Wnt/B-Catenin signalling during liver metabolism, chronic liver disease and hepatocarcinogenesis

Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their sig­nalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis

Wnt/B-Catenin signalling during liver metabolism, chronic liver disease and hepatocarcinogenesis

Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their sig­nalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis

Diuretic activity of ethanolic extract of whole plant of Sphaeranthus indicus linn in albino rats

Background: Sphaeranthus indicus Linn (S. indicus Linn) is a medicinal plant widely used in Indian traditional system of medicine for treating various ailments. The aim of the study was to evaluate diuretic activity by Lipschitz method in albino rats.Methods: Thirty albino rats were grouped into five groups and each contained six rats. Group I (control group) received 25ml/kg each of 0.9% sodium chloride orally. Group II (standard) received Hydrochlorothiazide 25 mg/kg orally dissolved in isotonic normal saline. Groups III, IV and V received ethanolic extracts of S. indicus Linn in doses 100mg/kg, 200mg/kg and 300mg/kg respectively dissolved in isotonic saline orally. The mice were put in metabolic cages and urine samples were collected for all the groups up to 24 hours after dosing. Urine was analysed for volume, urinary excretion ratio, diuretic activity, sodium and potassium composition electrolytes. Data was analysed using SPSS version 16 for windows.Results: Single dose administration of S. indicus in doses of 100, 200 and 300 mg/Kg as compared to Hydrochlorothiazide (25 mg/kg)have significantly (p<0.001, ANOVA) increased total urine output along with an increase in concentration of sodium and potassium. S. indicus Linn 300 mg/Kg produced greater diuretic activity, which is comparable to the effect of standard.Conclusions: The extract treated rats showed a dose dependent increase in urine volume. Maximum diuretic and kaliuretic activity were observed at the dose of 300 mg/kg of the extract. The present study supports and confirms the basis for folklore use of S. indicus Linn as a diuretic agent

Function of caspase-14 in trophoblast differentiation

<p>Abstract</p> <p>Background</p> <p>Within the human placenta, the cytotrophoblast consists of a proliferative pool of progenitor cells which differentiate to replenish the overlying continuous, multi-nucleated syncytiotrophoblast, which forms the barrier between the maternal and fetal tissues. Disruption to trophoblast differentiation and function may result in impaired fetal development and preeclampsia. Caspase-14 expression is limited to barrier forming tissues. It promotes keratinocyte differentiation by cleaving profilaggrin to stabilise keratin intermediate filaments, and indirectly providing hydration and UV protection. However its role in the trophoblast remains unexplored.</p> <p>Methods</p> <p>Using RNA Interference the reaction of control and differentiating trophoblastic BeWo cells to suppressed caspase-14 was examined for genes pertaining to hormonal, cell cycle and cytoskeletal pathways.</p> <p>Results</p> <p>Transcription of hCG, KLF4 and cytokeratin-18 were increased following caspase-14 suppression suggesting a role for caspase-14 in inhibiting their pathways. Furthermore, hCG, KLF4 and cytokeratin-18 protein levels were disrupted.</p> <p>Conclusion</p> <p>Since expression of these molecules is normally increased with trophoblast differentiation, our results imply that caspase-14 inhibits trophoblast differentiation. This is the first functional study of this unusual member of the caspase family in the trophoblast, where it has a different function than in the epidermis. This knowledge of the molecular underpinnings of trophoblast differentiation may instruct future therapies of trophoblast disease.</p

SFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium

Nitric oxide (NO) plays a critical role in endothelial functions such as cellular migration, vascular permeability and angiogenesis. Angiogenesis, the formation of new blood vessels from "pre-existing" ones is a carefully regulated process and essential during reproduction, development and wound healing. Previously our lab group reported that Secreted Frizzled-Related Protein 4 (sFRP4) could inhibit angiogenesis in both in vitro and in vivo conditions. sFRP4 belongs to a family of secreted glycoproteins that function as antagonists of the canonical Wnt signalling pathway. Although the pro-apoptotic role of sFRP4 is well discussed in literature, little is known in regards to its anti-angiogenic property. The objective of this study was to elucidate sFRP4 implications in NO biology of the endothelium. Results demonstrate that sFRP4 causes endothelial dysfunction by suppressing NO-cGMP signaling and elevating corresponding ROS levels. The imbalance between NO and ROS levels results in apoptosis and subsequent leakiness of endothelium as confirmed in vivo (Texas red/Annxin - CAM assay) and in vitro (Monolayer permeability assay) conditions. Furthermore utilizing peptides synthesized from the CRD domain of sFRP4, our results showed that while these peptides were able to cause endothelial dysfunctions, they did not cause apoptosis of the endothelial cells. Thereby confirming that sFRP4 can mediate its anti-angiogenic effect independent of its pro-apoptotic property. In conclusion, the current study reports that sFRP4-mediated anti-angiogenesis occurs as a result of impaired NO-cGMP signaling which in turn allow for elevation of redox levels and promotion of apoptosis of endothelial cells

Impact of perioperative period on disease-free survival among carcinoma ovary patients treated with the interval cyto-reductive surgery at a tertiary cancer centre in Kerala, India: a retrospective study

Background: Global incidence of ovarian malignancies is 300,000 as per GLOBOCAN 2018. The treatment protocol for advanced ovarian malignancies (stage IIIc and stage IV) includes neo-adjuvant chemotherapy and surgery followed by adjuvant chemotherapy. Aims of the study was to determine the effect of duration of chemo interruption on disease free survival of ovarian malignancies treated by interval cytoreduction followed by surgery.Methods: A total 48 patients were studied for events such as recurrence, death, patient’s status on last follow up, peri-operative period between 3rd cycle of chemo therapy and 4th cycle of chemo therapy. Based on the median duration of peri operative period patients was classified as early or delayed receivers of adjuvant chemo therapy. Difference in duration of over-all survival and disease-free survival was analysed through Kaplan Meier survival analysis using log-rank test. Hazard ratio adjusted for background characteristics such as staging, performance status, grade of tumour were analysed using cox proportional hazard model.Results: The two peri operative period categories based on mean value (85 days) didn’t show any significant association to disease free interval (minimum-21days, maximum-146 days, Hr = 1.3, p-value = 0.52). Other established factors like stage, extent of resection, response to chemotherapy, also didn’t show any significant association. Serum marker level showed a significant negative correlation with disease free survival (minimum-9 days, maximum-30659, p-value =.04, Hr = 3.19).Conclusions: The study could not establish any correlation between peri operative period and median disease-free survival. The small sample size is a limiting factor, well controlled randomized trials may needed for further clarification

Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt ß-catenin signaling via the Wnt antagonist secreted frizzled related protein-4

Background: Identification of breast cancer stem cells as the chemo-resistant and tumor-initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radio-resistant stem-like cells, termed as the cancer stem cells (CSCs) and their eradication could significantly enhance clinical outcomes. Most of the presently administered chemotherapeutics target the tumor bulk but are ineffective against the CSCs. We report here that diosgenin (DG), a naturally occurring steroidal saponin, could effectively inhibit CSCs from three breast cancer cell lines, MCF7, T47D and MDA-MB-231, by inducing apoptosis and inhibiting the CSC associated phenotypes. Methods: CSCs were enriched in these cells lines, characterized for CSC traits by immunocytochemistry and flow cytometry. Proliferation and apoptosis assays were performed in these breast CSCs in the presence of DG to obtain the inhibitory concentration. Apoptosis was confirmed with gene expression analysis, Western blotting and propidium iodide staining. TCF-LEF reporter assay, sFRP overexpression and RNAi silencing studies were performed to study regulation of the Wnt pathway. Statistical significance was evaluated by a two-sided Student's t-test. Results: Using the TCF-LEF reporter system, we show the effect of DG on CSCs is predominantly through the network regulating CSC self renewal, the Wnt ß-catenin pathway. Specifically, the Wnt antagonist, the secreted frizzled related protein 4, (sFRP4), had a defining role in the action of DG. Gain-of-function of sFRP4 in CSCs could improve the response to DG wherein CSC mediators were inhibited, ß-catenin was down regulated and the effectors of epithelial to mesenchymal transition and pro-invasive markers were repressed. Conversely, the loss-of-function of sFRP4 had a reverse effect on the CSC population which therein became enriched, their response to DG treatment was modest, ß-catenin levels increased, GSK3ß expression decreased and the expression of epithelial markers of CSC was completely abrogated. Conclusion: These findings demonstrate the effect of DG on inhibiting the resilient breast CSCs which could provide a benchmark for the development of DG-based therapies in breast cancer treatment. © 2017 Bhuvanalakshmi, Basappa, Rangappa, Dharmarajan, Sethi, Kumar and Warrier

Bhoo Samruddhi : A Compendium of Success Stories, Research Report IDC-2

Across the world, rainfed areas are hotspots of poverty, malnutrition and degradation of natural resources. In India, of 142 m ha of arable lands, 60% is rainfed. Karnataka has the second largest area under rainfed agriculture only after Rajasthan in the country. Farmers’ crop yields in dryland areas are quite low (1.0 -1.5 t ha-1), about two to five times below potential yield. Recent findings from the ‘Comprehensive Assessment of Water for Food and Water for Life’ revealed that the millennium development goal of reducing the number of poor people by half can be met only through efficient use of scarce water resources for agriculture. Food production can be increased substantially in rainfed areas by applying enhanced water use efficiency measures, improving soil health status, and implementing other new technologies in an integrated approach. It is evident that the vast potential of rainfed agriculture can be unlocked by using available scientific technologies including improved cultivars. Recognizing the problem, the Department of Agriculture (DoA), Government of Karnataka (GoK), has adopted science-led initiatives for achieving impact oriented development in the state. In this endeavor, it has sought to bring in international expertise to unlock the potential of rainfed agriculture in the state. Bhoochetana, the farmer-centric initiative taken up by GoK has benefited more than 4.3 million farm households in the state. In addition, the government has initiated a number of innovative measures to improve agricultural production and livelihood of farmers in the state during the last four years. Realizing high impacts in terms of increased agricultural productivity, increased gross value of agriculture production and improved livelihoods, the state government requested ICRISAT to lead a consortium of CGIAR institutions working in India, and to operationalize impact oriented research for development with the aim of improving rural livelihoods. The ICRISAT-led consortium took up this challenge and established a “proof of concept” for translating strategic research knowledge into improving livelihoods through scaling up of the participatory research for development (PR4D) model. A number of meetings and stakeholder consultations were held to identify constraints and problems of all four pilot locations, and the project was begun in 2013-14..

Critical Review of Methods for Sampling, Analysis, and Monitoring of Vapor-Phase Toluene Diisocyanate

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91959/1/TLVpaper2002.pd

Bhoochetana : A Compendium of Success Stories, Research Report IDC-3

The Government of Karnataka has upscaled the learnings from the Sujala-ICRISAT initiative to enhance agricultural productivity in the dryland areas of the state by bridging the yield gap between farmers’ fields and achievable yields with the help of science-based productivity enhancement interventions. The mission project on rainfed agriculture called “Bhoochetana” was launched by the Government of Karnataka during 2009-10 to benefit dryland farmers in 30 districts. The principle of consortium, convergence, capacity building and collective action as proposed by ICRISAT to address the issues of efficiency, economics, equity and environmental protection was adopted. The consortium partners involved in Bhoochetana are three State Agricultural Universities (UAS, Bangalore; Dharwad; and Raichur;), the Watershed Development Department (WDD), the Department of Economics and Statistics (DES), and other line departments of the Government of Karnataka, ICRISAT and the Department of Agriculture which is the nodal agency for the mission project. Farm facilitators and Lead farmers have assumed the role of trainers to train large numbers of farmers on collective action and capacity building. During the second and third year, project activities were expanded to all 30 districts in addition to the six districts of the Sujala watershed program where soil health mapping had already been completed, along with participatory selection of appropriate cultivars of the major crops. In all 30 districts efforts have been made to collect soil samples by adopting a stratified soil sampling method and covering a large number of villages..