Diabetic Neuropathy: Review on Molecular Mechanisms

Diabetic Mellitus ◽

Mitochondrial Dysfunctions ◽

Therapeutic Value ◽

Diabetic Population ◽

Insulin Insensitivity

: Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience such as tingling and burning sensation, hyperalgesia, numbness etc. Globally, 50-60% of the diabetic population is suffering from such symptoms like microvascular complication. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions causing neuropathy. Among these pathways, pathways like Polyol pathway and PARP pathway are some of the most intensively studied pathways whereas pathways like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in management of DPN. This review hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for treatment of DPN.

The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽

10.1098/rsob.130067 ◽

2013 ◽

Vol 3 (6) ◽

pp. 130067 ◽

Cited By ~ 16

Author(s):

Gopal P. Sapkota

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Mapk Phosphorylation ◽

Mesenchymal Transition ◽

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

Claudin-1 is linked to presence of implants and micropapillary pattern in serous borderline epithelial tumours of the ovary

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205292 ◽

2018 ◽

Vol 71 (12) ◽

pp. 1060-1064 ◽

Cited By ~ 2

Author(s):

Ahmed El-Balat ◽

Iryna Schmeil ◽

Khayal Gasimli ◽

Nicole Sänger ◽

Thomas Karn ◽

...

Keyword(s):

Figo Stage ◽

Borderline Tumour ◽

Peritoneal Implants ◽

Gynecology And Obstetrics ◽

Pathway Activation ◽

Therapeutic Value ◽

Epithelial Tumours ◽

Micropapillary Pattern

AimsExpression of Claudin-1 has been associated with prognosis in several cancers. Here we investigated the expression pattern of Claudin-1 in borderline tumours of the ovary (BOT).MethodsWe analysed a cohort of 114 cases of borderline tumour (BOT). Claudin-1 expression was studied by immunohistochemistry using a polyclonal antibody and was compared with clinical and histopathological characteristics.ResultsStrong Claudin-1 expression was found in 30 cases (26.3%) independent of histological subtype. Expression was significantly less frequent in International Federation of Gynecology and Obstetrics (FIGO) stage I (p= 0.045), while the presence of microinvasion did not correlate with Claudin-1 expression. In contrast, we detected a highly significant association of Claudin-1 expression with the presence of peritoneal implants (p=0.003) and micropapillary pattern (p=0.047), which are features exclusively seen in serous BOT. Moreover, when we restricted our analysis to the subtype of serous BOT, the association of Claudin-1 expression with peritoneal implants (p<0.001) and micropapillary pattern (p =0.003) remained highly significant.ConclusionsIn conclusion, Claudin-1 expression is associated with the presence of peritoneal implants and micropapillary pattern, which have been shown to be associated with poor prognosis. We speculate that overexpression of Claudin-1 might be linked to the mitogen-activated protein kinase pathway activation in BOT and suggest further studies to define its prognostic and potential therapeutic value.

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

Biomolecules ◽

10.3390/biom9110735 ◽

2019 ◽

Vol 9 (11) ◽

pp. 735 ◽

Cited By ~ 79

Author(s):

Vaishali Aggarwal ◽

Hardeep Tuli ◽

Ayşegül Varol ◽

Falak Thakral ◽

Mukerrem Yerer ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Protein Kinase ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Reactive Oxygen ◽

Oxygen Species ◽

High Concentrations

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

Saccharomyces cerevisiae and Caffeine Implications on the Eukaryotic Cell

Nutrients ◽

10.3390/nu12082440 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2440

Author(s):

Lavinia Liliana Ruta ◽

Ileana Cornelia Farcasanu

Keyword(s):

Saccharomyces Cerevisiae ◽

Protein Kinase ◽

Molecular Mechanisms ◽

Eukaryotic Cell ◽

Pleiotropic Effect ◽

Active Principle ◽

Cell Integrity ◽

Tor Signaling ◽

Caffeine–a methylxanthine analogue of the purine bases adenine and guanine–is by far the most consumed neuro-stimulant, being the active principle of widely consumed beverages such as coffee, tea, hot chocolate, and cola. While the best-known action of caffeine is to prevent sleepiness by blocking the adenosine receptors, caffeine exerts a pleiotropic effect on cells, which lead to the activation or inhibition of various cell integrity pathways. The aim of this review is to present the main studies set to investigate the effects of caffeine on cells using the model eukaryotic microorganism Saccharomyces cerevisiae, highlighting the caffeine synergy with external cell stressors, such as irradiation or exposure to various chemical hazards, including cigarette smoke or chemical carcinogens. The review also focuses on the importance of caffeine-related yeast phenotypes used to resolve molecular mechanisms involved in cell signaling through conserved pathways, such as target of rapamycin (TOR) signaling, Pkc1-Mpk1 mitogen activated protein kinase (MAPK) cascade, or Ras/cAMP protein kinase A (PKA) pathway.

Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.277.5.g953 ◽

1999 ◽

Vol 277 (5) ◽

pp. G953-G959 ◽

Cited By ~ 7

Author(s):

Jean Morisset ◽

JoséCristobal Aliaga ◽

Ezéquiel L. Calvo ◽

Judith Bourassa ◽

Nathalie Rivard

Keyword(s):

Cell Cycle ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Regulatory Proteins ◽

Cyclin Dependent Kinase ◽

Mapk Activation ◽

Pancreas Regeneration ◽

Cell Cycle Regulatory Proteins

Pancreatic growth occurs after CCK, CCK-induced pancreatitis, and pancreatectomy; the mechanisms involved remain unknown. This study evaluates mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins after pancreatectomy to understand the cellular and molecular mechanisms involved in pancreas regeneration. Rats were killed 1–12 days after pancreatectomy, and p42/p44 MAPK activation, expression of the cyclins D and E, cyclin-dependent kinase (Cdk)-2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of the cyclin kinase inhibitors p15, p21, and p27 were examined. Pancreatic remnants exhibited sustained p42/p44 MAPK activation within 8 h. Cyclins D1 and E showed maximal expression after 2 and 6 days, coinciding with maximal hyperphosphorylation of pRb and Cdk2 activity. The expression of p15 vanished after 12 h, p27 disappeared gradually, and p21 increased early. The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion. In conclusion, sustained activation of p42/p44 MAPKs and Cdk2 along with overexpression of cyclins D1 and E and reduction of p15 and p27 cyclin inhibitors occurred early after pancreatectomy and are active factors involved in signaling that leads to pancreas regeneration.

Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.23.3.1095-1111.2003 ◽

2003 ◽

Vol 23 (3) ◽

pp. 1095-1111 ◽

Cited By ~ 62

Author(s):

Leticia Labriola ◽

Mariana Salatino ◽

Cecilia J. Proietti ◽

Adalí Pecci ◽

Omar A. Coso ◽

...

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Primary Cultures ◽

Type I ◽

Mobility Shift ◽

T47d Cells ◽

ABSTRACT The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro.

Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen‑activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin

Molecular Medicine Reports ◽

10.3892/mmr.2018.8504 ◽

2018 ◽

Cited By ~ 7

Author(s):

Juncheng Zhuo ◽

Qiaohuang Zeng ◽

Dake Cai ◽

Xiaohui Zeng ◽

Yuxing Chen ◽

...

Keyword(s):

Protein Kinase ◽

Animal Models ◽

Diabetic Mellitus ◽

High Fat ◽

Type 2 Diabetic Mellitus ◽

Protein Kinase Signaling ◽

Type 2 Diabetic

Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

Pathology Research International ◽

10.1155/2012/172894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 33

Author(s):

Hayato Nakagawa ◽

Shin Maeda

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Cellular Effects ◽

Wide Range ◽

Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

Clinical Science ◽

10.1042/cs20070430 ◽

2008 ◽

Vol 115 (7) ◽

pp. 203-218 ◽

Cited By ~ 262

Author(s):

Anthony J. Muslin

Keyword(s):

Molecular Mechanisms ◽

Cardiovascular Health ◽

Mapk Pathway ◽

Science Research ◽

Pharmacological Therapy ◽

Model Systems ◽

Extracellular Signal ◽

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle

The Journal of Cell Biology ◽

10.1083/jcb.200606051 ◽

2006 ◽

Vol 174 (5) ◽

pp. 625-630 ◽

Cited By ~ 61

Author(s):

Vlastimil Srsen ◽

Nicole Gnadt ◽

Alexander Dammermann ◽

Andreas Merdes

Keyword(s):

Cell Cycle ◽

Molecular Mechanisms ◽

Human Fibroblasts ◽

S Phase ◽

Nuclear Antigen ◽

Ki 67 ◽

Centrosome Proteins ◽

Centrosome Protein

Previous evidence has indicated that an intact centrosome is essential for cell cycle progress and that elimination of the centrosome or depletion of individual centrosome proteins prevents the entry into S phase. To investigate the molecular mechanisms of centrosome-dependent cell cycle progress, we performed RNA silencing experiments of two centrosome-associated proteins, pericentriolar material 1 (PCM-1) and pericentrin, in primary human fibroblasts. We found that cells depleted of PCM-1 or pericentrin show lower levels of markers for S phase and cell proliferation, including cyclin A, Ki-67, proliferating cell nuclear antigen, minichromosome maintenance deficient 3, and phosphorylated retinoblastoma protein. Also, the percentage of cells undergoing DNA replication was reduced by >50%. At the same time, levels of p53 and p21 increased in these cells, and cells were predisposed to undergo senescence. Conversely, depletion of centrosome proteins in cells lacking p53 did not cause any cell cycle arrest. Inhibition of p38 mitogen-activated protein kinase rescued cell cycle activity after centrosome protein depletion, indicating that p53 is activated by the p38 stress pathway.