P38MAPK cascade

Abstract: Over the past decade several related intracellular signaling pathways, collectively known as mitogen-activated protein kinase (MAPK) signaling cascades, have been elucidated [1±3]. These cascades play a key role in the transmission of extracellular signals to their intracellular targets and thus initiate cellular processes such as proliferation, differentiation, development, stress response, and apoptosis. Each of these signaling cascades consists of three to six tiers of protein kinases that sequentially activate each other by phosphorylation. Four distinct MAPK cascades are currently known and are named according to the subgroup of their MAPK components [Figure 1]: . The extracellular signal-regulated kinase (ERK) cascade, which was the first MAPK cascade elucidated and is the subject of this review. . The Jun N-terminal kinase (JNK) cascade, also known as stressactivated protein kinase 1 (SAPK1), is activated by various types of cellular stresses including the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1, osmolar stress and shear stress, but also by hormones and growth factors. . The p38MAPK cascade is another stress-activated MAPK cascade and is therefore known as SAPK2-4. . The Big MAPK (BMK also known as ERK5) cascade is the fourth MAPK cascade, so called due to the size of BMK, 110 kDa, compared to 40±45 kDa of the other MAPKs. The BMK is activated by oxidative stress and hyperosmolarity as well as by mitogens such as serum and growth factors. This review will focus on the ERK cascade and is composed of two parts. In the first part we describe the components of the ERK cascade, its activation and regulation [Figure 2]. In the second part we review the current knowledge on the involvement of the ERK cascade in various disease processes and its potential role as a target for the development of new medications.

Abstract: Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.

Abstract: Rituximab has been established as an effective and safe therapy for cutaneous B-cell lymphoma (CBCL). Different survival pathways, that is the Raf/MEK/Erk- or the p38MAPK cascade, have been suggested as downstream mediators of rituximab and may be involved in treatment failure. Biopsies from four patients, suffering from different subtypes of CBCL, which were obtained at various time points of relapse during or after therapy with 375 mg rituximab per m2 of body surface area, were analysed for the expression of CD20, CD3, Ki-67, Raf-kinase inhibitory protein (RKIP) and bcl-2 by immunohistochemistry. No CD20-loss variants, that is the suggested main tumour escape mechanism to rituximab therapy, were observed in any specimen of relapsing CBCL. Notably, the expression of proapoptotic RKIP remained increased in these tumour samples. This was concomitated by a constant to slightly reduced proliferation status as demonstrated by Ki-67 staining. However, relapsing CBCL exhibited a strong upregulation of the antiapoptotic molecule bcl-2 in comparison to pretherapeutic levels. The immunohistochemical analyses of this case series of rituximab refractory CBCL suggest that upregulation of bcl-2 may play a major role in therapy resistance.

Abstract: Excessive apoptosis of proximal tubule cell is closely related to the development of diabetes Recent evidence suggests that adiponectin (ADPN) protects cells from high glucose induced apoptosis However, the precise mechanisms remain poorly understood We sought to investigate the role of p38 mitogen-activated protein kinase (p38 MAPK) and AMP activated protein kinase (AMPK) in anti-apoptotic of adiponectin under high glucose condition in rat tubular NRK-52E cells Cells were cultured in constant and oscillating high glucose media with or without recombinant rat adiponectin for 48 h Cell counting kit-8 (CCK-8) was used to detect cell viability, flow cytometry and Hoechst Staining were applied to investigate cell apoptosis, and western blotting was used to examine protein expression, such as phospho-AMPK and phospho-p38MAPK Exposure to oscillating high glucose exerted lower cell viability and higher early apoptosis than constant high glucose, which were both partially prevented by adiponectin Further studies revealed that adiponectin suppressed p38MAPK phosphorylation, but led to an increase in AMPK α phosphorylation Compared to stable high glucose group, blockage of p38MAPK cascade with SB203580 attenuated apoptosis significantly, but failed to affect the phosphorylation level of AMPK While AMPK inhibitor, Compound C, increased apoptosis and remarkably inhibited the p38MAPK phosphorylation Adiponectin exert a crucial protective role against apoptosis induced by high glucose via AMPK/p38MAPK pathway