Chemopreventive action of Imatinib, a tyrosine kinase inhibitor in the regulation of angiogenesis and apoptosis in rat model of lung cancer.

The present study explored the events of angiogenesis and apoptosis in 7,12-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat and its chemoprevention with Imatinib, a receptor tyrosine kinase inhibitor. Further, it includes  lipopolysaccharide (LPS) mediating inflammation along with DMBA for the promotion of lung carcinogenesis. The animals received a single intratracheal instillation of DMBA (20 mg/kg body weight) in olive oil and LPS (0.6 mg/kg body weight) to induce tumors in 16 weeks. Besides morphology and histology of the lung tissues, RT-PCR, western blots, and immunofluorescence were performed for the expression of apoptotic and angiogenic proteins. Apoptosis was studied by mitochondrial Bcl-2/Bax ratio and staining with the dyes Acridine orange/ethidium bromide of the isolated Broncho epithelial cells. Also, mitochondrial membrane potential (ΔΨM) was studied by JC-1. The study revealed that the expression of VEGF, MMP-2, MMP-9, and the chemokine MCP-1 to be very high in DMBA and DMBA + LPS groups, while Bcl-2 also shows an elevated expression. These results were restored with Imatinib treatment. The pro-apoptotic proteins, Bax, Bad, Apaf-1, and Caspase-3 were highly diminished in DMBA and DMBA + LPS groups which were recovered with Imatinib treatment.

Identifying key components for a psychological intervention for people with vitiligo - a quantitative and qualitative study in the United Kingdom using web-based questionnaires of people with vitiligo and healthcare professionals.

BACKGROUND: Psychological interventions are recommended as part of routine management of vitiligo. However, the development and effectiveness of such interventions have been rarely addressed. This study aimed to identify key components for a psychological intervention for people with vitiligo. This is the first time perspectives of people with vitiligo, and healthcare professionals (HCPs) have been directly explored to inform intervention content and delivery. OBJECTIVES: To identify 1. which psychological difficulties are highlighted that can be targeted by an intervention; 2. what is important in terms of intervention content and delivery. METHODS: Web-based questionnaires containing both quantitative and qualitative items were completed by people with vitiligo and HCPs. Questionnaires collected data from people with vitiligo on demographics, clinical features, psychological difficulties and priority areas for psychological interventions, including ideas on delivery and content. HCPs questionnaires collected data on psychological difficulties reported, use of psychological interventions and suitability within health services. Quantitative data were analysed using descriptive statistics, and qualitative data utilized thematic framework analysis. RESULTS: A total of 100 people with vitiligo (66% female, 92% Caucasian) and 39 HCPs (54% dermatologists) participated. Key areas of difficulty were the impact of vitiligo, coping, issues with appearance/body image and the sun, and medical interactions. Vitiligo on sensitive sites was associated with more psychological impact. Interventions directed at increasing acceptance, confidence and self-esteem, as well as managing embarrassment, were important. These issues could be managed through interventions such as cognitive behavioural therapy, mindfulness and acceptance and commitment therapy. Both people with vitiligo and HCPs favoured individual interventions. CONCLUSION: Vitiligo has significant impact, requiring ongoing psychosocial support. There is a strong need for a psychoeducational intervention with focus on acceptance and managing social impact. The results of this study are the first steps to informing the development of a patient-centred psychological intervention.

Role of GSK-3ß in Regulation of Canonical Wnt/ß-catenin Signaling and PI3-K/Akt Oncogenic Pathway in Colon Cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents because of their ability in blocking cellular proliferation, and thereby tumor development, and also by promoting apoptosis. GSK-3ß, a serine threonine kinase and a negative regulator of the oncogenic Wnt/ß-catenin signaling pathway, plays a critical role in the regulation of oncogenesis. Celecoxib and etoricoxib, the two cyclooxygenase-2 (COX-2) selective NSAIDs, and Diclofenac, a preferential COX-2 inhibitory NSAID, had shown uniformly the chemopreventive and anti-neoplastic effects in the early stage of colon cancer by promoting apoptosis as well as an over-expression of GSK-3ß while down-regulating the PI3-K/Akt oncogenic pathway.

Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients from Malda district, West Bengal- A case study.

Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients was established in Malda district of West Bengal. Out of 182 participants examined, 80 (43.9%) participants showed clinical features of arsenicosis, characterized by arsenical skin lesion (pigmentation and keratosis), while 102 participants did not have any such lesion (control). Experimental results of the twenty eight soils (own field) of the participants showed the mean Olsen extractable and total arsenic concentration of 0.206 and 6.70mgkg-1, respectively. Arsenic concentration in rice grain ranged from 2.00 to 1260µgkg-1 with the mean value of 146µgkg-1. The hazard quotient (HQ) for intake of As by human through consumption of rice varied from 0.03 to 3.52. HQ exceeds 1.0 for drinking water and rice grain grown in the study area in many cases. As high as 77.6% variation in As content in rice grain could be explained by the solubility-free ion activity model. Toxic limit of extractable As in soil for rice in relation to soil properties and human health hazard, associated with consumption of rice grain by human, was established. For example, the permissible limit of Olsen extractable As in soil would be 0.43mgkg-1 for rice cultivation, if soil pH and organic carbon content were 7.5% and 0.50%, respectively. However, the critical limit of Olsen extractable As in soil would be 0.54mgkg-1, if soil pH and organic carbon were 8.5% and 0.75%, respectively. The conceptual framework of fixing the toxic limit of arsenic in soils with respect to soil properties and human health under modeling-framework was established.

Aggregates of quadrupolar dyes for two-photon absorption: the role of intermolecular interactions.

We present a theoretical investigation of small aggregates of quadrupolar (A-π-D-π-A or D-π-A-π-D) charge-transfer dyes, with attention focused on the role of intermolecular interactions in determining their optical properties. We tackle the theoretical issue by adopting essential-state models (ESMs), which describe an isolated molecule in terms of a minimal number of electronic states, corresponding to the resonance structures. ESMs quite naturally describe intermolecular interactions relaxing the dipolar approximation and accounting for molecular polarizabilities. The approach is applied to curcuminoid and squaraine dyes, two families of chromophores with weak and strong quadrupolar character, respectively. The method is validated against experiment and for curcuminoids also against time-dependent density functional theory. ESMs rationalize the strong ultra-excitonic effects recurrently observed in the experimental optical spectra of aggregates of highly polarizable quadrupolar dyes, offering a valuable tool to exploit the supramolecular design of material properties.

Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer.

Uncontrolled cell proliferation is the hallmark of cancer, and cancer cells have typically acquired damage to genes that directly regulate their cell cycles. The synthesis of DNA onto the end of chromosome during the replicative phase of cell cycle by telomerase may be necessary for unlimited proliferation of cells. Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. We studied the regulation of telomerase and telomerase reverse transcriptase catalytic subunit (TERT) by diclofenac and curcumin, alone and also in combination, in 1, 2-dimethylhydrazine dihydrochloride-induced colorectal cancer in rats. The relationship of telomerase activity with tumors suppressor proteins (p51, Rb, p21), cell cycle machinery, and apoptosis was also studied. Telomerase is highly expressed in DMH group and its high activity is associated with increased TERT expression. However, telomerase is absent or is present at lower levels in normal tissue. CDK4, CDK2, cyclin D1, and cyclin E are highly expressed in DMH as assessed by RT-PCR, qRT-PCR, Western blot, and immunofluorescence analysis. Diclofenac and curcumin overcome these carcinogenic effects by downregulating telomerase activity, diminishing the expression of TERT, CDK4, CDK2, cyclin D1, and cyclin E. The anticarcinogenic effects shown after the inhibition of telomerase activity by diclofenac and curcumin may be associated with upregulation of tumor suppressor proteins p51, Rb, and p21, whose activation induces the cells cycle arrest and apoptosis.

Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer.

Phosphatidylinositol 3-kinase (PI3-K)/PTEN/Akt signaling is over activated in various tumors including colon cancer. Activation of this pathway regulates multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth that underlie the biology of a cancer cell. In the present study, the chemopreventive effects have been observed of Diclofenac, a preferential COX-2 inhibitory non-steroidal anti-inflammatory drugs, and Curcumin, a natural anti-inflammatory agent, in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats. The tumor-promoting role of PI3-K/Akt/PTEN signal transduction pathway and its association with anti-apoptotic family of proteins are also observed. Both Diclofenac and Curcumin downregulated the PI3-K and Akt expression while promoting the apoptotic mechanism. Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members (Bad and Bax) while decreasing the anti-apoptotic Bcl-2 protein. An up-regulation of cysteine protease family apoptosis executioner, such as caspase-3 and -9, is seen. Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding, as also evident by negative glide score of Bcl-2. These drugs stimulated apoptosis by increasing reactive oxygen species (ROS) generation and simultaneously decreasing the mitochondrial membrane potential (ΔΨ M). Diclofenac and Curcumin showed anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway, inducing apoptosis, increasing ROS generation, and decreasing ΔΨ M. The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together, rather than individually.

Prevalence and distribution of White Spot Syndrome Virus in cultured shrimp.

White Spot Syndrome Virus (WSSV) is a dsDNA virus causing White Spot Syndrome Disease (WSSD) in shrimp with almost 100% morality rate within 3-10 days. In Bangladesh, WSSD is one of the major impediments of shrimp farming. This study first investigated the prevalence and distribution of WSSV in cultured shrimps of the coastal regions in Bangladesh. A total of 60 shrimp samples, collected from the 25 shrimp farms of different coastal regions (Satkhira, Khulna, Bagerhat and Cox's Bazar), were analysed during 2013-2014 by conventional PCR using VP28 and VP664 gene-specific primers; 39 of 60 samples were found WSSV positive. SYBR green real-time PCR using 71-bp amplicon for VP664 gene correlated well with conventional PCR data. The prevalence rates of WSSV among the collected 60 samples were Satkhira 79%, Khulna 50%, Bagerhat 38% and Cox's Bazar 25%. Sequencing of WSSV-positive PCR amplicons of VP28 showed 99% similarity with WSSV NCBI Ref/Seq Sequences. Molecular analysis of the VP28 gene sequences of WSSV revealed that Bangladeshi strains phylogenetically affiliated to the strains belong to India. This work concluded that WSSV infections are widely distributed in the coastal regions cultured shrimp in Bangladesh.

Geostatistical approach for management of soil nutrients with special emphasis on different forms of potassium considering their spatial variation in intensive cropping system of West Bengal, India.

A large part of precision agriculture research in the developing countries is devoted towards precision nutrient management aspects. This has led to better economics and efficiency of nutrient use with off-farm advantages of environmental security. The keystone of precision nutrient management is analysis and interpretation of spatial variability of soils by establishing management zones. In this study, spatial variability of major soil nutrient contents was evaluated in the Ghoragacha village of North 24 Parganas district of West Bengal, India. Surface soil samples from 100 locations, covering different cropping systems of the village, was collected from 0 to 15 cm depth using 100×100 m grid system and analyzed in the laboratory to determine organic carbon (OC), available nitrogen (N), phosphorus (P), and potassium (K) contents of the soil as well as its water-soluble K (KWS), exchangeable K (KEX), and non-exchangeable forms of K (KNEX). Geostatistical analyses were performed to determine the spatial variation structure of each nutrient content within the village, followed by the generation of surface maps through kriging. Four commonly used semivariogram models, i.e., spherical, exponential, Gaussian, and linear models were fitted to each soil property, and the best one was used to prepare surface maps through krigging. Spherical model was found the best for available N and P contents, while linear and exponential model was the best for OC and available K, and for KWS and KNEK, Gausian model was the best. Surface maps of nutrient contents showed that N content (129-195 kg ha(-1)) was the most limiting factor throughout the village, while P status was generally very high ( 10-678 kg ha(-1)) in the soils of the present village. Among the different soil K fractions, KWS registered the maximum variability (CV 75%), while the remaining soil K fractions showed moderate to high variation. Interestingly, KNEX content also showed high variability, which essentially indicates reserve native K exploitation under intensive cultivation. These maps highlight the necessity of estimating the other soil K fractions as well for better understanding of soil K supplying capacity and K fertilization strategy rather than the current recommendations, based on the plant-available K alone. In conclusion, the present study revealed that the variability of nutrient distribution was a consequence of complex interactions between the cropping system, nutrient application rates, and the native soil characteristics, and such interactions could be utilized to develop the nutrient management strategies for intensive small-holder system.

Dolastatin, along with Celecoxib, stimulates apoptosis by a mechanism involving oxidative stress, membrane potential change and PI3-K/AKT pathway down regulation.

BACKGROUND: Phosphoinositide 3-kinase (PI3-K) is an important regulator of oncogenesis and apoptosis in various types of cancers including colon cancer. A combinatorial strategy of using Cyclooxygenase-2 inhibitor, Celecoxib and Dolastatin, a linear peptide from marine mollusks of Indian Ocean origin has shown anti-neoplastic effects in colon cancer in a rat model. METHODS: The signal transduction pathway of PI3-K/AKT and the downstream signaling proteins had been studied in an early stage of colon carcinogenesis (DMH induced) by gene and protein expression, apoptotic studies by colonocyte apoptotic bleb assay, intracellular calcium level by fluorescence spectrometry, mitochondrial membrane potential by Rhodamine 123 flow cytometry and Reactive oxygen species measurement. Molecular docking analysis was employed to study the interaction of oncogenic proteins and the ligand, Celecoxib and Dolastatin. RESULTS: Apoptotic cell index was lowered with DMH while both the drugs increased it and inhibited PI3-K and AKT expression. Docking studies revealed both the proteins targeted by the drugs via an ATP binding site. An increased expression of GSK-3ß, pro-apoptotic protein Bad, transcription factor Egr-1, tumor suppressor protein PTEN while a downregulation of G1-associated cell cycle protein, Cyclin D1 and increased intracellular calcium as well as reactive oxygen species were observed. Also, the number of cells having a higher mitochondrial membrane potential was lowered. CONCLUSION: Celecoxib and Dolastatin inhibited the tumor development through regulation of the PI3-K/AKT pathway which can act as a novel target for these drugs. GENERAL SIGNIFICANCE: The anti-cancer properties of Dolastatin, a peptide isolated from marine mollusks in colorectal cancer is shown.

Natural resolution or intervention for fluid collections in acute severe pancreatitis.

BACKGROUND: Revisions in terminology of fluid collections in acute pancreatitis have necessitated reanalysis of their evolution and outcome. The course of fluid collections in patients with acute pancreatitis was evaluated prospectively. METHODS: Consecutive adults with acute pancreatitis, who had contrast-enhanced CT (CECT) within 5-7 days of symptom onset, were enrolled in a prospective cohort study in a tertiary-care centre. Patients were treated according to standard guidelines. Follow-up transabdominal ultrasonography was done at 4-week intervals for at least 6 months. CECT was repeated at 6-10 weeks, or at any time if there were new or persistent symptoms. Asymptomatic collections were followed until spontaneous resolution. Risk factors for pancreatic pseudocysts or walled-off necrosis (WON) were assessed in multivariable analyses. RESULTS: Of 122 patients with acute pancreatitis, 109 were analysed. Some 91 patients (83·5 per cent) had fluid collections at baseline. Eleven of 29 with interstitial oedematous pancreatitis had acute peripancreatic fluid collections, none of which evolved into pseudocysts. All 80 patients with acute necrotizing pancreatitis had at least one acute necrotizing collection (ANC); of these, five patients died (2 after drainage), three underwent successful drainage within 5 weeks, and collections resolved spontaneously in 33 and evolved into WON in 39. By 6 months' follow-up, WON had required drainage in eight patients, resolved spontaneously in 23 and was persistent but asymptomatic in seven. Factors associated with increased risk of WON were blood urea nitrogen 20 mg/dl or more (odds ratio (OR) 10·96, 95 per cent c.i. 2·57 to 46·73; P = 0·001) and baseline ANC diameter greater than 6 cm (OR 14·57, 1·60 to 132·35; P = 0·017). Baseline ANC diameter over 6 cm was the only independent predictor of either the need for drainage or persistence of such collections beyond 6 months (hazard ratio 6·61, 1·77 to 24·59; P = 0·005). CONCLUSION: Pancreatic pseudocysts develop infrequently in oedematous acute pancreatitis. Only one-quarter of ANCs either require intervention or persist beyond 6 months, whereas more than one-half of WONs resolve without any intervention within 6 months of onset. Baseline diameter of ANC(s) is an important predictor of outcome.

Testicular effects of monensin, a golgi interfering agent in male rats.

OBJECTIVE: The present study was undertaken to explore the effects of monensin, a potent Golgi disturbing agent on male fertility. METHODS: Male Wistar rats were administered monensin at the dose levels of 2.5, 5, and 10 mg/kg b wt. Animals were sacrificed after 67 days of the treatment. The activities of lactate dehydrogenase (LDH), ATPase, acid phosphatase and thiamine pyrophosphatase (TPPase) were measured in the testis. Cytochemical assay of Golgi body marker enzyme, thiamine pyrophosphatase was also performed. Ultrastructural changes in testis were studied by Transmission electron microscopy. Sperm number and motility were also examined. RESULTS AND DISCUSSION: The alterations in the activities of above mentioned enzymes indicate the pronounced effect of the drug on the functioning of spermatogenic cells. The findings from electron microscopy such as membrane disruption, swelling and disintegration of Golgi apparatus strongly suggest the interference of monensin with the functioning of Golgi apparatus in the spermatogenic cells. Data from the sperm number and motility as well as the fertility studies and the resulted litter size further points towards the antifertility effects of monensin in male rats. CONCLUSION: The findings from the present study strongly indicated the effects of monensin on the testis, involving alterations in key enzyme activities and changes at the ultrastructural level.

Self-administration of hospital-based narrowband ultraviolet B (TL-01) phototherapy: a feasibility study in an outpatient setting.

BACKGROUND: Self-administration of narrowband (TL-01) ultraviolet (UV)B phototherapy by patients at home is a safe and effective mode of treatment. Could selected patients self-administer phototherapy in hospital? OBJECTIVES: To assess the feasibility of outpatient self-administration of UVB phototherapy as a potential service development. METHODS: A total of 20 patients with psoriasis (n = 15) and eczema (n = 5) (13 female, mean age 32 years, range 17-56 years) were included in this pilot project. Patients underwent a training programme over 2 days, which included a minimal erythemal dose test and supervised treatment, prior to commencing self-administration of phototherapy. Questionnaires were used to gather feedback from patients and staff. RESULTS: Treatment data were collected for 18 of the 20 patients. The mean number of exposures was 25 (range 3-45), and the mean cumulative dose was 16 J cm(-2) (range 0·23-41·27 J cm(-2) ). No unexpected adverse effects were noted. These results were similar to those of a sample group of outpatients who had nurse-administered UVB phototherapy, for whom the mean number of exposures was 24 (range 4-49) and the mean cumulative dose was 17 J cm(-2) (range 0·53-71·16 J cm(-2) ). Thirteen patients completed the questionnaires. All concluded that the training programme sufficiently prepared them for self-administering phototherapy, and 12 reported that they would be happy to self-administer treatment in the future. CONCLUSIONS: Self-administration of UVB phototherapy is practicable, safe and effective for most selected patients. This mode of treatment provides training and support for patients to gain more control over management of their skin disease, empowering them to take an active role in their treatment. Self-administration of UVB phototherapy by outpatients provides an intermediate level of care between nurse-administered hospital phototherapy and self-administered home phototherapy.

Effect of cationic ionophore monensin on the lipid composition and fluidity of rat epididymal spermatozoal membrane.

The present study was aimed at exploring the effect of monensin, an antibiotic carboxylic polyether ionophore specific for Na(+), on the structural, chemical, and physiological changes of the epididymal sperm of Wistar rats. Animals received monensin at the dose of 3.5 mg/kg body weight daily orally for 70 days, a treatment duration that corresponds to the spermatogenic cycle in rats. At the end of the treatment regime, three regions of the epididymis were separated and the spermatozoa were collected. The plasma membranes of the spermatozoa were isolated and lipid composition, such total lipid, phospholipid, cholesterol, and ganglioside-sialic acid, was studied. Membrane dynamic behavior was investigated by lipid translational fluidity by pyrene excimer formation and rotational diffusion by diphenyl hexatriene polarization and anisotropy parameter. Structural changes in membrane were also evaluated by the dye-binding study with anilino naphthalene sulphonic acid. The results showed marked changes in lipid compositions, fluidity parameters, and kinetics of fluorescent dye binding in the epididymis, and it can be concluded that monensin, by interfering with normal physiological changes in spermatozoal maturation, may provide the basis of certain molecular intervention in the fertilizing capability of the epididymal spermatozoa and thereby may induce antifertility properties in male rats.

Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF.

Angiogenesis is a physiological process involving growth of new blood vessels from pre-existing ones; however, it also plays a critical role in tumor progression. It favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore targeting angiogenesis will be profitable as a mechanism to inhibit tumor's lifeline. Further, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF)-master switch in angiogenesis and other molecules in the neoplastic and pro-inflammatory milieu. We studied the role of two important chemokines [monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-lα] alongwith VEGF and matrix metalloproteinases (MMPs) in non-steroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effect in experimental colon cancer in rat. 1,2-Dimethylhydrazine (DMH, 30 mg/kg body weight, subcutaneously (s.c.) once-a-week) for 18 wk was used as pro-carcinogen and diclofenac (8 mg/kg body weight, orally daily) as the preferential cyclooxygenase-2 (COX-2) inhibitor. Expression of COX-2 and VEGF was found to be significantly elevated in the DMH-treated group as compared to the control, which was lowered notably by Diclofenac co-administration with DMH. Gelatin zymography showed prominent MMP-9 activity in the DMH-treated rats, while the activity was nearly absent in all the other groups. Expression of MCP-1 was found to be markedly increased whereas MIP-1α expression was found to be decreased in colonic mucosa from DMH-treated rats, which was reversed in the DMH + Diclofenac group. Our results indicate potential role of chemokines alongwith VEGF in angiogenesis in DMH-induced cancer and its chemoprevention with diclofenac.