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We show in rat lung microvessel endothelial cells (RLMVEC) that endocytosis is a critical determinant of activation of mitogen-activated protein kinase (MAPK) and thereby regulates endothelial monolayer integrity. In RLMVEC grown in serum-free medium, we observed that albumin supplementation induced the phosphorylation of p38 MAPK within 30 min, which persisted for up to 2 h. Engagement of the endocytic machinery regulated the activation of p38 MAPK that contributed to endothelial cell proliferation and reduction of apoptosis. We also observed an interaction between the caveolar protein caveolin-1 and p38 MAPK with reciprocal coimmunoprecipitation assays and colocalization using double-label immunofluorescence staining. Knockdown of caveolin-1 expression with small interfering RNA significantly reduced endocytosis and activation of p38 MAPK and interfered with the ability of endothelial cells to form a confluent monolayer. Thus caveolae-mediated endocytosis and concomitant activation of p38 MAPK may help to maintain endothelial monolayer integrity by signaling proliferation and survival of endothelial cells. stress mitogen-activated protein kinase; caveolin-l; transforming growth factor-[beta] signaling; cell proliferation

p38[alpha], p38[beta], p38[delta] and p38[delta] are four isoforms of p38 mitogen-activated protein (MAP) kinase (MAPK) involved in multiple cellular functions such as cell proliferation, differentiation, apoptosis, and inflammation response. In the present study, we examined the mRNA expression pattern of each of the four isoforms during erythroid differentiation of primary erythroid progenitors. We show that p38[alpha] and p38[gamma] transcripts are expressed in early hematopoietic progenitors as well as in late differentiating erythroblasts, whereas p38[delta] mRNA is only expressed and active during the terminal phase of erythroid differentiation. On the other hand, p38[beta] is minimally expressed in early CD[34.sup.+] hematopoietic progenitors but not expressed in lineage-committed erythroid progenitors. We also determined the phosphorylation/activation of p38[alpha], MAPK kinase 3/6, and MAPKAP-2 in response to erythropoietin and stem cell factor. We found that phosphorylation of p38[alpha], MAPK kinase kinase 3/6 and MAPKAP-2 occurs only upon growth factor withdrawal in primary erythroid progenitors. Moreover, our data indicate that activation of p38[alpha] does not induce apoptosis or promote proliferation of erythroid progenitors. On the other hand, under steady-state culture conditions, both p38[alpha] and p38[delta] isoforms are increasingly phosphorylated activated in the terminal phase of differentiation. This increased phosphorylation/ activity was accompanied by up-regulation of heat shock protein 27 phosphorylation. Finally, we demonstrate that tumor necrosis factor [alpha], an inflammatory cytokine that is modulated by p38[alpha], is expressed by differentiating erythroblasts and inhibition of p38[alpha] or tumor necrosis factor [alpha] results in reduction in differentiation. Taken together, our data demonstrate that both p38[alpha] and [delta] isoforms function to promote the late-stage differentiation of primary erythroid progenitors and are likely to be involved in functions related to erythrocyte membrane remodeling and enucleation.

Coumaroyl tyramine (CT) and coumaroyl tryptamine (CTr) are neutral hydroxycinnamic acid amides (HCAAs) that accumulate in plants in response to pathogen infection. In this study, we showed that inoculation of Pseudomonas syringae pv. tomato DC3000 (Pto) and Erwinia carotovora carotovora (ECC) increased the accumulation of CT in Arabidopsis thaliana leaves at 24 h post-inoculation. Both CT and CTr increased the accumulation of PATHOGENESIS-RELATED 1 (PR1) protein. However, CT and CTr had no significant effect on resistance to biotrophic pathogens in both compatible and incompatible plant–pathogen interactions. Nonetheless, our results revealed that CTr plays a critical role in increasing plant susceptibility to the necrotrophic pathogen ECC. Exogenous application of CT and CTr increased the induction of callose deposition in both the absence and presence of ECC. Increased callose deposition was detected in salicylic acid induction-deficient Arabidopsis mutant sid2 but to a lesser extent in ethylene signaling mutants, ein2-1 and etr1. Overall, our results suggest that ethylene signaling is related to CT and CTr-induced callose deposition and contributes to plant defense against pathogens, whereas salicylic acid is not required for this response. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers worldwide. The diagnosis, prognosis and therapeutic monitoring of CRC depends largely on tissue biopsy. However, due to tumor heterogeneity and limitations such as invasiveness, high cost and limited applicability in longitudinal monitoring, liquid biopsy has gathered immense attention in CRC. Liquid biopsy has several advantages over tissue biopsy including ease of sampling, effective monitoring, and longitudinal assessment of treatment dynamics. Furthermore, the importance of liquid biopsy is signified by approval of several liquid biopsy assays by regulatory bodies indicating the powerful approach of liquid biopsy for comprehensive CRC screening, diagnostic and prognostics. Several liquid biopsy biomarkers such as novel components of the microbiome, non-coding RNAs, extracellular vesicles and circulating tumor DNA are extensively being researched for their role in CRC management. Majority of these components have shown promising results on their clinical application in CRC including early detection, observe tumor heterogeneity for treatment and response, prediction of metastases and relapse and detection of minimal residual disease. Therefore, in this review, we aim to provide updated information on various novel liquid biopsy markers such as a) oral microbiota related bacterial network b) gut microbiome-associated serum metabolites c) PIWI-interacting RNAs (piRNAs), microRNA(miRNAs), Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and d) circulating tumor DNAs (ctDNA) and circulating tumor cells (CTC) for their role in disease diagnosis, prognosis, treatment monitoring and their applicability for personalized management of CRC. [ABSTRACT FROM AUTHOR]

Nuclear factor kappa B cells (NF‐κB) activation causes induction of the noncanonical IκB kinases (I‐kappa‐B kinase epsilon (IKKε) and TANK‐binding kinase 1 (TBK1) in liver and fat after high fat diet which followed activating of cascade of counter‐inflammation that conserves energy storage. Chrysin (5,7‐dihydroxyflavone), a natural flavonoid, present in many plants, honey and propolis, used conventionally to treat numerous ailments. The present study was aimed to identify the protective role of chrysin on the glucose lowering and insulin sensitivity in diet induced obese (DIO) mice by regulating IKKε/TBK1. Chrysin administered therapeutically (60, 100, 200 mg/kg body weight) and preventive mode (200 mg/kg body weight) for 4 and 10 weeks respectively to DIO mice. At last fasting blood glucose, oral glucose tolerance test, serum lipid profile, as well as the expression level of IKKε/TBK1 and triglyceride in the liver tissue were assessed. DIO mice showed impaired glucose tolerance, reduced weight gain, elevated hepatic IKKε/TBK1 expression, fatty acid infiltration triglyceride and increased in plasma insulin and glucose. Chrysin in both therapeutic and preventive mode normalized the altered levels of the same. Overall chrysin improves glycemic control and insulin sensitivity through regulating expression of IKKε/TBK1 in liver of DIO mice. [ABSTRACT FROM AUTHOR]