Search

Takotsubo syndrome is a condition characterised by temporary acute left ventricular dysfunction with regional wall abnormalities extending beyond a single coronary artery territory. Initially thought to be benign, this condition, which is challenging to distinguish from acute coronary syndrome, has substantial morbidity and mortality. The mechanism behind this condition remains elusive, but multiple theories have been proposed. Although beta blockers and angiotensin-converting enzyme inhibitors are used as treatments for left ventricular dysfunction, currently, there are no randomised controlled trials to support their use. In this paper, we review the latest evidence regarding aetiologies, pathophysiology, diagnostic criteria, prognosis, complications and management of Takotsubo syndrome., (© 2024 Royal Australasian College of Physicians.)

Background Objectives: Anopheles stephensi is responsible for the transmission of malaria in urban areas. Vector competence of An. stephensi from a non-malarious (Coimbatore) and highly malarious (Chennai) urban areas in Tamil Nadu state of India, was investigated to find the reason for non-transmission of malaria in Coimbatore., Methods: Vector competence (susceptibility/refractoriness) of An. stephensi mosquitoes from Chennai (malarious) and Coimbatore (non-malarious) to Plasmodium vivax (Chennai) was investigated. Bioassays were carried out concurrently in both these strains by artificial membrane feeding technique using the same malaria-infected blood. An. stephensi were dissected to observe infection in midgut and salivary gland. The parasite infection, oocyst and sporozoite positivity rate, the oocyst load, correlation between male-female gametocyte ratio and infection, and Survival Analysis of parasitic stages during sporogony were analyzed and compared., Results: The overall infection rate was 45.8 and 41.2 percent in Chennai and Coimbatore, respectively. Oocyst count ranged from 1-80 and 1-208 respectively and not statistically significant. Oocyst positivity was high from Day 8-21 in both strains. The Mean Survival Day (MSD) for oocyst was Day 14 in both strains. Sporozoite was observed in four experiments in each of the strains and the MSD for sporozoites was Day 20 in Chennai and Day 17 in Coimbatore., Interpretation Conclusion: An. stephensi of Chennai and Coimbatore are equally susceptible to P. vivax infection and non-transmission of malaria in Coimbatore can be attributed to external factors such as the presence of preferential breeding habitat, vector density, vector survival, and weather. The only difference observed was the comparatively shortened oocyst maturation time in the Coimbatore strain which requires further investigation., (Copyright © 2024 Copyright: © 2024 Journal of Vector Borne Diseases.)

Background: Ventricular septal rupture (VSR) following acute myocardial infarction is rare in the modern revascularisation era. Nevertheless, clinical awareness is paramount, as presentation may vary., Case Presentation: A middle-aged male with no history of cardiovascular disease developed progressive heart failure symptoms while travelling abroad. Initial workup revealed a prominent systolic murmur, but findings were inconsistent with acute coronary syndrome. Transthoracic echocardiogram showed a small hypokinetic area in the basal septum, preserved left ventricular function and no significant valvulopathy. Despite the absence of chest pain, an invasive angiography revealed occlusion of a septal branch emerging from the left anterior descending artery, otherwise patent coronary arteries. Despite administration of diuretics, the patient remained symptomatic and presented two months later to his primary care provider with a persisting systolic murmur. He was subsequently referred to the outpatient cardiology clinic where echocardiography revealed a large VSR involving the basal anteroseptum of the left ventricle with a significant left-to-right shunt. After accurate radiological and haemodynamic assessment of the defect, he successfully underwent elective surgical repair., Interpretation: Although traditionally associated with large transmural myocardial infarctions, VSR may arise also from minor, subclinical events. A new-onset murmur is a valuable hint for the alert clinician.

Intravenous immunoglobulin (IVIg), which is used to treat multiple neurological conditions, may be associated with serious adverse reactions. The individual neurological disease characteristics associated with adverse reactions, along with strategies to prevent and treat adverse reactions, are uncertain. A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library to summarise studies that report adverse reactions of IVIg therapy in patients with neurological disease. There were 65 studies included in the review. The reported rates of adverse reactions vary widely, but the best evidence suggests rates between 25 and 34% per patient. Common adverse reactions include headache and laboratory abnormalities. Less common but serious adverse reactions included thromboembolic complications and anaphylaxis. Overall, there is a lack of high-quality comparative data to definitively determine if any specific neurological indications are associated with a higher risk of adverse reactions. However, individual neurological disease characteristics possibly associated with an increased likelihood of adverse reactions include limited mobility (as in certain neuromuscular conditions), paraproteinaemia (as in certain peripheral neuropathies), and cardiomyopathy (as in certain myopathies). There is limited evidence to support the effectiveness of prevention and treatment strategies, which may include modification to dose, reduced infusion rate, and premedication. Further studies regarding methods to prevent and treat IVIg-ARs in neurology patients are required., (© 2023 S. Karger AG, Basel.)

The prevalence of 5-hydroxydihydrofuran-2(3 H )-one moiety in natural products is exploited for the first time using coronarin D, a labdane diterpene, to afford Ugi reaction product 1a and interrupted Ugi product 2a . The potential of the Ugi reaction was further extended to l-phenylalanine, 2-aminopyridine, and d-glucosamine, which afforded Ugi reaction products 3a-f , 4 , and 5a-d , respectively. Cytotoxicity studies in RAW cells reveal that compounds 3e and 5b were non-toxic up to 50 µM, and these compounds were able to reduce the LPS stimulated NO production in RAW cells in par with the standard anti-inflammatory drug dexamethasone.

Background: Identifying predictors of preterm birth (PTB) in high-burden regions is important as PTB is the leading cause of global child mortality., Methods: This analysis was nested in a longitudinal study of human immunodeficiency virus (HIV) incidence in Kenya. HIV-seronegative women enrolled in pregnancy had nucleic acid amplification tests (chlamydia and gonorrhea), rapid plasma reagin (syphilis), wet mount microscopy (Trichomonas and yeast), and Gram stain (bacterial vaginosis); sexually transmitted infection (STI) treatment was provided. PTB predictors were determined using log-binomial regression., Results: Among 1244 mothers of liveborn infants, median gestational age at enrollment was 26 weeks (IQR, 22-31), and at delivery was 39.1 weeks (IQR, 37.1-40.9). PTB occurred in 302 women (24.3%). Chlamydia was associated with a 1.59-fold (P = .006), gonorrhea a 1.62-fold (P = .04), and incident HIV a 2.08-fold (P = .02) increased PTB prevalence. Vaginal discharge and cervical inflammation were associated with PTB, as were age ≤21 (prevalence ratio [PR] = 1.39, P = .001) and any STI (PR = 1.47, P = .001). Associations with chlamydia and incident HIV remained in multivariable models., Conclusions: STIs and incident HIV in pregnancy predicted PTB despite treatment, suggesting the need for earlier treatment and interventions to decrease genital inflammation., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: The delivery of healthcare at home has expanded to intravenous infusions of monoclonal antibodies. A recently developed model of care for home infusions of natalizumab for people with relapsing-remitting multiple sclerosis was evaluated. This pilot study of home infusions of natalizumab and usual care (attendance in a hospital out-patients' clinic) compared safety, feasibility, patient satisfaction, effectiveness and costs., Methods: In this randomised AB/BA crossover trial, 37 adults were randomised to usual care (n = 19) or home infusions (n = 18). After three infusions, patients crossed over to the alternate treatment for another three infusions. Patient safety outcomes and adherence, satisfaction, quality of life, disability and costs were compared., Results: No adverse events were recorded from 207 infusions from 35 patients across both home and clinic infusions. There was no difference in adherence (p = 0.71) and infection rates (p = 0.84) between home and clinic settings. Satisfaction with "convenience" of home infusions was significantly greater (p = 0.008) but there were no differences in quality of life measures. Excluding pharmacy, costs were A$74 lower per infusion at home, including A$16 of patients" out-of-pocket costs., Interpretation: There were no differences in safety and effectiveness between clinic and home infusions of natalizumab. The home infusions were shown to be feasible, more convenient and less expensive than usual care. Larger scale studies are required to verify these preliminary findings, particularly around safety and management of hypersensitivity adverse events in the home setting and for equivalence of clinical outcomes., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

A mobile septage treatment unit was built in India using readily available filters and membranes (mesh fabric, sand, granular activated carbon (GAC), microfilter, ultrafilter) and installed on the bed of a small truck. The target application was emptying of septic or sewage holding tanks and concentration of suspended solids while generating a liquid that could be discharged. The system was evaluated for operational and treatment performance while processing septage in the field at 108 sites in Tamil Nadu, India. After one phase of evaluation (Phase I), the system was improved and three replicate systems with slight modifications were fabricated for a second round of evaluation (Phase II) alongside the original, but modified unit. In Phase I, 105 m 3 of septage was processed at an average flow of 623 L h -1 and with high removal efficiencies: 83% chemical oxygen demand (COD), 75% total suspended solids (TSS), and 98.4% total coliform (TC). In Phase II, the original and three new systems combined treated 168 m 3 of septage. One of the new systems doubled in capacity and processed septage at an average flow of 2700 L h -1 while the other three averaged 1290 L h -1 . The removal efficiencies in Phase II were 80% COD, 81% TSS, and 99% TC averaged between the four systems. Pass through of soluble contaminants (e.g. soluble COD, NH 3 -N) remain the primary challenge for treatment performance. Success may be limited with some septage due to seasonality, location, or septage age, and further validation and optimization may be necessary. However, the septage in this study was treated to local standards, and the system offers a method of onsite treatment while reducing the need of costly and often inefficient septage emptying services. Further, the system can be produced at a cost competitive to traditional septage hauling trucks., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multicomponent reactions (MCRs) using dienaminodioate with post-benzylic oxidative transformation mediated by DDQ that afforded a diverse array of products are described. An unprecedented rearrangement of 1,2-dihydropyridines (1,2-DHPs), 3CR products, to 2-pyridones in good yields with a broad substrate scope by DDQ-mediated benzylic oxidation via a pyridinium intermediate is reported. Treatment of the pyridinium intermediate with tert-butyl isocyanide afforded isomerized 1,2-DHPs, analogous to Ritter amides. Further diversification using 3CR products bearing a benzylic group, predictably, promoted the synthesis of 2-pyridone with a benzylideneamine group and a benzo[d]oxazole appended biaryl group by DDQ. A formal 1,6-reduction product from 2-pyridone in the presence of NaBH4 is also observed.

Natalizumab is an effective treatment for multiple sclerosis that requires 4-weekly infusions that are usually provided in hospital outpatient clinics. In this study, a model of care (MOC), an overarching design for the provision of a health care service, was developed to permit home infusions of natalizumab. The proposed new MOC comprised 9 dimensions, in addition to the central concept of patient-centered care at home. The new MOC is responsive to patient needs and prioritizes the nurse-patient therapeutic relationship. It provides practical examples of patient-centered care to guide clinical practice for this patient population in the home setting.

Fucoidan is a marine sulfated polysaccharide, which is extracted from brown seaweed that has a wide range of bioactivities including anti-cancer properties. However, the underlying mechanism of fucoidan on its anti-cancer and apoptotic activity against colon cancer cell line Caco-2 remains to be elucidated. Hence, the present study evaluated the cytotoxicity, apoptotic and anti-cancer activity of fucoidan extracted from brown seaweed Sargassum cinereum against Caco-2 cell line. Cytotoxicity, morphological examination of nuclei, mitochondrial membrane potential, flow cytometry, reactive oxygen species (ROS) formation and detection of apoptotic efficacy of fucoidan were assessed by different assay protocols. Fucoidan inhibited growth of Caco-2 cells in a dose-dependent manner. IC 50 concentration of fucoidan was found to be 250 μg/ml. AO/EB, Hoechst and Annexin V/PI staining confirmed the apoptosis induced by fucoidan in Caco-2 cells. Fucoidan was also found to increase ROS production and augment mitochondrial membrane permeability. The findings of the study suggest that fucoidan exerts potent anti-cancer and apoptotic effect on Caco-2 cells by enhancing ROS production. Thus, fucoidan may be used as a promising therapeutic regimen against various cancer cell types., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Current resorbable and non-resorbable membranes act as a physical barrier to avoid connective and epithelial tissue downgrowth into the defect, favoring the regeneration of periodontal tissues. These conventional membranes possess many structural and bio-functional limitations. We hypothesized that the next-generation of guided tissue regeneration (GTR) membranes for periodontal tissue engineering will be a biologically active, spatially designed nanofibrous biomaterial that closely mimics the native extra-cellular matrix (ECM)., Methods: GTR membranes made of poly(ε-Caprolactone) with a molecular weight of 80,000 reinforced with different weight concentrations of nano-Hydroxyapatite/Bioactive glass (2%, 5%, 10%, 15%) is fabricated by the method of electrospinning. After fabrication, in vitro properties are evaluated., Results: The electrospun nanofibrous membranes possessed excellent mechanical properties initially and after one month of degradation in phosphate buffer solution (PBS). Moreover, none of the fabricated membranes were found to be cytotoxic at lower concentrations and higher concentrations. Comparing the overall properties, PCL (poly(e-caprolactone)) + BG (Bioactive glass) 2% exhibited superior cell attachment and percentage of viable cells, increased fiber and pore diameter which satisfies the ideal properties needed for GTR membranes., Conclusion: Composite nanofibrous membranes prepared by electrospinning are suitable for use as a GTR membrane and are a useful prototype for further development of a final membrane for clinical use.

Coral mucus is one of the key localization in the coral holobiont, as this serves as an energy rich substrate for a wide range of abundant, diverse and multifunctional microbiota. However, very little is known about the functional role of bacterial communities in their associations with corals. In the present study, a total of 48 isolates were obtained from Porites lutea wherein the genus of Bacillus sp. and Vibrio sp. were predominant. Bio-prospecting the coral mucus revealed the existence of (10.42%) antagonistic bacteria against the tested bacterial pathogens. Molecular taxonomy (16S rRNA) proved the identity of these antagonistic bacteria belong to Enterobacter cloacae (CM1), Bacillus subtilis (CM2), Bacillus sp. (CM11) and Bacillus marisflavi (CM12). The secondary screening emphasized that the ethyl acetate extract of B. subtilis showed strong antagonistic effect, followed by the chloroform extract of E. cloacae and ethyl acetate extract of B. marisflavi. The antagonistic activity was statistically confirmed by Principal Component Analysis and Hierarchical Cluster Analysis. The privileged coral mucus associated bacterial (CMAB) solvent extracts inhibited the bacterial pathogens at 100 μg/ml (MIC) and ceased the growth at 200 μg/ml (MBC). The hemolytic and brine shrimp lethality assays disclosed the non-toxic nature of solvent extracts of CMAB. Altogether, the present investigation brought out the diversity of bacteria associated with the mucus of P. lutea. In addition, bio-prospecting corroborated the CMAB as the potential source of pharmacologically important bioactive compounds against a wide range of bacterial pathogens., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Easily accessible 3,3'-diindolylmethanes (DIMs) were utilized to generate a focused library of indolo[2,3- b ]quinolines ( 2 ), chromeno[2,3- b ]indoles ( 3 ), and 3-alkenyl-oxindoles ( 4 ) under 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated oxidative conditions. DIMs with ortho-NHTosyl (NHTs) phenyl group afforded indolo[2,3- b ]quinolines ( 2 ), whereas DIMs with ortho-hydroxy phenyl groups yielded chromeno[2,3- b ]indoles ( 3 ) and 3-alkenyl-oxindoles ( 4 ). The mild conditions and excellent yields of the products make this method a good choice to access a diverse library of bioactive molecules from a common starting material. Two optimized compounds 2a and 2n displayed excellent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). Compound 2a showed the minimum inhibitory concentration values in the concentration between 1 and 4 μg/mL, whereas compound 2n revealed the values of 1-2 μg/mL. Furthermore, both the compounds were highly bactericidal and capable to kill the MRSA completely within 360 min. Collectively, the results suggested that both compounds 2a and 2n possess enormous potential to be developed as anti-MRSA agents., Competing Interests: The authors declare no competing financial interest.

Coral reefs are degraded by the synergistic action of climate and anthropogenic stressors. Coral cover in the Palk Bay reef at the northern Indian Ocean largely declined in the past decade due to frequent bleaching events, tsunami and increased fishing activities. In this study, we carried out a comparative assessment to assess the differences in the recovery and resilience of three spatially distant reefs viz. Vedhalai, Mandapam and Pamban along Palk Bay affected by moderate, severe and low fishing pressure respectively. The assessment was based on the juvenile coral recruitment pattern and its survivability combined with availability of hard substratum, live coral cover and herbivore reef fish stock. The Vedhalai reef has the highest coral cover (14.6 ± 6.3%), and ≥90% of the live corals in Vedhalai and Mandapam were affected by turf algal overgrowth. The density of herbivore reef fish was low in Vedhalai and Mandapam reefs compared to the Pamban reef with relatively few grazing species. The juvenile coral diversity and density were high in the Pamban reef and low in Vedhalai and Mandapam reefs despite high hard substratum cover. In total, 22 species of juvenile corals of 10 genera were recorded in Palk Bay. Comparison of the species diversity of juvenile corals with adult ones suggested that the Pamban reef is connected with other distant reefs whereas Vedhalai and Mandapam reefs were self-seeded. There was no statistically significant difference in the survivability of juvenile corals between the study sites, and in total, ≥90% of the juvenile corals survived the high sedimentation stress triggered by the northeast monsoon and bleaching stress that occurred recurrently. Our results indicated that the human activities indirectly affected the juvenile coral recruitment by degrading the live coral cover and contributed to the spatial variation in the recovery and resilience of the Palk Bay reef. Low species diversity of the juvenile corals will increase the vulnerability of the Palk Bay reef to species-specific endemic threats.

Coral reef ecosystems are disturbed in tandem by climatic and anthropogenic stressors. A number of factors act synergistically to reduce the live coral cover and threaten the existence of reefs. Continuous monitoring of the coral communities during 2012-2014 captured an unprecedented growth of macroalgae as a bloom at Gulf of Mannar (GoM) and Palk Bay (PB) which are protected and unprotected reefs, respectively. The two reefs varying in their protection level enabled to conduct an assessment on the response of coral communities and their recovery potential during and after the macroalgal bloom. Surveys in 2012 revealed a live coral cover of 36.8 and 14.6% in GoM and PB, respectively. Live coral cover was lost at an annual rate of 4% in PB due to the Caulerpa racemosa blooms that occurred in 2013 and 2014. In GoM, the loss of live coral cover was estimated to be 16.5% due to C. taxifolia bloom in 2013. Tissue regeneration by the foliose and branching coral morphotypes aided the recovery of live coral cover in GoM, whereas the chances for the recovery of live coral cover in PB reef were low, primarily due to frequent algal blooms, and the existing live coral cover was mainly due to the abundance of slow-growing massive corals. In combination, results of this study suggested that the recovery of a coral reef after a macroalgal bloom largely depends on coral species composition and the frequency of stress events. A further study linking macroalgal bloom to its specific cause is essential for the successful intervention and management.

Purpose: Present study was undertaken to evaluate the antiamnesic effect of Sesamum indicum (S. indicum) seeds (standardized for sesamin, a lignan, content) in scopolamine, a muscarinic antagonist intoxicated mice., Methods: Male Swiss albino mice (18-22 g bw) were pretreated with methanolic extract of sesame seeds (MSSE) (100 and 200 mg/kg/day, p.o) for a period of 14 days. Scopolamine (0.3 mg/kg, i.p.) was injected on day 14, 45 ± 10 min after MSSE administration. Antiamnesic effect of MSSE was evaluated using step-down latency (SDL) on passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. To unravel the mechanism of action, we examined the effects of MSSE on the genes such as acetyl cholinesterase (AChE), muscarinic receptor M1 subtype (mAChRM 1 ), and brain derived neurotrophic factor (BDNF) expression within hippocampus of experimental mice. Further, its effects on bax and bcl-2 were also evaluated. Histopathological examination of hippocampal CA 1 region was performed using cresyl violet staining., Results: MSSE treatment produced a significant and dose dependent increase in step down latency in passive avoidance test and decrease in transfer latency in elevated plus maze in scopolamine intoxicated injected mice. MSSE down-regulated AChE and mAChRM 1 and up-regulated BDNF mRNA expression. Further, it significantly down-regulated the bax and caspase 3 and up-regulated bcl-2 expression in scopolamine intoxicated mice brains. Mice treated with MSSE showed increased neuronal counts in hippocampal CA 1 region when compared with scopolamine-vehicle treated mice., Conclusion: Sesame seeds have the ability to interact with cholinergic components involved in memory function/restoration and also an interesting candidate to be considered for future cognitive research. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1955-1963, 2016., (© 2015 Wiley Periodicals, Inc.)

A simple eco-friendly approach for the hasty synthesis of stable, potent and benign silver nanoparticles (AgNPs) using seagrass, Syringodium isoetifolium was proposed and described here. The UV-Vis, DLS, XRD, AFM, FESEM, EDX and HRTEM analysis highly characterized and confirmed the presence of polydispersed (2-50nm) spherical and stable AgNPs. FT-IR and phytochemical analysis suggested that the proteins act as reducing and also as capping agent. A hypothetical approach using bioinformatics tools revealed that the Phytochrome B protein of S. isoetifolium might be responsible for the biosynthesis of NPs. Furthermore, biosynthesized AgNPs showed magnificent antibacterial activity against thirteen clinical bacterial pathogens with maximum zone of inhibition of 14.3±0.12mm due to their smaller size and longer stability even at minimal nanomolar (nM) concentration. In addition, the MIC and MBC values also suggested the same. Moreover, the percentage of haemolysis (8.49±3.10 to 73.34±1.79%) and haemolytic index revealed the satisfactory biocompatibility of AgNPs that showed less/no haemolysis up to 3nM concentration. Further, the toxicity effect of biosynthesized AgNPs against the brine shrimp, Artemia salina exhibited significantly increasing mortality (13±4.7 to 100%) with LC 50 value at 4nM concentration. Thus, the optical property, crystal structure, size, shape, stability, bactericidal activity, cytotoxicity, and biocompatibility apparently proved that the biologically synthesized AgNPs have typical properties of nanomaterials., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro-angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail(-/-) and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia., Methods and Results: Reduced vascularization assessed by real-time 3-dimensional Vevo ultrasound imaging and CD31 staining was evident in Trail(-/-) mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral TRAIL administration significantly improved limb perfusion, capillary density, and vascular smooth-muscle cell content in both Trail(-/-) and wildtype mice. Fibroblast growth factor-2, a potent angiogenic factor, increased TRAIL expression in human microvascular endothelial cell-1, with fibroblast growth factor-2-mediated proliferation, migration, and tubule formation inhibited with TRAIL siRNA. Both fibroblast growth factor-2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAIL-inducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3-day ischemic hindlimbs of Trail(-/-) mice. Furthermore, TRAIL-induced proliferation, migration, and tubule formation was blocked by scavenging H2O2, or by inhibiting nitric oxide synthase activity. Importantly, TRAIL-inducible endothelial nitric oxide synthase phosphorylation at Ser-1177 and intracellular human microvascular endothelial cell-1 cell nitric oxide levels were NOX4 dependent., Conclusions: This is the first report demonstrating that TRAIL can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of TRAIL on human microvascular endothelial cell-1 cells is downstream of fibroblast growth factor-2, involving NOX4 and nitric oxide signaling. These data have significant therapeutic implications, such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

A metal-free one-pot cascade annulation of acyclic substrates dienaminodioate, cinnamaldehydes and allyl amine was achieved for the synthesis of polyfunctional biaryl-2-carbaldehydes. The reaction proceeds at room temperature by a trifluoroacetic acid mediated Diels-Alder pathway. Synthetic applications of the resulting biaryl-2-carbaldehyde have been demonstrated by conversion into an array of diverse molecules with biological and materials chemistry relevance. The present work offers a complementary route to the existing metal mediated cross-coupling methods for the preparation of biaryls.

The bacterial bioluminescence assay is one of the novel means for toxicity detection. The bioluminescence response of 2 marine bioluminescent bacteria was tested upon their long-term exposure to 9 different reverse osmosis (RO) rejects with varying chemical composition sampled from various dye industries. Bioluminescent bacteria were cultured in the RO reject samples, at different concentrations, and their growth rate and luminescence was measured for 24 h. The RO reject samples caused sublethal effects upon exposure and retarded the growth of bacteria, confirming their toxic nature. Further, continuation of the exposure showed that the initial luminescence, though reduced, recovered and increased beyond the control cultures irrespective of cell density, and finally decreased once again. The present study emphasizes the need of evolving a long-term exposure assay and shows that the method followed in this study is suitable to evaluate the toxicants that exert delayed toxicity, using lower concentrations of toxicants as well as coloured samples.

Coral reef fishes are exploited without the knowledge of their sustainability and their possible effect in altering the community structure of a coral reef ecosystem. Alteration of the community structure could cause a decline in the health of coral reefs and its services. We documented the coral community structure, status of live corals and reef fish assemblages in Palk Bay at the reef fishing hotspots and its nearby reef area with minimum fishing pressure and compared it with a control reef area where reef fishing was banned for more than two decades. The comparison was based on the percent cover of different forms of live corals, their diversity and the density and diversity of reef fishes. The reef fish stock in the reef fishing hotspots and its neighbouring reef was lower by 61 and 38%, respectively compared to the control reef. The herbivore fish Scarus ghobban and Siganus javus were exploited at a rate of 250 and 105 kg month(-1) fishermen(-1), respectively, relatively high comparing the small reef area. Live and dead corals colonized by turf algae were predominant in both the reef fishing hotspots and its nearby coral ecosystems. The percent cover of healthy live corals and live corals colonized by turf algae was <10 and >80%, respectively, in the intensively fished coral ecosystems. The corals were less diverse and the massive Porites and Favia colonies were abundant in the intensive reef fishing sites. Results of this study suggest that the impact of reef fish exploitation was not solely restricted to the intensively fished reefs, but also to the nearby reefs which play a critical role in the resilience of degraded reef ecosystems.

Malaysia has successfully reduced maternal mortality through several efforts which, in the broad sense, include (i) the overall socio-economic development of the country; (ii) strengthened health services; and (iii) specific efforts and initiatives for the reduction of maternal mortality, one of which is the audit of maternal deaths by the confidential enquiry into maternal deaths., (© 2014 Royal College of Obstetricians and Gynaecologists.)

A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement is Zyflamend, a polyherbal preparation with potent anti-inflammatory activities and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1 and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis., (Copyright © 2011 UICC.)

Phosphatase Producing Bacteria (PPB) and Inorganic Phosphate Solubilizing Bacteria (IPSB) are important to reef nutrition. These microbes and phosphate concentration play a significant role in the productivity of coral reef ecosystems. A study was conducted in Gulf of Mannar coral reef ecosystem to understand the diversity of these groups of bacteria and their competence in mineralizing the phosphate. The PPB isolates were identified under six genera i.e. Bacillus, Pseudomonas, Micrococcus, Vibrio, Arthrobacter and Brevibacterium. Likewise, the IPSB isolates were also identified that belong to six genera i.e. Bacillus, Arthrobacter, Pseudomonas, Flavobacterium, Flavomonas and Micrococcus. Among the PPB and IPSB strains, Bacillus represented more number of species than others. PPB exhibited maximum activity between pH 8 and 9 and the lowest was at pH 6. Among the phosphatase producers Bacillus cereus (546) showed maximum activity (0.333 mmol/l P) at pH 8. In general, the phosphatase activity in most of the Bacillus species varied with reference to different pH. The species Bacillus megaterium (573) showed highest phosphate solubilizing activity (0.906 mmol/l P) by producing 2-ketogluconic acid. The production of organic acids and phosphatase enzymes by these bacterial groups are responsible for the conversion of insoluble inorganic and organic phosphates into soluble forms which are available for the reef organisms., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fungi in coral reefs exist as endoliths, endobionts, saprotrophs and as pathogens. Although algal and fungal endoliths in corals were described way back in 1973, their role in microboring, carbonate alteration, discoloration, density banding, symbiotic or parasitic association was postulated almost 25 years later. Fungi, as pathogens in corals, have become a much discussed topic in the last 10 years. It is either due to the availability of better tools for investigations or greater awareness among the research communities. Fungi which are exclusive as endoliths (endemic) in corals or ubiquitous forms seem to play a role in coral reef system. Fungi associated with sponges and their role in production or induction of secondary metabolites in their host is of primary interest to various pharmaceutical industries and funding agencies. Fungal enzymes in degradation of coral mucus, and plant detritus hold great promise in biotechnological applications. Unravelling fungal diversity in corals and associated reef organisms using culture and culture-independent approaches is a subject gaining attention from research community world over.

Objective: The strongest susceptibility locus of psoriatic arthritis (PsA) is within the major histocompatibility complex (MHC) region (psoriasis susceptibility region 1, or PSORS1), and HLA-Cw*06:02 has been reported as the PSORS1 susceptibility allele. Non-HLA genes within the MHC region have also been implicated in PsA, but because of the strong linkage disequilibrium at chromosome 6p21, it is difficult to make a distinction between susceptibility alleles and linked markers. Recent studies have demonstrated that the association between PsA and the tumor necrosis factor (TNF) promoter polymorphism TNF*-857 is independent of PSORS1. The aim of this study was to replicate the independent association of TNF*-857 in patients with PsA., Methods: A total of 909 patients with PsA and 1,315 healthy controls originating from the UK, Germany, and Italy were typed for TNF*-857 and for the estimated risk alleles of HLA-Cw*06:02., Results: Overall, the results of genotyping in these 3 case-control cohorts replicated the finding that the frequency of carriers of TNF*-857 TT/CT who were negative for the PSORS1 risk allele was significantly higher among patients with PsA compared with control subjects (30% versus 21%; P = 9.17 × 10(-5))., Conclusion: The results of this collaborative study indicate that TNF*-857T is a susceptibility allele for PsA independent of the PSORS1 allele., (Copyright © 2011 by the American College of Rheumatology.)

Ricin is one of the most potent and deadly plant toxins from the seeds of Ricinus communis. In view of its high toxicity, ricin is being used as an immunotoxin in cancer therapy. Ricin also has several isoforms with differential glycosylation depending on the seed variety. Our study shows three isoforms designated 1, 2 and 3, which differed in their surface charge, resulting in a different behavior on cation exchange chromatography, two dimensional (pI 5.5-8.7) and native PAGE. The molecular masses of isoform-1, 2 and 3 were measured as 63.55 kDa, 64.03 kDa and 62.8 kDa, respectively, by MALDI-TOF/MS. In vitro studies with monkey kidney (Vero) cells showed a time dependent increase in cytotoxicity of the isoforms evaluated by extracellular lactate dehydrogenase activity and mitochondrial dehydrogenase assay. These isoforms also induce oxidative stress and DNA damage. Among the isoforms, isoform-3 was quick to generate reactive oxygen species (ROS), (in 90 min) and exhibited maximum cytotoxicity. Morphological changes, catalase activity and DNA fragmentation were significantly higher with isoform-3 treatment compared to others. The glycosylation studies by MALDI-TOF/MS showed that isoform-3 is highly glycosylated with high sugar levels containing more of hybrid/complex type glycopeptides with mannose as hexose units. These experimental evidences clearly suggest that isoform-3 is superior in its early ROS generation, potency to induce oxidative stress and cytotoxicity, that could be due to it's higher glycosylation levels which make isoform-3 as an ideal candidate for immunotoxin studies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background & Objectives: Field trials of lambda-cyhalothrin 10 CS (ICON 10 CS) in indoor residual spraying (IRS) with 25 mg a.i./m2 against Anopheles culicifacies was undertaken vs malathion IRS (25% WP-2 g a.i./m2) in Tumkur district, Karnataka; vs deltamethrin IRS (2.5% WP-20 mg a.i./m2) in Dharmapuri district; and vs lambda-cyhalothrin (10 WP-25 mg a.i./m2) in Ramanathapuram district, Tamil Nadu, India., Methods: Spray operations in the experimental villages were done by the National Institute of Malaria Research (NIMR) and in the control villages by the respective State Health Department staff. Persistence of efficacy of insecticide sprayed in villages was assessed by contact bioassays against vector mosquitoes. Entomological indicators such as per structure density, parity rates of vector mosquitoes and sporozoite rates were measured in all the three study areas using standard procedures. Mass blood surveys and active fever case detections were carried out in experimental and control villages to study the impact of IRS on malaria transmission., Results: Persistence of effectiveness of ICON 10 CS was observed up to 2-3 months in all the three study areas. ICON 10 CS was found effective at par with or better than the insecticides used in the national programme in reducing the mosquito densities and in interrupting malaria transmission in the study villages. Vector density, parity rates and malaria cases considerably reduced in the ICON 10 CS-sprayed villages., Conclusion: Field trials at three sites have established that ICON 10 CS formulation was relatively more effective than malathion 25% WP, deltamethrin 2.5% WP and lambda-cyhalothrin 10% WP in some evaluation parameters like indoor resting mosquitoes, parity rates in vector mosquitoes and persistence of effectiveness. It can be used for IRS for malaria vector control with two rounds of spray at an interval of 3 months for curtailing the malaria transmission and an additional round is recommended in perennial malaria transmission areas.

T-2 toxin is a cytotoxic fungal secondary metabolite produced by different species of Fusarium such as F. sporotichioides, F. poae, F. equiseti, F. acuminatum etc. This class of mycotoxins causes a number of pathologies including nervous disorders, cardiovascular alterations, immunodepression and hemostatic derangements. In the present study, mechanism of T-2 toxin induced alteration of blood-brain barrier (BBB) permeability was assessed in terms of oxidative stress, gene expression of MMP-9, MMP-2 and their inhibitors TIMP-1 and TIMP-2, activation of inflammatory cytokines in both brain and peripheral tissue spleen. Gel zymography was used to show the activity of MMP-9 and MMP-2. The percutaneous exposure of 1 LD50 T2 toxin caused a reversible alteration in BBB permeability as observed by extravasation of Evans blue dye. Maximum dye level was observed on day 3 and reduced by day 7. A significant GSH depletion was observed on days 1 and 3. Brain ROS and lipid peroxidation levels increased significantly on 1 and 3 days and decreased by day 7. The SOD levels in brain showed significantly higher activity on 3 days (4-fold) and 7 days (5-fold) of toxin exposure compared to control. A similar trend was observed with catalase enzyme levels. The gene expression analysis of cNOS and iNOS showed varying levels of expression on different time points of post exposure. MMP-9 expression was significantly high on days 3 and 7 in brain with corresponding alteration in TIMP-1. MMP-2 and TIMP-2 showed no effect. Gene expression analysis of the inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α showed elevated levels on day 7 in brain. As spleen plays an important role in inflammatory response we analyzed MMP-9, MMP-2 and inflammatory cytokines in spleen. The MMP-9 was activated on day 7. MMP-2 activity was found to be elevated on 3 and 7 days and TIMP-2 mRNA level increased on 1 and 3 days in spleen. Inflammatory cytokines, IL-1 α, IL-1β, IL-6 and TNF-α showed elevated levels on days 1 and 3 in spleen indicating an early effect in spleen than in brain. In summary, the results of the study showed that the T-2 induced alteration in BBB permeability is mediated through oxidative stress, activation of MMP-9, and proinflammatory cytokines in brain as well as contribution from peripheral tissue spleen., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Okadaic acid (OA) is a specific and potent protein phosphatase inhibitor and tumor promoter. The present study establishes the role of reactive oxygen species (ROS) and mitogen activated protein kinases in cell death induced by okadaic acid. The study showed that okadaic acid is cytotoxic at 10 nM with an IC50 of 100 nM in U-937 cells. The CVDE assay and mitochondrial dehydrogenase assay showed a time dependent cytotoxicity. The phase contrast visualization of the OA treated cells showed the apoptotic morphology and was confirmed with esterase staining for plasma membrane integrity. OA activated caspases-7, 9 and 3, PARP cleavage and induced nuclear damage in a time and dose dependent manner. Compromised mitochondrial membrane potential, release of cytochrome-c and apoptosis inducing factor confirms the involvement of mitochondria. A time dependent decrease in glutathione levels and a dose dependent increase in ROS with maximum at 30 min were observed. ROS scavenger-N-acetyl cysteine, mitochondrial stabilizer-cyclosporin-A, and broad spectrum caspase inhibitor Z-VAD-FMK inhibited the OA induced caspase-3 activation, DNA damage and cell death but caspase-8 inhibitor had no effect. OA activated p38 MAPK and JNK in a time dependent manner, but not ERK½. MAP kinase inhibitors SB203580, SP600125 and PD98059 confirm the role of p38 MAPK and JNK in OA induced caspase-3 activation and cell death. Over all, our results indicate that OA induces cell death by generation of ROS, and activation of p38 MAPK and JNK, and executed through mitochondrial mediated caspase pathway.

Because tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is being tested in cancer patients. Unfortunately, patients develop resistance to the cytokine, therefore, agents that can sensitize cells to TRAIL are urgently needed. In this study, we investigated whether dibenzylideneacetone (DBA) can sensitize cancer cells to TRAIL and potentiates TRAIL-induced apoptosis. As indicated by accumulation of the membrane phospholipid phosphatidylserine, DNA breaks, intracellular esterase activity, and activation of caspase-8, -9, and -3, we concluded that DBA potentiated TRAIL-induced apoptosis in colon cancer cells. DBA also converted TRAIL resistant-cells to TRAIL-sensitive. When examined for the mechanism, we found that DBA decreased the expression of antiapoptotic proteins and decoy receptor-2 and increased proapoptotic proteins. DBA also induced both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 by small interfering RNA (SiRNA) reduced the sensitizing effect of DBA on TRAIL-induced apoptosis. In addition, DBA increased the expression of CHOP proteins. Knockdown of CHOP by siRNA decreased the induction of DBA-induced DR5 expression and apoptosis. Induction of receptors by DBA, however, was p53-independent, as deletion of p53 had no effect on receptor induction. We observed that DBA-induced induction of DR5 and DR4 was mediated through generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of death receptors and suppression of cell survival proteins by DBA. Overall, our results show that DBA potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of ROS and CHOP mediated pathways., (© 2010 AACR.)

Bioluminescence is a biochemical process occurring in many organisms. Bacterial bioluminescence has been investigated extensively that lead to many applications of such knowledge. Quorum sensing in the bioluminescent bacteria is a chemical signal process to recognize the strength of its own population to start luminescence in harmony. There is a mechanism in these bacteria to also recognize inter-species strength. When there is a higher number of these bacteria, the possibility and frequency of cell-cell physical contact will be high. In this study, the physical proximity was artificially enhanced between cells and the effect on luminescence in the concentrated cells in the normal culture medium and in the presence of other non-bacterial cell-free supernatants was investigated. The role of such physical contact in the quorum sensing in the bioluminescence is not known. Increase in the luminescence of V. fischeri when concentrated shows that the presence of physical proximity facilitates the quorum sensing for their bioluminescence., (Copyright © 2009 John Wiley & Sons, Ltd.)

Reverse pharmacology, also called the "bedside to bench" approach, that deals with new uses for a well known molecular entity has been used extensively in cancer drug development to identify novel compounds and delineate their mechanisms of action. Here, we show that nimbolide, a triterpenoid isolated from Azadirachta indica, enhanced the apoptosis induced by inflammatory cytokines and chemotherapeutic agents in tumor cells. This limonoid abrogated the expression of proteins associated with cell survival (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF), all regulated by nuclear factor (NF)-κB. Nimbolide inhibited the activation of NF-κB induced by carcinogens and inflammatory stimuli. Constitutively active NF-κB found in most tumor cells was also inhibited. We found that suppression of NF-κB activation by nimbolide was caused by inhibition of IκB kinase (IKK), which led to suppression of IκBα phosphorylation and degradation, nuclear translocation, DNA binding, and gene transcription. Reducing agent reversed the action of the limonoid, suggesting the involvement of a cysteine residue. Replacement of Cys(179) of IKK-β with alanine abolished the effect of nimbolide, suggesting that Cys(179) plays a critical role in inhibiting the NF-κB activation. Overall, our results indicate that nimbolide can sensitize tumor cells to chemotherapeutic agents through interaction with IKK, leading to inhibition of NF-κB-regulated proteins.

Development of resistance to TRAIL, an apoptosis-inducing cytokine, is one of the major problems in its development for cancer treatment. Thus, pharmacological agents that are safe and can sensitize the tumor cells to TRAIL are urgently needed. We investigated whether gossypol, a BH3 mimetic that is currently in the clinic, can potentiate TRAIL-induced apoptosis. Intracellular esterase activity, sub-G(1) cell cycle arrest, and caspase-8, -9, and -3 activity assays revealed that gossypol potentiated TRAIL-induced apoptosis in human colon cancer cells. Gossypol also down-regulated cell survival proteins (Bcl-x(L), Bcl-2, survivin, XIAP, and cFLIP) and dramatically up-regulated TRAIL death receptor (DR)-5 expression but had no effect on DR4 and decoy receptors. Gossypol-induced receptor induction was not cell type-specific, as DR5 induction was observed in other cell types. Deletion of DR5 by siRNA significantly reduced the apoptosis induced by TRAIL and gossypol. Gossypol induction of the death receptor required the induction of CHOP, and thus, gene silencing of CHOP abolished gossypol-induced DR5 expression and associated potentiation of apoptosis. ERK1/2 (but not p38 MAPK or JNK) activation was also required for gossypol-induced TRAIL receptor induction; gene silencing of ERK abolished both DR5 induction and potentiation of apoptosis by TRAIL. We also found that reactive oxygen species produced by gossypol treatment was critical for TRAIL receptor induction and apoptosis potentiation. Overall, our results show that gossypol enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and the up-regulation of TRAIL death receptors through the ROS-ERK-CHOP-DR5 pathway.

The discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB-regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB-regulated gene products, which provides novel insight into a half-century old drug., (©2010 AACR.)

Pancreatic cancers generally respond poorly to chemotherapy, prompting a need to identify agents that could sensitize tumors to treatment. In this study, we investigated the response of human pancreatic cells to γ-tocotrienol (γ-T3), a novel, unsaturated form of vitamin E found in palm oil and rice bran oil, to determine whether it could potentiate the effects of gemcitabine, a standard of care in clinical treatment of pancreatic cancer. γ-T3 inhibited the in vitro proliferation of pancreatic cancer cell lines with variable p53 status and potentiated gemcitabine-induced apoptosis. These effects correlated with an inhibition of NF-κB activation by γ-T3 and a suppression of key cellular regulators including cyclin D1, c-Myc, cyclooxygenase-2 (COX-2), Bcl-2, cellular inhibitor of apoptosis protein, survivin, vascular endothelial growth factor (VEGF), ICAM-1, and CXCR4. In an orthotopic nude mouse model of human pancreatic cancer, p.o. administration of γ-T3 inhibited tumor growth and enhanced the antitumor properties of gemcitabine. Immunohistochemical analysis indicated a correlation between tumor growth inhibition and reduced expression of Ki-67, COX-2, matrix metalloproteinase-9 (MMP-9), NF-κB p65, and VEGF in the tissue. Combination treatment also downregulated NF-κB activity along with the NF-κB-regulated gene products, such as cyclin D1, c-Myc, VEGF, MMP-9, and CXCR4. Consistent with an enhancement of tumor apoptosis, caspase activation was observed in tumor tissues. Overall, our findings suggest that γ-T3 can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing NF-κB-mediated inflammatory pathways linked to tumorigenesis., (©2010 AACR.)

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with multiple beneficial activities, but its optimum potential is limited by poor bioavailability, in part due to the lack of solubility in aqueous solvents. To overcome the solubility problem, we have recently developed a novel cyclodextrin complex of curcumin (CDC) and examined here this compound for anti-inflammatory and antiproliferative effects. Using the electrophoretic mobility shift assay, we found that CDC was more active than free curcumin in inhibiting TNF-induced activation of the inflammatory transcription factor NF-kappaB and in suppressing gene products regulated by NF-kappaB, including those involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). CDC was also more active than free curcumin in inducing the death receptors DR4 and DR5. Annexin V staining, cleavage of caspase-3 and PARP, and DNA fragmentation showed that CDC was more potent than free curcumin in inducing apoptosis of leukemic cells. Antiproliferative assays also demonstrated that CDC was more active than free curcumin in suppressing proliferation of various cancer cell lines. The cyclodextrin vehicle had no effect in these assays. Compared with free curcumin, CDC had a greater cellular uptake and longer half-life in the cells. Overall we demonstrated that CDC had superior attributes compared with free curcumin for cellular uptake and for antiproliferative and anti-inflammatory activities., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G(1) cell cycle arrest revealed that gamma-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that gamma-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that gamma-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by gamma-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by gamma-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by gamma-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that gamma-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins., ((c) 2010 AACR.)

Thymoquinone (TQ), derived from the medicinal spice Nigella sativa (also called black cumin), has been shown to exhibit anti-inflammatory and anti-cancer activities. In this report we employed polymer-based nanoparticle approach to improve upon its effectiveness and bioavailability. TQ was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and the stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy confirmed particle diameter between 150 and 200nm. Electrophoretic gel shift mobility assay showed that TQ nanoparticles (NP) were more active than TQ in inhibiting NF-kappaB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), those are markers of cell proliferation, metastasis and angiogenesis, respectively. TQ-NP were also more potent than TQ in suppressing proliferation of colon cancer, breast cancer, prostate cancer, and multiple myeloma cells. Esterase staining for plasma membrane integrity revealed that TQ-NP were more potent than TQ in sensitizing leukemic cells to TNF- and paclitaxel-induced apoptosis. Overall our results demonstrate that encapsulation of TQ into nanoparticles enhances its anti-proliferative, anti-inflammatory, and chemosensitizing effects., (Published by Elsevier Inc.)

Curcumin, a component of turmeric (Curcuma longa), exhibits anti-inflammatory and anti-proliferative activities through the generation of reactive oxygen species (ROS). Curcumin (diferuloylmethane) contains two hydroxyl, two methoxy and two phenyl groups but how these groups contribute to its activity is poorly understood. We synthesized analogues that varied in inclusion of these groups and compared their activity. We found that bisdemethylcurcumin (BDC) was more potent than curcumin as an anti-inflammatory agent as indicated by suppression of TNF-induced NF-kappaB activation, more potent as an anti-proliferative agent, and more potent in inducing ROS. Hispolon, which lacks one aromatic unit in relation to curcumin, also exhibited enhanced anti-inflammatory and anti-proliferative activities. When synthetic curcumin (Cur-S) was compared with bisdemethylcurcumin (BDC), hispolon, hispolon methyl ether (HME), dehydroxy hispolon (DH), hydroxy hispolon (HH), methoxy hispolon methyl ether (MHME), and methoxy hispolon (MH), we found that following order of anti-inflammatory activity: BDC=Hispolon>HME>HH>Cur-S>MHME>MH>DH; for anti-proliferative: Hispolon>BDC>MHME>Cur-S>MH>HME=HH>DH; and for prooxidant: BDC>Cur-S=MHME>HH>MH+HME>DH (254-1414 mean fluorescence intensity). Thus, dehydroxy hispolon was least potent for all three activities. Overall the results indicate that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7(th) position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin., (2010 Elsevier Inc. All rights reserved.)

Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.

NF-kappaB, a transcription factor first discovered in 1986, is now known to be closely connected to the process of tumorogenesis based on a multiplicity of evidence. (1) NF-kappaB is activated in response to tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli that account for as much as 95% of all cancers. (2) The transcription factor has been linked with transformation of cells. (3) It is constitutively active in most tumor cells. (4) It has also been linked with the survival of cancer stem cells, an early progenitor cell that has acquired self-renewal potential. (5) NF-kappaB regulates the expression of most anti-apoptotic gene products associated with the survival of the tumor. (6) It also regulates the gene products linked with proliferation of tumors. (7) The transcription factor controls the expression of gene products linked with invasion, angiogenesis, and metastasis of cancer. (8) While most carcinogens activate NF-kappaB, most chemopreventive agents suppress its activation. These observations suggest that NF-kappaB is intimately intertwined with cancer growth and metastasis. The mechanism that leads to constitutive activation of NF-kappaB in hematological, gastrointestinal, genitourinary, gynecological, thoracic head and neck, breast, and skin cancers, and the ways NF-kappaB is activated are the topics of discussion in this review.

Objective: To use a modified Sharp score (MSS) to measure radiologic progression and to assess its relationship to other radiologic features, peripheral joint disease, and physical function in psoriatic arthritis (PsA)., Methods: Two sets of hand radiographs (median interval 5.75 years) in 139 patients with established PsA were scored using an MSS. Seventy-four patients had standardized clinical joint and Health Assessment Questionnaire (HAQ) scores and other radiologic features of PsA documented at baseline and followup (median interval 5 years)., Results: Radiologic damage was present in 58% of patients at baseline and 74% at followup. The median MSS and its components, erosion score and joint space abnormality score, were significantly greater at followup (P < 0.001). The median MSS progression was +1.08 units/year. There was strong correlation between MSS and clinical joint scores at baseline and followup (r = 0.72 and r = 0.81, respectively). There was weak correlation between MSS and HAQ at baseline (r = 0.29), but stronger correlation at followup (r = 0.48). There was a strong association between MSS and other characteristic radiologic features of PsA (bony proliferation, periostitis, bony ankylosis) at baseline and followup (P < 0.001). However, the presence of soft-tissue swelling on radiographs at baseline was the only radiologic parameter associated with an increased rate of change of MSS (corrected P < 0.006)., Conclusion: The MSS shows good construct validity with measures of peripheral joint involvement such as clinical joint scores and other radiologic features of PsA, and is able to demonstrate that radiologic damage is progressive beyond early disease.

Microbiological studies in a modified extensive shrimp culture system at Nambuthalai, southeast coast of India were carried out fora period of 120 days. Population dynamics and distribution profile of luminous bacteria and total heterotrophic bacteria in the water sediment and animal samples were monitored. Luminous bacteria associated with exoskeleton, gills and gut were isolated and quantified. The total heterotrophic bacterial counts ranged from 1.3 x 10(4) to 25.3 x 10(4) CFU ml(-1) in water and 1.5 x 10(6) to 26.2 x 10(6) CFU g(-1) in sediment. The V. harveyi population density varied between 0.6 x 10(4) and 8.8 x 10(4) LCFU ml(-1) in water and from 1.2 x 10(6) to 10.4 x 10(6) LCFU g(-1) sediment respectively. The gut of the animal was found to harbor high density of V. harveyi than gills and exoskeleton. The total heterotrophic bacteria and V. harveyi population density showed increasing trend during the culture period. The high V harveyi density observed in this study at the end of the culture period correlated with the outbreak of white spot disease.