Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function

Coto, Eliécer; Díaz‐Corte, Carmen; Tranche, Salvador; Gómez, Juan Manuel López; Alonso, Belén; Iglesias, Sara; Reguero, Julián R.; López‐Larrea, Carlos; Coto-Segura, Pablo

doi:10.1016/j.humimm.2018.03.008

Cited by 35 publications

(29 citation statements)

References 36 publications

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“…5 We speculated that besides NF-κB signal pathway, Besides NLRs, NF-κB pathway activation has been acknowledged to be important in diabetes for altering cytokine secretion and antigen presentation in innate immune cells. 39,40 In the present study, we found NF-κB was activated by AGEs stimulation. After blocking NF-κB signal pathway, increased expression of pro-inflammatory cytokine (IL-1β), NLRP1, NLRP3, and ASC induced by AGEs was down-regulated, indicating that AGEs activate NLRP1-and NLRP3inflammasome through NF-κB signal pathway, and finally inducing inflammation.…”

Section: Discussionsupporting

confidence: 62%

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The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

Zhang

et al. 2019

J of Periodontal Research

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Background and Objective Diabetes influences the frequency and development of periodontitis. Inflammation of human periodontal ligament cells (HPDLCs) participates in this pathologic process. Hence, this study aims to explore whether advanced glycation end products (AGEs), by‐products of diabetes, could exaggerate inflammation induced by muramyl dipeptide (MDP) in HPDLCs, and whether nucleotide‐binding oligomerization domain‐like receptors (NLRs) signaling pathway was involved. Material and Methods Human periodontal ligament cells were pre‐treated with 100 μg/mL AGEs for 24 hours and stimulated with 10 μg/mL MDP for 24 hours. IL‐6, IL‐1β, and RAGE were detected, and the activation of NF‐κB signaling pathway was observed. The expression of NLRs was evaluated with or without silencing RAGE or blocking NF‐κB pathway under AGEs stimulation. Statistical analyses were performed by using independent sample t test. Results Advanced glycation end products induced significant increase of inflammatory cytokines in HPDLCs (P < 0.05). Results of western blot (WB) showed that after 45 minutes stimulation of AGEs, p‐p65/p65 ratio peaked; AGEs promoted the expression of NLRP1, NLRP3, and apoptosis‐associated speck‐like protein containing a CARD (ASC). After silencing RAGE or blocking NF‐κB pathway, the up‐regulation of NLRs protein caused by AGEs was attenuated. Additionally, AGEs pre‐treatment could enhance the inflammatory response of MDP and the expression of NLRs, which were demonstrated by more expression of IL‐6, IL‐1β, NOD2, NLRP1, NLRP3, and ASC. Conclusion Advanced glycation end products induced inflammatory response in HPDLCs via NLRP1‐inflammasome and NLRP3‐inflammasome activation in which NF‐κB signal pathway was involved. Besides, AGEs promoted the inflammatory response of MDP via NOD2, NLRP1‐inflammasome, and NLRP3‐inflammasome.

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Section: Discussionsupporting

confidence: 62%

“…Besides NLRs, NF‐κB pathway activation has been acknowledged to be important in diabetes for altering cytokine secretion and antigen presentation in innate immune cells . In the present study, we found NF‐κB was activated by AGEs stimulation.…”

Section: Discussionsupporting

confidence: 59%

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

Zhang

et al. 2019

J of Periodontal Research

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“…It has been shown that activated NF‐κB could bind to miR‐448 promoter inhibiting its expression in breast cancer cells . Additionally, in T2D, inflammatory response was induced by various stimuli pathway including LPS/TLR4 concomitantly with the activation of NF‐κB . However, it is unclear whether the decreased miR‐448 in diabetic macrophages is attributed to activated NF‐κB or other regulation mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…[37] Additionally, in T2D, inflammatory response was induced by various stimuli pathway including LPS/ TLR4 concomitantly with the activation of NF-jB. [38] However, it is unclear whether the decreased miR-448 in diabetic macrophages is attributed to activated NF-jB or other regulation mechanisms. Thus, more mechanistic studies need to be performed to address the outstanding issue in the future study.…”

Section: Discussionmentioning

confidence: 99%

Suppression of TLR4 by miR-448 is involved in Diabetic development via regulating Macrophage polarization

Zhao

Wang

et al. 2018

Journal of Pharmacy and Pharmacology

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Objectives Lipopolysaccharide (LPS) contributed to the development and progression of type 2 diabetes mellitus (T2D), while TLR4 is reported to mediate the LPS‐induced inflammation in macrophages. However, the potential molecular mechanisms for TLR4‐mediated macrophages activation in T2D have not yet to be fully clarified. Methods Type 2 diabetes models in C57BL/6J mice were generated by a combination administration of streptozotocin (STZ) and a high‐fat diet (HFD). Cell proportions of M1 and M2 macrophages were analyzed using flow cytometry. Expression profiles of miR‐448 and TLR 4 were determined by qRT‐PCR and Western blot. Key findings LPS/IFN‐γ significantly induced M1 polarization in macrophages characterized by the increased levels of TNF‐α, IL‐6, IL‐12, iNOS and decreased levels of TNF‐β, CCL‐22, IL‐10 and Arg‐1, with a higher expression of toll‐like receptor 4 (TLR4) in vitro. Consistently, T2D mice‐derived macrophages had a significantly elevated expression of TLR4 mRNA and decreased expression of miR‐448. We further confirmed that miR‐448 could inhibit TLR4 expression by targeting the 3′‐UTR of TLR4, rescuing the LPS/IFN‐γ‐induced M1 macrophage polarization. Conclusions Taken together, our results indicated that decreased miR‐448 in diabetic macrophages may contribute to LPS‐induced M1 polarization by targeting TLR4, thereby modulating T2D development.

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“…It is specifically involved in anti-inflammatory effects, and that inflammation is linked to insulin resistance and diabetes. Two common NFKB1 variants were found to be involved in T2D in an elderly cohort [85]. A transcriptome and proteome study demonstrated that NFKB1 were increased in expression in diabetic subjects [86].…”

Section: Compound-target-pathway (Ctp) Network and Main Active Constimentioning

confidence: 97%

A systematic analysis of natural α-glucosidase inhibitors from flavonoids of Radix scutellariae using ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology

Wang

Tan

Wang

et al. 2020

BMC Complement Med Ther

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Background: Flavonoids from plant medicines are supposed to be viable alternatives for the treatment of type 2 diabetes (T2D) as less toxicity and side effects. Radix scutellariae (RS) is a widely used traditional medicine in Asia. It has shown great potential in the research of T2D. However, the pharmacological actions remain obscured due to the complex chemical nature of plant medicines.Methods: In the present study, a systematic method combining ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology was developed to screen α-glucosidase inhibitors from flavonoids of RS, and explore the underlying mechanism for the treatment of T2D.Results: The n-butanol part of ethanol extract from RS showed a strong α-glucosidase inhibition activity (90.55%, IC 50 0.551 mg/mL) against positive control acarbose (90.59%, IC 50 1.079 mg/mL). A total of 32 kinds of flavonoids were identified from the extract, and their ESI-MS/MS behaviors were elucidated. Thirteen compounds were screened as α-glucosidase inhibitors, including viscidulin III, 2′,3,5,6′,7-pentahydroxyflavanone, and so on. A compound-target-pathway (CTP) network was constructed by integrating these α-glucosidase inhibitors, target proteins, and related pathways. This network exhibited an uneven distribution and approximate scale-free property. Chrysin (k = 87), 5,8,2′-trihydroxy-7-methoxyflavone (k = 21) and wogonin (k = 20) were selected as the main active constituents with much higher degree values. A protein-protein interaction (PPI) weighted network was built for target proteins of these α-glucosidase inhibitors and drug targets of T2D. PPARG (C d = 0.165, C b = 0.232, C c = 0.401), ACACB (C d = 0.155, C b = 0.184, C c = 0.318), NFKB1 (C d = 0.233, C b = 0.161, C c = 0.431), and PGH2 (C d = 0.194, C b = 0.157, C c = 0.427) exhibited as key targets with the highest scores of centrality indices. Furthermore, a core subnetwork was extracted from the CTP and PPI weighted network. Type II diabetes mellitus (hsa04930) and PPAR signaling pathway (hsa03320) were confirmed as the critical pathways.(Continued on next page) Conclusions: These results improved current understanding of natural flavonoids on the treatment of T2D. The combination of ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology provides a novel strategy for the research of plant medicines and complex diseases.

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Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function

Cited by 35 publications

References 36 publications

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

Suppression of TLR4 by miR-448 is involved in Diabetic development via regulating Macrophage polarization

A systematic analysis of natural α-glucosidase inhibitors from flavonoids of Radix scutellariae using ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology

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