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Fulltext Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance

Zhang Y, Yan W, Collins MA, Bednar F, Rakshit S, Zetter BR, et al.

Cancer Res, 2013 Oct 15;73(20):6359-74.
PMID: 24097820 DOI: 10.1158/0008-5472.CAN-13-1558-T

Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target.

Matched MeSH terms: MAP Kinase Signaling System/physiology*
14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells

Tan HK, Muhammad TST, Tan ML

Toxicol Appl Pharmacol, 2016 06 01;300:55-69.
PMID: 27049118 DOI: 10.1016/j.taap.2016.03.017

14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.

Matched MeSH terms: MAP Kinase Signaling System/physiology
Fulltext SA-Mediated Regulation and Control of Abiotic Stress Tolerance in Rice

Nadarajah K, Abdul Hamid NW, Abdul Rahman NSN

Int J Mol Sci, 2021 May 25;22(11).
PMID: 34070465 DOI: 10.3390/ijms22115591

Environmental or abiotic stresses are a common threat that remains a constant and common challenge to all plants. These threats whether singular or in combination can have devastating effects on plants. As a semiaquatic plant, rice succumbs to the same threats. Here we systematically look into the involvement of salicylic acid (SA) in the regulation of abiotic stress in rice. Studies have shown that the level of endogenous salicylic acid (SA) is high in rice compared to any other plant species. The reason behind this elevated level and the contribution of this molecule towards abiotic stress management and other underlying mechanisms remains poorly understood in rice. In this review we will address various abiotic stresses that affect the biochemistry and physiology of rice and the role played by SA in its regulation. Further, this review will elucidate the potential mechanisms that control SA-mediated stress tolerance in rice, leading to future prospects and direction for investigation.

Matched MeSH terms: MAP Kinase Signaling System/physiology
A critical role of TRPM2 channel in Aβ42 -induced microglial activation and generation of tumor necrosis factor-α

Alawieyah Syed Mortadza S, Sim JA, Neubrand VE, Jiang LH

Glia, 2018 03;66(3):562-575.
PMID: 29143372 DOI: 10.1002/glia.23265

Amyloid β (Aβ)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Aβ-induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-α (TNF-α), a key cytokine implicated in AD. Exposure to 10-300 nM Aβ42 induced concentration-dependent microglial activation and generation of TNF-α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ42 -induced microglial activation and generation of TNF-α. Mechanistically, Aβ42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). Aβ42 -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ42 -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ42 -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in Aβ42 -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation.

Matched MeSH terms: MAP Kinase Signaling System/physiology
Effects of thyroxine on expression of proteins related to thyroid hormone functions (TR-α, TR-β, RXR and ERK1/2) in uterus during peri-implantation period

Sayem ASM, Giribabu N, Muniandy S, Salleh N

Biomed Pharmacother, 2017 Dec;96:1016-1021.
PMID: 29221723 DOI: 10.1016/j.biopha.2017.11.128

INTRODUCTION: Thyroid hormone is known to play important role during embryo implantation, however mechanisms underlying its actions in uterus during peri-implantation period has not been fully identified. In this study, we hypothesized that thyroid hormone could affect expression of proteins related to its function, where these could explain mechanisms for its action in uterus during this period.
METHODS: Female rats, once rendered hypothyroid via oral administration of methimazole (0.03% in drinking water) for twenty-one days were mated with fertile euthyroid male rats at 1:1 ratio. Pregnancy was confirmed by the presence of vaginal plug and this was designated as day-1. Thyroxine (20, 40 and 80 μg/kg/day) was then subcutaneously administered to pregnant, hypothyroid female rats for three days. A day after last injection (day four pregnancy), female rats were sacrificed and expression of thyroid hormone receptors (TR-α and β), retinoid X receptor (RXR) and extracellular signal-regulated kinase (ERK1/2) in uterus were quantified by Western blotting while their distribution in endometrium was visualized by immunofluorescence.
RESULTS: Expression of TRα-1, TRβ-1 and ERK1/2 proteins in uterus increased with increasing doses of thyroxine however no changes in RXR expression was observed. These proteins were found in the stroma with their distribution levels were relatively higher following thyroxine treatment.
CONCLUSIONS: Increased expression of TRα-1, TRβ-1 and ERK1/2 at day 4 pregnancy in thyroxine-treated hypothyroid pregnant rats indicate the importance of thyroxine in up-regulating expression of these proteins that could help mediate the uterine changes prior to embryo implantation.

Matched MeSH terms: MAP Kinase Signaling System/physiology*
Fulltext Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection

Gunaseelan S, Ariffin MZ, Khanna S, Ooi MH, Perera D, Chu JJH, et al.

Nat Commun, 2022 Feb 16;13(1):890.
PMID: 35173169 DOI: 10.1038/s41467-022-28533-z

Hand, foot and mouth disease (HFMD) caused by Human Enterovirus A71 (HEVA71) infection is typically a benign infection. However, in minority of cases, children can develop severe neuropathology that culminate in fatality. Approximately 36.9% of HEVA71-related hospitalizations develop neurological complications, of which 10.5% are fatal. Yet, the mechanism by which HEVA71 induces these neurological deficits remain unclear. Here, we show that HEVA71-infected astrocytes release CXCL1 which supports viral replication in neurons by activating the CXCR2 receptor-associated ERK1/2 signaling pathway. Elevated CXCL1 levels correlates with disease severity in a HEVA71-infected mice model. In humans infected with HEVA71, high CXCL1 levels are only present in patients presenting neurological complications. CXCL1 release is specifically triggered by VP4 synthesis in HEVA71-infected astrocytes, which then acts via its receptor CXCR2 to enhance viral replication in neurons. Perturbing CXCL1 signaling or VP4 myristylation strongly attenuates viral replication. Treatment with AZD5069, a CXCL1-specific competitor, improves survival and lessens disease severity in infected animals. Collectively, these results highlight the CXCL1-CXCR2 signaling pathway as a potential target against HFMD neuropathogenesis.

Matched MeSH terms: MAP Kinase Signaling System/physiology