How the Western Diet Thwarts the Epigenetic Efforts of Gut Microbes in Ulcerative Colitis and Its Association with Colorectal Cancer.

Ulcerative colitis (UC) is an autoimmune disease in which the immune system attacks the colon, leading to ulcer development, loss of colon function, and bloody diarrhea. The human gut ecosystem consists of almost 2000 different species of bacteria, forming a bioreactor fueled by dietary micronutrients to produce bioreactive compounds, which are absorbed by our body and signal to distant organs. Studies have shown that the Western diet, with fewer short-chain fatty acids (SCFAs), can alter the gut microbiome composition and cause the host's epigenetic reprogramming. Additionally, overproduction of H2S from the gut microbiome due to changes in diet patterns can further activate pro-inflammatory signaling pathways in UC. This review discusses how the Western diet affects the microbiome's function and alters the host's physiological homeostasis and susceptibility to UC. This article also covers the epidemiology, prognosis, pathophysiology, and current treatment strategies for UC, and how they are linked to colorectal cancer.

Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions.

Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (ChfrΔEC) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in ChfrΔEC mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in ChfrΔEC mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.

Imperatorin suppresses IL-1ß-induced iNOS expression via inhibiting ERK-MAPK/AP1 signaling in primary human OA chondrocytes.

Joint inflammation is a key player in the pathogenesis of osteoarthritis (OA). Imperatorin, a plant-derived small molecule has been reported to have anti-inflammatory properties; however, its effect on chondrocytes is not known. Here, we investigated the effects of Imperatorin on interleukin-1ß (IL-1ß) induced expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in primary human OA chondrocytes and cartilage explants culture under pathological conditions and explored the associated signaling pathways. We pretreated chondrocytes or explants with Imperatorin (50 µM) followed by IL-1ß (1 ng/ml), and the culture supernatant was used to determine the levels of nitrite production by Griess assay and chondrocytes were harvested to prepare cell lysate or RNA for gene expression analysis of iNOS by Western blot or qPCR and in explants by immunohistochemistry (IHC). Pretreatment of primary chondrocytes and cartilage explants with Imperatorin suppressed IL-1ß induced expression of iNOS and NO production. Imperatorin blocked the IL-1ß-induced phosphorylation of ERK-MAPK/AP1 signaling pathway to suppress iNOS expression. The role of ERK in the regulation of iNOS expression was verified by using ERK inhibitor. Interestingly, we also found that Imperatorin binds to iNOS protein and inhibits its activity in vitro. Our data demonstrated that Imperatorin possess strong anti-inflammatory activity and may be developed as a therapeutic agent for the management of OA.

Antioxidant, Antimicrobial Activity and Medicinal Properties of Grewia asiatica L.

Since ancient time, India is a well known subcontinent for medicinal plants where diversity of plants is known for the treatment of many human disorders. Grewia asiatica is a dicot shrub belonging to the Grewioideae family and well known for its medicinally important fruit commonly called Falsa. G. asiatica, a seasonal summer plant is distributed in the forest of central India, south India, also available in northern plains and western Himalaya up to the height of 3000 ft. Fruits of G. asiatica are traditionally used as a cooling agent, refreshing drink, anti-inflammatory agent and for the treatment of some urological disorders. Recent advancement of Falsa researches concluded its antimicrobial and anti-diabetic activity. Since ancient time medicinal plants are traditionally used for the treatment of different diseases G. asiatica fruit is the edible and tasty part of the plant, now considered as a valuable source of unique natural product for the development of medicines which are used in different disease conditions like anti-diabetic, anti-inflammatory, anti-cancerous and antimicrobial. Now a days, G. asiatica is being used in different Ayurvedic formulation for the cure of different types of diseases. Different pharmacological investigations reveal the presence of phenols, saponnins, flavonoids and tannins compound in the fruits. Present review highlights the phytopharmacological and different traditional use of G. asiatica which is mentioned in ancient Ayurvedic texts. This review stimulates the researchers and scientists for further research on G. asiatica.

Generation of Knock down Tools for Transcription Factor 7-like-2 (TCF7L2) and Evaluation of its Expression Pattern in Developing Chicken Optic Tectum.

UNLABELLED: Backgroud: TCF7L2 encodes for a transcription factor that plays a significant role in the Wnt signaling pathway and has been implicated in schizophrenia and blood glucose homeostasis. During embryonic development, TCF7L2 is expressed widely in the midbrain and forebrain regions of mouse brain. However, expression data of TCF7L2 and its functional studies are much scarcer for chicken brain. Our study demonstrated interesting expression pattern of TCF7L2 in the optic tectum of developing chicken embryo. Further study was undertaken to develop and test the knock down tools for TCF7L2 in the developing chicken embryo which would help in its functional characterization. METHODS: An RNAi based strategy was chosen to knock down TCF7L2A. miRNA based construct was designed and developed to target TCF7L2. However these miRNA construct may or may not be effective in knocking down their target gene, therefore the efficiency of the miRNA construct in knocking down TCF7L2 was tested. First the efficiency was measured in vitro using a sensor assay. The efficient pre-miRNA was cloned in an avian retrovirus to achieve in vivo knock down in the developing chicken embryo. RCAS-miRNA construct targeting TCF7L2, was electroporated in the tectum of embryonic day 3.5 chicken embryo. The extent of in vivo knock down of TCF7L2 by the RCAS-miRNA-TCF7L2 was examined using RNA in situ hybridization technique. RESULTS: TCF7L2 showed strong layer specific expression from embryonic day 5 to embryonic day 13 which is also the important time window for tectal development. In addition to the layer specific expression, TCF7L2 is also strongly expressed in the pre-tegmentum area of the tectum. The TCF7L2 transcript showed marked decrease in the region that was electroporated with RCAS-miRNA-TCF7L2. CONCLUSION: Therefore this study has led to the generation and validation of RCAS-pre miRNA-TCF7L2 which effectively knocks down TCF7L2 in vivo and thus has paved the way for further functional characterization of TCF7L2 in the chicken optic tectum.