Quercitrin attenuates osteoporosis in ovariectomized rats by regulating mitogen-activated protein kinase (MAPK) signaling pathways

ABSTRACT Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a high-throughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCE Chikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo . Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections.

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Understanding MAPK Signaling Pathways in Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms21072346 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2346 ◽

Cited By ~ 16

Author(s):

Jicheng Yue ◽

José M. López

Keyword(s):

Signaling Pathways ◽

Positive Feedback ◽

Cell Model ◽

Mapk Signaling ◽

Feedback Loops ◽

Mitogen Activated Protein Kinase ◽

Cellular Mechanisms ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Mapk Signaling Pathways

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

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Weaning Induced Hepatic Oxidative Stress, Apoptosis, and Aminotransferases through MAPK Signaling Pathways in Piglets

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/4768541 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 26

Author(s):

Zhen Luo ◽

Wei Zhu ◽

Qi Guo ◽

Wenli Luo ◽

Jing Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Redox Status ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Control Group ◽

Hepatic Oxidative Stress ◽

Mitogen Activated Protein ◽

D 20 ◽

Mapk Signaling Pathways

This study investigated the effects of weaning on the hepatic redox status, apoptosis, function, and the mitogen-activated protein kinase (MAPK) signaling pathways during the first week after weaning in piglets. A total of 12 litters of piglets were weaned at d 21 and divided into the weaning group (WG) and the control group (CG). Six piglets from each group were slaughtered at d 0 (d 20, referred to weaning), d 1, d 4, and d 7 after weaning. Results showed that weaning significantly increased the concentrations of hepatic free radicals H2O2and NO, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), while significantly decreasing the inhibitory hydroxyl ability (IHA) and glutathione peroxidase (GSH-Px), and altered the level of superoxide dismutase (SOD). The apoptosis results showed that weaning increased the concentrations of caspase-3, caspase-8, caspase-9 and the ratio of Bax/Bcl-2. In addition, aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT) in liver homogenates increased after weaning. The phosphorylated JNK and ERK1/2 increased, while the activated p38 initially decreased and then increased. Our results suggested that weaning increased the hepatic oxidative stress and aminotransferases and initiated apoptosis, which may be related to the activated MAPK pathways in postweaning piglets.

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Role of Mitogen- and Stress-Activated Kinases in Ischemic Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200206000-00001 ◽

2002 ◽

Vol 22 (6) ◽

pp. 631-647 ◽

Cited By ~ 267

Author(s):

Elaine A. Irving ◽

Mark Bamford

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Protein Kinase ◽

Signaling Pathways ◽

Focal Cerebral Ischemia ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Amino Terminal ◽

Biological Responses ◽

Mitogen Activated Protein

Protein kinase-mediated signaling cascades constitute the major route by which cells respond to their extracellular environment. Of these, three well-characterized mitogen-activated protein kinase (MAPK) signaling pathways are those that use the extracellular signal-regulated kinase (ERK1/2) or the stress-activated protein kinase (p38/SAPK2 or JNK/SAPK) pathways. Mitogenic stimulation of the MAPK-ERK1/2 pathway modulates the activity of many transcription factors, leading to biological responses such as proliferation and differentiation. In contrast, the p38/SAPK2 and JNK/SAPK (c-Jun amino-terminal kinase/stress-activated protein kinase) pathways are only weakly, if at all, activated by mitogens, but are strongly activated by stress stimuli. There is now a growing body of evidence showing that these kinase signaling pathways become activated following a variety of injury stimuli including focal cerebral ischemia. Whether their activation, however, is merely an epiphenomenon of the process of cell death, or is actually involved in the mechanisms underlying ischemia-induced degeneration, remains to be fully understood. This review provides an overview of the current understanding of kinase pathway activation following cerebral ischemia and discusses the evidence supporting a role for these kinases in the mechanisms underlying ischemia-induced cell death.

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Rosavin suppresses osteoclastogenesis in vivo and in vitro by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways

Annals of Translational Medicine ◽

10.21037/atm-20-4255 ◽

2021 ◽

Vol 9 (5) ◽

pp. 383-383

Author(s):

Wenhao Zhang ◽

Weijie Zhang ◽

Liang Huo ◽

Ying Chai ◽

Zhiyang Liu ◽

...

Keyword(s):

Protein Kinase ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Nuclear Factor ◽

Kappa Light Chain ◽

Mitogen Activated Protein ◽

Light Chain Enhancer ◽

Mapk Signaling Pathways

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Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?

International Journal of Molecular Sciences ◽

10.3390/ijms221910260 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10260

Author(s):

Constantin Stefani ◽

Daniela Miricescu ◽

Iulia-Ioana Stanescu-Spinu ◽

Remus Iulian Nica ◽

Maria Greabu ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Factors ◽

Growth Factor ◽

Protein Kinase ◽

Signaling Pathways ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cancer Pathogenesis ◽

The Impact ◽

Mapk Signaling Pathways

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.

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The Mitogen-Activated Protein Kinase Signaling Pathway Stimulates Mos mRNA Cytoplasmic Polyadenylation duringXenopus Oocyte Maturation

Molecular and Cellular Biology ◽

10.1128/mcb.19.3.1990 ◽

1999 ◽

Vol 19 (3) ◽

pp. 1990-1999 ◽

Cited By ~ 63

Author(s):

Emily L. Howard ◽

Amanda Charlesworth ◽

Joseph Welk ◽

Angus M. MacNicol

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Oocyte Maturation ◽

Cyclin B1 ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Protein Accumulation ◽

Cytoplasmic Polyadenylation ◽

Mitogen Activated Protein ◽

Mrna Polyadenylation

ABSTRACT The Mos protein kinase is a key regulator of vertebrate oocyte maturation. Oocyte-specific Mos protein expression is subject to translational control. In the frog Xenopus, the translation of Mos protein requires the progesterone-induced polyadenylation of the maternal Mos mRNA, which is present in the oocyte cytoplasm. Both theXenopus p42 mitogen-activated protein kinase (MAPK) and maturation-promoting factor (MPF) signaling pathways have been proposed to mediate progesterone-stimulated oocyte maturation. In this study, we have determined the relative contributions of the MAPK and MPF signaling pathways to Mos mRNA polyadenylation. We report that progesterone-induced Mos mRNA polyadenylation was attenuated in oocytes expressing the MAPK phosphatase rVH6. Moreover, inhibition of MAPK signaling blocked progesterone-induced Mos protein accumulation. Activation of the MAPK pathway by injection of RNA encoding Mos was sufficient to induce both the polyadenylation of synthetic Mos mRNA substrates and the accumulation of endogenous Mos protein in the absence of MPF signaling. Activation of MPF, by injection of cyclin B1 RNA or purified cyclin B1 protein, also induced both Mos protein accumulation and Mos mRNA polyadenylation. However, this action of MPF required MAPK activity. By contrast, the cytoplasmic polyadenylation of maternal cyclin B1 mRNA was stimulated by MPF in a MAPK-independent manner, thus revealing a differential regulation of maternal mRNA polyadenylation by the MAPK and MPF signaling pathways. We propose that MAPK-stimulated Mos mRNA cytoplasmic polyadenylation is a key component of the positive-feedback loop, which contributes to the all-or-none process of oocyte maturation.

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Transcriptomic analysis reveals MAPK signaling pathways affect the autolysis in baker's yeast

FEMS Yeast Research ◽

10.1093/femsyr/foaa036 ◽

2020 ◽

Vol 20 (5) ◽

Author(s):

Xiao Li ◽

Han Ye ◽

Chao-Qun Xu ◽

Xiang-ling Shen ◽

Xiao-Long Zhang ◽

...

Keyword(s):

Signaling Pathways ◽

Mapk Signaling ◽

Baker’S Yeast ◽

Mitogen Activated Protein Kinase ◽

Baker's Yeast ◽

Kegg Pathways ◽

Mitogen Activated Protein ◽

Yeast Autolysis ◽

Protein Rich ◽

Mapk Signaling Pathways

Abstract Yeast autolysis refers to the process in which cells degrade and release intracellular contents under specific conditions by endogenous enzymes such as proteases, nucleases and lipid enzymes. Protein-rich baker's yeast is widely used to produce yeast extract in food industry, however, the molecular mechanism related to baker's yeast autolysis is still unclear. In this study, RNA-seq technology and biochemical analysis were performed to analyze the autolysis processes in baker's yeast. The differentially expressed genes (DEGs), 27 autolysis-related euKaryotic Ortholog Groups (KOG) and three types of autolysis-induced Gene Ontology (GO) were identified and analyzed in detail. A total of 143 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways under autolysis were also assigned. Interestingly, the DEGs were significantly enriched in the mitogen-activated protein kinase (MAPK) signaling pathways and metabolic pathways, and key genes MID2, MTL1, SLT2, PTP2, HKR1 and GPD1 may play important roles in autolysis. Further quantitative PCR was performed to verify the expression pattern in baker's yeast autolysis. Together, all these results indicated that MAPK pathways might play an essential role during autolysis process through inhibiting the metabolism and disrupting cell wall in baker's yeast. This result may provide important clues for the in-depth interpretation of the yeast autolysis mechanism.

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