TLR4 is a link between diabetes and Alzheimer’s disease

Huang, Nanqu; Jin, Hai; Zhou, Shaoyu; Shi, Jingshan; Jin, Feng

doi:10.1016/j.bbr.2016.08.047

Cited by 91 publications

(53 citation statements)

References 126 publications

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“…Inadequate clearance of IS leads to its accumulation in circulation, which may promote the glomerular injury of residual nephrons, leading to a faster loss of RKF [8-11]. In agreement with this notion, IS was shown to trigger mesangial cell (MC) proliferation and extracellular matrix deposition [12, 13]. As a type of native glomerular cells, MCs are very sensitive to various insults [14-18].…”

Section: Introductionmentioning

confidence: 67%

“…Similar as COX-2 inhibition [13], mPGES-1 silencing inhibited IS-induced MC proliferation as evidenced by the blocked cell cycle progression and reduced cell number. Meanwhile, the PGE 2 production induced by IS was also blunted.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we reported that IS significantly promoted cell cycle progression via upregulating COX-2 expression in mesangial cells [13]. However, whether mPGES-1/PGE 2 (a downstream cascade of COX-2) plays a role in mediating COX-2 effect on MC proliferation is still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…COX-1 and COX-2 chiefly regulate the production of five major prostaglandins (PGE 2 , PGI 2 , PGD 2 , PGF 2α , and TXA2) by supplying the substrate (PGH 2 ) to the prostaglandin synthetic enzymes including mPGES-1 [22]. Our previous study showed that IS significantly increased the COX-2 (not COX-1) expression to promote MC proliferation [13]. However, it still needs evidence to define the specific prostaglandin in mediating COX-2 effect on promoting MC proliferation.…”

Section: Introductionmentioning

confidence: 99%

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mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

Sun

Ding

et al. 2017

Cell Physiol Biochem

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Background/Aims: We previously reported that indoxyl sulfate (IS) could cause mesangial cell (MC) proliferation via a cyclooxygenase (COX)-2-dependent mechanism. However, the specific prostaglandin contributing to COX-2 effect on IS-induced MC proliferation remained unknown. Thus, the present study was undertaken to examine the role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived Prostaglandin E2 (PGE₂) in IS-induced MC proliferation. Methods: IS was administered to the MCs with or without mPGES-1 siRNA pretreatment to induce the MC proliferation which was determined by cell cycle analysis, DNA synthesis, and the expressions of cyclins. In another experimental setting, PGE₂ was applied to the MCs to examine its direct effect on MC proliferation, as well as the regulation of prostaglandin E receptors (EPs) by qRT-PCR. Results: With the administration of IS, mPGES-1(not mPGES-2 and cytosolic PGES) was significantly upregulated at both protein and mRNA levels in line with a promoted MC proliferation. Interestingly, silencing mPGES-1 reduced cell number in S and G2 phases and blocked the upregulation of cyclin A2 and cyclin D1 in parallel with blunted PGE₂ release after IS treatment, indicating that mPGES-1-derived PGE₂ could contribute to MC proliferation. Furthermore, we confirmed that exogenous PGE₂ could directly trigger the proliferative response in MCs. Lastly, we observed a selective upregulation of EP2 after PGE2 treatment and enhanced phosphorylation of NF-κB following IS administration in MCs, suggesting the potential involvements of EP2 and NF-κB in this pathological process. Conclusion: mPGES-1-derived PGE₂ contributed to IS-induced mesangial cell proliferation.

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

Sun

Ding

et al. 2017

Cell Physiol Biochem

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“…Another study also demonstrated that blocking TLR4 signaling also rescue neuronal survival in diabetic rats [102]. Chronic triggering of TLR4 pathway induces both insulin resistance and amyloid beta deposition [103]. It has been suggested that TLR4 action is mediated by NFkB signaling pathway [104].…”

Section: Molecular Pathways Of Diabetes Mellitus Pathogenesismentioning

confidence: 94%

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Ferrari¹

2017

Integr Obesity Diabetes

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Oxidative and nitrosative stress reactions are implicated in cell and organ damage due to diabetes mellitus. In both type 1 and type 2 DM there is a massive oxidative and nitrosative stresses which have been associated with intensive changes on both antioxidant enzyme systems (SOD, CAT, GPx, GSH) and total antioxidant capacity (TAC) causing peroxidative damage to lipids, proteins, nucleic acids and carbohydrates which can be used as DM biomarkers. Molecular pathophysiology of diabetes mellitus envolves induction of the the NFkB and p38-MAPK cell signaling pathways by Rac, TNF-α, TLR4, decrease of antioxidant defenses, and direct mitochondrial damage. Knowledge of molecular pathways is essential for research of newer preventive and therapeutic approaches in diabetes mellitus complications (atherosclerosis, myocardial damage, endothelial dysfunction, and renal failure).urine, feces, tissue sample), vegetable or fruit extract or even foods or pharmaceuticals [14][15][16].This article review and update the clinical, cellular, and molecular knowledge of free radicals and antioxidant defenses in diabetes mellitus. Ethiopathogenesis of diabetes mellitus I and IIDiabetes mellitus has been conceptualized as a group of metabolic disorders characterized by hyperglicemia as a result of insulin secretion failure and/or lacking of insulin action on target cells. The chronic diabetic hyperglicemic state has been related to long-term organ damage especially to the heart, endothelium and blood vessels, nerves, kidney, and eyes [17][18][19].

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Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

2020

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Introduction Rigorous research in the last few years has shown that in addition to the classical mechanism of neurodegeneration, certain unconventional mechanisms may also lead to neurodegenerative disease. One of them is a widely studied metabolic disorder: type 2 diabetes mellitus (T2DM). We now have a clear understanding of glucose‐mediated neurodegeneration, mostly from studies in Alzheimer's disease (AD) models. AD is recognized to be significantly associated with hyperglycemia, even earning the term “type 3 diabetes.” Here, we review first the pathophysiology of AD, both from the perspective of classical protein accumulation, as well as the newer T2DM‐dependent mechanisms supported by findings from patients with T2DM. Secondly, we review the different pathways through which neurodegeneration is aggravated in hyperglycemic conditions taking AD as a case study. Finally, some of the current advances in AD management as a result of recent research developments in metabolic disorders‐driven neurodegeneration are also discussed. Methods Relevant literatures found from PubMed search were reviewed. Results Apart from the known causes of AD, type 2 diabetes opens a new window to the AD pathology in several ways. It is a bidirectional interaction, of which, the molecular and signaling mechanisms are recently studied. This is our attempt to connect all of them to draw a complete mechanistic explanation for the neurodegeneration in T2DM. Refer to Figure 3. Conclusion The perspective of AD as a classical neurodegenerative disease is changing, and it is now being looked at from a zoomed‐out perspective. The correlation between T2DM and AD is something observed and studied extensively. It is promising to know that there are certain advances in AD management following these studies.

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TLR4 is a link between diabetes and Alzheimer’s disease

Cited by 91 publications

References 126 publications

mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Neurodegeneration in type 2 diabetes: Alzheimer's as a case study

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