematological malignancies. We have also enlisted resources that can be helpful in drug repurposing.

Self-Tuning fuzzy controller for sun-tracker system using Gray Wolf Optimization (GWO) technique.

The demand of electric power consumption is increasing very rapidly worldwide and to fulfill this requirement, solar energy is one of the most viable solution as renewable energy source. Photovoltaic (PV) cell based sun-tracker system (STS) produces maximum current when sunlight vertically incident on its surface. Hence, there is a need of optimized continuous axis position control of STS to achieve maximum output current. This task can be done on the basis of the fuzzy control system. Usually, in the traditional fuzzy control system (FCS), tuning of designed fuzzy parameter is done by trial and error method. However, this type of FCS parameter tuning approach may or may not give optimal solution. Thus, in presented work, an optimal tuning technique with Takagi, Sugeno and Kang (TSK) fuzzy controller (TFC) using Gray Wolf Optimization (GWO) for STS has been proposed. In order to validate the proposed work, different objective functions have been employed to carry out fuzzy controller parameter optimization. A comparative analysis has been performed on the basis of three parameters: settling time, maximum-overshoot and optimal fuzzy parameter on different constrain set. The results obtained with the GWO optimization algorithm were also compared with other popular population algorithms, i.e. Whale Optimization Technique (WOT) and Particle Swarm Optimization (PSO) algorithms.

Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recognized as a key mediator of inflammation and has been frequently observed to be upregulated in PDAC. Several lines of evidence suggest that NF-κB pathways play a crucial role in PDAC development, progression and resistance. In this review, we focused on emphasizing the recent advancements in the involvement of NF-κB in PADC's progression and resistance. We also highlighted the interaction of NF-κB with other signaling pathways. Lastly, we also aim to discuss how NF-κB could be an excellent target for PDAC prevention or therapy. This review could provide insight into the development of novel therapeutic strategies by considering NF-κB as a target to prevent or treat PDAC.

Highly selective acylation of polyamines and aminoglycosides by 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones.

5-Acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones, accessible from arylpropargyl phenyldiazoacetates, are highly selective acyl transfer reagents for di- and polyamines, as well as aminoalcohols and aminothiols. As reagents with a carbon-based leaving group, they have been applied for benzoyl transfer with a broad selection of substrates containing aliphatic amino in combination with other competing nucleophilic functional groups. The substrate scope and levels of selectivity for direct benzoyl transfer exceed those of known benzoylating reagents. With exceptional selectivity for acylation between primary amines bound to primary and secondary carbons, these new reagents have been used in direct site-selective monobenzoylation of aminoglycoside antibiotics.

Outbreak investigation of fever mimicking dengue in Havelock Island, an important tourist destination in the Andaman & Nicobar Archipelago, 2014.

An upsurge of fever cases of unknown origin, but resembling dengue and leptospirosis was reported in Havelock, Andaman & Nicobar Islands, an important tourism spot, during May 2014. Investigations were carried out to determine the aetiology, and to describe the epidemiology of the outbreak. The data on fever cases attending Primary Health Centre (PHC), Havelock showed that the average number of cases reporting per week over the last 2 years was 46·1 (95% confidence interval 19·4-72·9). A total of 27 (43·5%) patients out of the 62 suspected cases were diagnosed as having DENV infection based on a positive enzyme immunoassay or reverse transcriptase-polymerase chain reaction. The overall attack rate was 9·4 cases/1000 population and it ranged between 2·8 and 18·8/1000 in different villages. The nucleotide sequencing showed that the virus responsible was DENV-3. DENV-3 was first detected in the Andaman & Nicobar Islands in 2013 among wharf workers in Port Blair and within a year it has spread to Havelock Island which is separated from South Andaman by 36 nautical miles.

Overexpression of heat shock GroEL stress protein in leptospiral biofilm.

Leptospira is the causative agent of leptospirosis, which is an emerging zoonotic disease. Recent studies on Leptospira have demonstrated biofilm formation on abiotic surfaces. The protein expressed in the biofilm was investigated by using SDS-PAGE and immunoblotting in combination with MALDI-TOF mass spectrometry. The proteins expressed in Leptospira biofilm and planktonic cells was analyzed and compared. Among these proteins, one (60 kDa) was found to overexpress in biofilm as compared to the planktonic cells. MALDI-TOF analysis identified this protein as stress and heat shock chaperone GroEL. Our findings demonstrate that GroEL is associated with Leptospira biofilm. GroEL is conserved, highly immunogenic and a prominent stress response protein in pathogenic Leptospira spp., which may have clinical relevance.

Elucidating the richness of bacterial groups in the gut of Nicobarese tribal community - Perspective on their lifestyle transition.

Lifestyle and dietary habits are crucial features that can alter the gut microbiome of humans. Humans, along with their gut microbes, have coevolved in order to sustain themselves in different environments. They were able to adapt themselves to the dietary sources available in their environment. The relation between humans and their gut microbiota and the link with coevolution forms an interesting aspect of research. To understand this association, the participation of ancient communities with less exposure to urbanization is a prerequisite. The current study quantifies the richness of bacterial groups in the gut of Nicobarese. This group of population is an ethnic community of Nicobar group of islands, who have migrated from the remote to rural and urban areas. Alterations in the dominant bacterial groups in relation to their lifestyle transition were emphasized, by comparing the participants from remote, rural and urban settings. The remote cohort remains diverse and stable than the other two cohorts and had higher numbers of Bacteroidetes. Prevotella forms the dominant genus in the Bacteroidetes phylum, indicating the carbohydrate-rich diet of remote Nicobarese. Whereas, the urban cohort is dominated by Bifidobacterium group rather than the Bacteroidetes. Implications of dietary patterns, the transition to different lifestyles and their impact on the microbiota among these cohorts are discussed.

Herbal medicine & healthcare practices among Nicobarese of Nancowry group of Islands - an indigenous tribe of Andaman & Nicobar Islands.

BACKGROUND & OBJECTIVES: Tribal people often depend on herbal medicines and the traditional knowledge practitioners (TKPs) serve as their healthcare service providers. This study was an attempt to document the use of medicinal plants by the Nicobarese of Nancowry group of Islands. METHODS: Field survey was conducted in all the five inhabited Islands of the Nancowry group of Islands. All the TKPs were interviewed with a questionnaire-guided ethnomedicinal survey protocol. Voucher specimens of all the cited plants (botanic species) were collected and a Community Biodiversity Register of Nicobarese of Nancowry was prepared. RESULTS: A total of 77 TKPs were identified, who together were using 132 medicinal plant species belonging to 113 genera and 62 families. The TKPs were treating a total of 43 ailments. Seven endemic and three rare plant species were recorded. The most common plant part used was leaves. Remedies were usually prepared using water as the excipient. Routes for administration of medicinal plant preparations were oral, topical and others. The information collected from the TKPs were collated in the form of Community Biodiversity Registers. INTERPRETATION & CONCLUSIONS: The present survey shows that the medicinal plants play a pivotal role in the healthcare of the Nicobarese tribe of Nancowry group of Islands. Efforts to document the medicinal plant species and the formulations used by them are necessary to prevent the loss of this precious knowledge.

Inhibition of ß-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear ß-catenin/TCF-1 complex: critical role of STAT-3.

Aberrant activation of ß-catenin/TCF signaling is related to the invasiveness of pancreatic cancer. In the present study, we evaluated the effect of capsaicin on ß-catenin/TCF signaling. In a concentration and time-dependent study, we observed that capsaicin treatment inhibits the activation of dishevelled (Dsh) protein DvI-1 in L3.6PL, PanC-1 and MiaPaCa-2 pancreatic cancer cells. Capsaicin treatment induced GSK-3ß by inhibiting its phosphorylation and further activated APC and Axin multicomplex, leading to the proteasomal degradation of ß-catenin. Expression of TCF-1 and ß-catenin-responsive proteins, c-Myc and cyclin D1 also decreased in response to capsaicin treatment. Pre-treatment of cells with MG-132 blocked capsaicin-mediated proteasomal degradation of ß-catenin. To establish the involvement of ß-catenin in capsaicin-induced apoptosis, cells were treated with LiCl or SB415286, inhibitors of GSK-3ß. Our results reveal that capsaicin treatment suppressed LiCl or SB415286-mediated activation of ß-catenin signaling. Our results further showed that capsaicin blocked nuclear translocation of ß-catenin, TCF-1 and p-STAT-3 (Tyr705). The immunoprecipitation results indicated that capsaicin treatment reduced the interaction of ß-catenin and TCF-1 in the nucleus. Moreover, capsaicin treatment significantly decreased the phosphorylation of STAT-3 at Tyr705. Interestingly, STAT-3 over expression or STAT-3 activation by IL-6, significantly increased the levels of ß-catenin and attenuated the effects of capsaicin in inhibiting ß-catenin signaling. Finally, capsaicin mediated inhibition of orthotopic tumor growth was associated with inhibition of ß-catenin/TCF-1 signaling. Taken together, our results suggest that capsaicin-induced apoptosis in pancreatic cancer cells was associated with inhibition of ß-catenin signaling due to the dissociation of ß-catenin/TCF-1 complex and the process was orchestrated by STAT-3.

Ethnomedicinal knowledge among Karens of Andaman & Nicobar Islands, India.

ETHNOPHARMACOLOGICAL RELEVANCE: This study documents the use of medicinal plants by Karens of Middle Andaman, of the Andaman and Nicobar Islands. In spite of the availability of modern medicines, Karens preferred herbal remedies provided by the Traditional Knowledge Practitioners (TKPs), who served as their healers. Hence, the aim of this study was to collect information from TKPs and determine the significance of plants utilized for medicinal purposes. The informant consensus factor (ICF) in relation to medicinal plants used was also estimated and analysed. MATERIALS AND METHODS: Field research was conducted in three villages of Middle Andaman, inhabited by Karens, during October 2010 - February 2013. TKPs were interviewed with a questionnaire-guided ethno-medical survey protocol. The data obtained were analysed using the informant consensus factor (ICF) and use value (UV). Voucher specimens of all the cited plants were deposited at Regional Medical Research Centre (ICMR), Port Blair. RESULTS: Use of 78 medicinal plant species belonging to 71 genera encompassing 48 families was recorded during the survey. These plants were used to treat 38 different ailments, and divided into ten categories of use. The highest ICF value (0.79) was observed for infections and infestations. The Zingiberaceae and Fabaceae families exhibited the highest number of species, and the plants with the highest use values were Typha angustifolia L., Millingtonia hortensis L. f. and Piper betle L. The most common growth form observed were herbs (42%). Among the several plant parts used, leaves were mostly preferred for preparation of medicines. Water was the main excipient used for mixing the herbs. CONCLUSIONS: This study documents the use of medicinal plants by Karens of the Andaman and Nicobar Islands. Phytochemical and pharmacological aspects of these plants need to be studied, to confirm their efficacy and safety, and determine their potential use in modern medicine.

Ethno medicine and healthcare practices among Nicobarese of Car Nicobar - an indigenous tribe of Andaman and Nicobar Islands.

ETHNOPHARMACOLOGICAL RELEVANCE: This study is an attempt to document the use of medicinal plants by Nicobarese tribe from the Car Nicobar Island of Andaman and Nicobar Islands. Inspite of the availability of modern healthcare facilities tribal people often take herbal medicines and Traditional Knowledge Practitioners (TKPs) serve as the local medical experts in Car Nicobar Island. AIM OF THE STUDY: The present study was to conduct an ethnomedicinal survey among the TKPs of Nicobarese tribe of the inhabitants of Car Nicobar Island, Andaman and Nicobar Islands, India. MATERIALS AND METHODS: Field research was conducted in 15 villages of Car Nicobar Island during March 2011-February 2012. TKPs were interviewed with a questionnaire-guided ethnomedical survey protocol. The data obtained were quantitatively analysed using the informant consensus factor (ICF) and use value (UV). Voucher specimens of all cited plants were collected and deposited at Regional Medical Research Centre (ICMR), Port Blair. RESULTS: Use of 150 medicinal plant species, belonging to 122 genera encompassing 59 families were recorded during the survey. These 150 species are employed to treat 47 different medicinal uses, divided into nine categories of use. The highest ICF (0.68) was obtained for the gastrointestinal system. The Euphorbiaceae family exhibited the highest number of citations, and the species with the highest UVs were Morinda citrifolia L., Tabernaemontana crispa Roxb. and Colubrina asiatica (L.) Brongn. Of the medicinal plants reported, the most common growth form was shrubs (28%). Among several parts of individual plant species which are used, leaves constitute the major portion in preparation of medicines. Remedies were generally prepared using water as the excipient. CONCLUSIONS: This study is an attempt to document the use of medicinal plants from the Car Nicobar Island of the Andaman and Nicobar Islands. Future phytochemical and pharmacological studies are needed to confirm the efficacy and safety of the identified plants.

CBP-mediated FOXO-1 acetylation inhibits pancreatic tumor growth by targeting SirT.

Here, we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated c-jun-NH2-kinase (JNK); forkhead box transcription factor, class O (FOXO1); and BIM in BxPC-3, AsPC-1, and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3 and PARP, indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, capsaicin treatment caused a steady increase in the nuclear expression of FOXO-1, leading to increased DNA binding. Capsaicin-mediated expression of BIM was found to be directly dependent on the acetylation of FOXO-1. The expression of CREB-binding protein (CBP) was increased, whereas SirT-1 was reduced by capsaicin treatment. Using acetylation mimic or defective mutants, our result demonstrated that phosphorylation of FOXO-1 was mediated through acetylation by capsaicin treatment. JNK inhibitor attenuated the phosphorylation of FOXO-1, activation of BIM, and abrogated capsaicin-induced apoptosis. Moreover, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis, whereas overexpression of FOXO-1 augmented its effects. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP, indicating the role of BIM in apoptosis. Oral administration of 5 mg/kg capsaicin substantially suppressed the growth of BxPC-3 tumor xenografts in athymic nude mice. Tumors from capsaicin-treated mice showed an increase in the phosphorylation of JNK, FOXO-1, BIM, and levels of CBP, cleavage of caspase-3, PARP, and decreased SirT-1 expression. Taken together, our results suggest that capsaicin activated JNK and FOXO-1, leading to the acetylation of FOXO-1 through CBP and SirT-1. Acetylated FOXO1 induced apoptosis in pancreatic cancer cells through BIM activation.

Shigellosis in Bay of Bengal Islands, India: clinical and seasonal patterns, surveillance of antibiotic susceptibility patterns, and molecular characterization of multidrug-resistant Shigella strains isolated during a 6-year period from 2006 to 2011.

This study aims to determine the clinical features and seasonal patterns associated with shigellosis, the antimicrobial resistance frequencies of the isolates obtained during the period 2006-2012 for 22 antibiotics, and the molecular characterization of multidrug-resistant strains isolated from endemic cases of shigellosis in the remote islands of India, with special reference to fluoroquinolone and third-generation cephalosporins resistance. During the period from January 2006 to December 2011, stool samples were obtained and processed to isolate Shigella spp. The isolates were evaluated with respect to their antibiotic resistance pattern and various multidrug resistance determinants, including resistance genes, quinolone resistance determinants, and extended-spectrum ß-lactamase (ESBL) production. Morbidity for shigellosis was found to be 9.3 % among children in these islands. Cases of shigellosis occurred mainly during the rainy seasons and were found to be higher in the age group 2-5 years. A wide spectrum of resistance was observed among the Shigella strains, and more than 50 % of the isolates were multidrug-resistant. The development of multidrug-resistant strains was found to be associated with various drug-resistant genes, multiple mutations in the quinolone resistance-determining region (QRDR), and the presence of plasmid-mediated quinolone-resistant determinants and efflux pump mediators. This report represents the first presentation of the results of long-term surveillance and molecular characterization concerning antimicrobial resistances in clinical Shigella strains in these islands. Information gathered as part of the investigations will be instrumental in identifying emerging antimicrobial resistance, for developing treatment guidelines appropriate for that community, and to provide baseline data with which to compare outbreak strains in the future.

Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE treatment decreased the interaction of AKT with XIAP. To establish the involvement of AKT in the apoptosis-inducing effects of CAPE, cells were transfected with AKT. Our results revealed that AKT overexpression attenuated the decrease in XIAP and significantly blocked CAPE-mediated apoptosis. Similarly, overexpression of XIAP further decreased CAPE-induced apoptosis. Taken together, our results suggest that CAPE suppresses phosphoinositide 3-kinase/AKT/XIAP pathway leading to apoptosis in melanoma tumor cells in vitro and in vivo.

Lymphatic filariasis elimination programme in Andaman and Nicobar Islands, India: drug coverage and compliance post eight rounds of MDA.

Lymphatic filariasis (LF) is endemic in the Andaman and Nicobar islands, including the lone foci for a diurnally sub-periodic form of Wuchereria bancrofti in the Nancowry group of islands. A programme to eliminate LF was launched in 2004 by the Directorate of Health Services, Andaman and Nicobar Administration which involved a single annual mass drug administration (MDA) using diethylcarbamazine (DEC) with albendazole. So far, eight rounds of MDA have been implemented through the Public Health Care network. The pattern of antifilarial drug distribution and compliance achieved in the on-going LF elimination programme in these islands has been assessed. This is the first systematic effort undertaken in these remote islands to assess the coverage and compliance with the LF elimination programme. This study covered 900 households in each of the 3 districts. There were a largest number of side effects in the Nicobar district (6.4%). Non-consumption of drugs ranged from 18.6% (Nicobar) to 42% (North and Middle Andaman). A survey revealed that almost 95.3% of the respondents had heard about MDA from the drug distributors. Therefore, the distributors should be involved in programmes designed to educate the community at risk of acquiring filarial infection and the possible side effects of the drugs.

Reactive intermediates produced from the metabolism of the vanilloid ring of capsaicinoids by p450 enzymes.

This study characterized electrophilic and radical products derived from the metabolism of capsaicin by cytochrome P450 and peroxidase enzymes. Multiple glutathione and ß-mercaptoethanol conjugates (a.k.a., adducts), derived from the trapping of quinone methide and quinone intermediates of capsaicin, its analogue nonivamide, and O-demethylated and aromatic hydroxylated metabolites thereof, were produced by human liver microsomes and individual recombinant human P450 enzymes. Conjugates derived from concomitant dehydrogenation of the alkyl terminus of capsaicin were also characterized. Modifications to the 4-OH substituent of the vanilloid ring of capsaicinoids largely prevented the formation of electrophilic intermediates, consistent with the proposed structures and mechanisms of formation for the various conjugates. 5,5'-Dicapsaicin, presumably arising from the bimolecular coupling of free radical intermediates was also characterized. Finally, the analysis of hepatic glutathione conjugates and urinary N-acetylcysteine conjugates from mice dosed with capsaicin confirmed the formation of glutathione conjugates of O-demethylated quinone methide and 5-OH-capsaicin in vivo. These data demonstrated that capsaicin and structurally similar analogues are converted to reactive intermediates by certain P450 enzymes, which may partially explain conflicting reports related to the cytotoxic, pro-carcinogenic, and chemoprotective effects of capsaicinoids in different cells and/or organ systems.

Apoptosis signal-regulating kinase 1-thioredoxin complex dissociation by capsaicin causes pancreatic tumor growth suppression by inducing apoptosis.

AIM: In this study, we evaluated the effect of capsaicin on the interaction of redox-sensitive thioredoxin (Trx)/apoptosis signal-regulating kinase 1 (ASK1) in pancreatic cancer cells. RESULTS: Capsaicin treatment downregulated Trx and increased the phosphorylation (activation) of ASK1 at Thr845 and kinase activity in AsPC-1 and BxPC-3 cells. Capsaicin treatment also activated downstream effector molecules MKK4/7, caspase-9, and caspase-3. Antioxidants tiron or PEG-catalase blocked the activation of ASK1 cascade by capsaicin and protected the cells from apoptosis, indicating the involvement of reactive oxygen species in the activation of ASK1. Our results further revealed that Trx overexpression suppressed the effects of capsaicin, whereas ASK1 overexpression enhanced the apoptosis-inducing effects of capsaicin. ß-mercaptoethanol, a reducing agent, blocked capsaicin-mediated activation of ASK1, indicating that Trx-ASK1 complex exists and requires reducing conditions in the cell. On the other hand, the Trx inhibitor (1-chloro-2-4-dinitrobenzene) increased capsaicin-induced ASK1 kinase activity, suggesting that Trx inhibition by capsaicin is essential for ASK1 activation. Oral administration of 5 mg capsaicin/kg body weight substantially suppressed the growth of tumors in xenograft and orthotopic mouse model. Tumors from capsaicin-treated mice showed reduced levels of Trx, increased phosphorylation of ASK1 at Thr845, and cleavage of caspase-3 and poly (ADP-ribose) polymerase. INNOVATION: Our results for the first time demonstrated a new perspective that Trx-ASK1 complex can be targeted by capsaicin in pancreatic cancer. CONCLUSION: Capsaicin reduces Trx expression and dissociates Trx-ASK1 complex resulting in the activation of ASK1 and downstream effectors leading to apoptosis in pancreatic tumor cells in vitro and in vivo.

Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells.

We evaluated the mechanism of capsaicin-mediated ROS generation in pancreatic cancer cells. The generation of ROS was about 4-6 fold more as compared to control and as early as 1 h after capsaicin treatment in BxPC-3 and AsPC-1 cells but not in normal HPDE-6 cells. The generation of ROS was inhibited by catalase and EUK-134. To delineate the mechanism of ROS generation, enzymatic activities of mitochondrial complex-I and complex-III were determined in the pure mitochondria. Our results shows that capsaicin inhibits about 2.5-9% and 5-20% of complex-I activity and 8-75% of complex-III activity in BxPC-3 and AsPC-1 cells respectively, which was attenuable by SOD, catalase and EUK-134. On the other hand, capsaicin treatment failed to inhibit complex-I or complex-III activities in normal HPDE-6 cells. The ATP levels were drastically suppressed by capsaicin treatment in both BxPC-3 and AsPC-1 cells and attenuated by catalase or EUK-134. Oxidation of mitochondria-specific cardiolipin was substantially higher in capsaicin treated cells. BxPC-3 derived ρ(0) cells, which lack mitochondrial DNA, were completely resistant to capsaicin mediated ROS generation and apoptosis. Our results reveal that the release of cytochrome c and cleavage of both caspase-9 and caspase-3 due to disruption of mitochondrial membrane potential were significantly blocked by catalase and EUK-134 in BxPC-3 cells. Our results further demonstrate that capsaicin treatment not only inhibit the enzymatic activity and expression of SOD, catalase and glutathione peroxidase but also reduce glutathione level. Over-expression of catalase by transient transfection protected the cells from capsaicin-mediated ROS generation and apoptosis. Furthermore, tumors from mice orally fed with 2.5 mg/kg capsaicin show decreased SOD activity and an increase in GSSG/GSH levels as compared to controls. Taken together, our results suggest the involvement of mitochondrial complex-I and III in capsaicin-mediated ROS generation and decrease in antioxidant levels resulting in severe mitochondrial damage leading to apoptosis in pancreatic cancer cells.