The Regulatory Roles of Mitogen-Activated Protein Kinase (MAPK) Pathways in Health and Diabetes: Lessons Learned from the Pancreatic β-Cell

Sidarala, Vaibhav; Kowluru, Anjaneyulu

doi:10.2174/1872214810666161020154905

Cited by 63 publications

(43 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While p38 and JNK, known as stress-activated protein kinase, are strongly activated by various cellular stresses, such as heat shock and oxidative stress, TNF-α and LPS, which play roles in cell proliferation and survival, are associated with the induction of apoptosis by cellular stresses [30]. In the present study, p38 and JNK phosphorylation occurred after cells were treated with LPS for 12 h. The major functional role of phosphorylated p38 and JNK lies in mediating the downstream substrates involved in the cell cycle and apoptosis [29]. Our results also suggest that the relative mRNA expressions of downstream genes of the p38 and JNK signaling pathways, including AP-1, ATF-2, ELK-1, and p53, were increased and that Stat3 expression was dramatically decreased after cells were treated with LPS, which may activate caspases and induce apoptosis [31, 32].…”

Section: Discussionmentioning

confidence: 62%

“…ERK1/2 are mostly activated by growth factors, such as epidermal growth factor and nerve growth factor, which play central roles in the control of cell proliferation [29, 30]. While p38 and JNK, known as stress-activated protein kinase, are strongly activated by various cellular stresses, such as heat shock and oxidative stress, TNF-α and LPS, which play roles in cell proliferation and survival, are associated with the induction of apoptosis by cellular stresses [30].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clostridium Tyrobutyricum Protect Intestinal Barrier Function from LPS-Induced Apoptosis via P38/JNK Signaling Pathway in IPEC-J2 Cells

Zhang¹,

Liu²,

Tao³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The intestinal mucosa forms a physical and metabolic barrier against the diffusion of pathogens, toxins, and allergens from the lumen into the circulatory system. Early weaning, a critical phase in swine production, can compromise intestinal barrier function through mucosal damage and alteration of tight junction integrity Maintenance of intestinal barrier function plays a pivotal role in optimum gastrointestinal health. In this study, we investigated the effects of Clostridium tyrobutyricum (C.t) on intestinal barrier dysfunction induced by lipopolysaccharide (LPS) and the underlying mechanisms involved in intestinal barrier protection. Methods: A Transwell model of IPEC-J2 cells was used to imitate the intestinal barrier. Fluorescence microscopy and flow cytometry were used to evaluate apoptosis. Real-time PCR was used to detect apoptosis-related genes and the downstream genes of the p38/c-Jun N-terminal kinase (JNK) signaling pathways. Western blotting was used to measure the expressions of tight junction proteins and mitogen-activated protein kinases. Results: C.t efficiently maintained trans-epithelium electrical resistance values and intestinal permeability after LPS-induced intestinal barrier disruption. The expressions of tight junction proteins (ZO-1, claudin-1, and occludin) were promoted when IPEC-J2 cells were treated with C.t. Fluorescence imaging and flow cytometry revealed that C.t qualitatively and quantitatively inhibited LPS-induced cell apoptosis. C.t also increased the relative expression of the anti-apoptotic gene Bcl-2 and decreased that of the apoptotic genes Bax and caspase-3/-8. Moreover, the protective effect of C.t on damaged intestinal cell models was associated with suppression of p38 and JNK phosphorylation, negative regulation of the relative expressions of downstream genes including AP-1, ATF-2, ELK-1, and p53, and activation of Stat3 expression. Conclusions: These findings indicate that C.t may promote intestinal integrity, suggesting a novel probiotic effect on intestinal barrier function.

show abstract

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Clostridium Tyrobutyricum Protect Intestinal Barrier Function from LPS-Induced Apoptosis via P38/JNK Signaling Pathway in IPEC-J2 Cells

Zhang¹,

Liu²,

Tao³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Post‐translational prenylation of small G‐proteins (Ras, Rho, Rac1, Cdc42, Rap1 and Rabs) is critical for GSIS to occur. It should be noted that tonic increase in Nox2‐mediated generation of ROS appears to favour cytoskeletal remodeling and activation of ERK1/2 signalling modules while suppressing stress kinases such as JNK1/2 (Figure ) . Interestingly, however, metabolic stress condition (glucotoxicity, lipotoxicity and ER stress) promotes sustained activation of Rac1, which, in turn, accelerates the Nox2‐ROS‐stress kinase signalling pathway leading to mitochondrial dysfunction, loss in GSIS and apoptotic demise of the islet β‐cell (Figure ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, sustained activation of Nox2 results in increased levels of ROS, which, in turn, promote Rac1‐induced activation of apoptotic JNK1/2, and inhibit ERK1/2 signalling pathways. Additional studies are needed to further validate this model (Reproduced with permission from Bentham‐Science)…”

Section: Discussionmentioning

confidence: 99%

Role of G‐proteins in islet function in health and diabetes

Kowluru

2017

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

Glucose-stimulated insulin secretion [GSIS] involves interplay between metabolic and cationic events. Seminal contributions from multiple laboratories affirm essential roles for small G-proteins [Rac1, Cdc42, Arf6, Rab27A] in GSIS. Activation of these signaling proteins promotes cytoskeletal remodeling, transport and docking of insulin granules on the plasma membrane for exocytotic secretion of insulin. Evidence in rodent and human islets suggests key roles for lipidation [farnesylation and geranylgeranylation] of these G-proteins for their targeting to appropriate cellular compartments for optimal regulation of effectors leading to GSIS. Interestingly, however, inhibition of prenylation appears to cause mislocalization of non-prenylated, but [paradoxically] activated G-proteins, in “inappropriate” compartments leading to activation of stress kinases and onset of mitochondrial defects, loss in GSIS and apoptosis of the islet β-cell. This review highlights our current understanding of roles of G-proteins and their posttranslational lipidation [prenylation] signaling networks in islet function in normal health, metabolic stress [glucolipotoxicity and ER stress] and diabetes. Critical knowledge gaps that need to be addressed for the development of therapeutics to halt defects in these signaling steps in β cells in models of impaired insulin secretion and diabetes are also highlighted and discussed.

show abstract

“…In some tissues, Plin5 has been reported to involve in the regulation of PI3K/Akt or MAPK pathways (p38 MAPK, ERK, and JNK) (21,24,40,44,49), which is the upstream modulators of Nrf2 in pancreatic β-cells (39,41). As evidenced by prior studies, excess ROS production and oxidative stress results in the activation of apoptotic p38 MAPK and JNK signaling, whereas activation of antiapoptotic PI3K/Akt and ERK pathways facilitates the translocation of Nrf2 into the nucleus, thereby activating the Nrf2/ARE pathway and alleviating oxidative damage (50,51). In the current study, p38 MAPK and JNK pathways were found to be activated but PI3K/Akt and ERK pathways were inhibited in β-cells under palmitate inducedoxidative stress.…”

Section: Discussionmentioning

confidence: 95%

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

et al. 2020

View full text Add to dashboard Cite

Oxidative stress induced by free fatty acid overload in pancreatic β-cells is a potential contributory factor to dysfunction of insulin secretion and apoptotic cell death. Perilipin 5 (Plin5) has been reported to ameliorate oxidative stress-mediated damage in non-insulin-secreting tissues. We tested the hypothesis that Plin5 plays a similar role in pancreatic β-cells, which are extremely sensitive to oxidative stress. Here, our in vitro data showed that Plin5-mediated alleviation of palmitate-triggered apoptosis involves the mitochondrial pathway. And the protective role of Plin5 on β-cells was partially dependent on its modulation in oxidative stress. Upregulation of Plin5 in INS-1 cells decreased reactive oxygen species production, enhanced cellular glutathione levels, and induced expression of antioxidant enzymes glutamate-cysteine ligase catalytic subunit and heme oxygenase-1. However, knocking out of Plin5 abolished all of these beneficial effects. Furthermore, by using the O 2− scavenger MnTMPyP, we verified that altering Plin5 expression impacted lipotoxic cell death partially via modulating oxidative stress. Mechanistic experiments revealed that Plin5 induced Nrf2-ARE system, a master regulator in the cellular adaptive response to oxidative stress, by activating PI3K/Akt and ERK signal pathways, contributing to the increase of antioxidant defense and consequently improving β-cell function and survival in the presence of lipotoxic oxidative stress. Overall, our findings indicate that Plin5 abrogates oxidative damage in INS-1 β-cells during lipotoxic stress partially through the enhancement of antioxidant defense involving the PI3K/Akt and ERK mediated Nrf2-ARE system.

show abstract

The Regulatory Roles of Mitogen-Activated Protein Kinase (MAPK) Pathways in Health and Diabetes: Lessons Learned from the Pancreatic β-Cell

Cited by 63 publications

References 90 publications

Clostridium Tyrobutyricum Protect Intestinal Barrier Function from LPS-Induced Apoptosis via P38/JNK Signaling Pathway in IPEC-J2 Cells

Clostridium Tyrobutyricum Protect Intestinal Barrier Function from LPS-Induced Apoptosis via P38/JNK Signaling Pathway in IPEC-J2 Cells

Role of G‐proteins in islet function in health and diabetes

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

Contact Info

Product

Resources

About