Aberrant regulation in mesangial cell proliferation, extracellular matrix (ECM) accumulation, oxidative stress, and inflammation under hyperglycemic condition contributes significantly to the ...occurrence and development of diabetic nephropathy (DN). However, the mechanisms underlying the hyperglycemia‐induced dysregulations have not been clearly elucidated. Here, we reported that high mobility group box 1 (HMGB1) was highly elevated in high glucose (HG)‐treated mesangial cells, and induced the phosphorylation, nuclear translocation, and DNA binding activity of NF‐κB via toll‐like receptor 4 (TLR4). Function assays showed that inhibition of HMGB1 mitigated HG‐induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via TLR4/NF‐κB pathway. Increasing evidence has shown that circRNA, a large class of noncoding RNAs, functions by binding with miRNAs and terminating regulation of their target genes. We further investigated whether HMGB1 is involved in circRNA–miRNA–mRNA regulatory network. First, HMGB1 was identified and confirmed to be the target of miR‐205, and miR‐205 played a protective role against HG‐induced cell injure via targeting HMGB1. Then circLRP6 was found to be upregulated in HG‐treated mesangial cells, and regulate HG‐induced mesangial cell injure via sponging miR‐205. Besides, overexpression of miR‐205 or knockdown of circLRP6 inhibited the NF‐κB signaling pathway. Collectively, these data suggest that circLRP6 regulates HG‐induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via sponging miR‐205, upregulating HMGB1 and activating TLR4/NF‐κB pathway. These findings provide a better understanding for the pathogenesis of DN.
1.
Inhibition of high mobility group box 1 (HMGB1) mitigated high glucose (HG)‐induced proliferation, oxidative stress, extracellular matrix (ECM) accumulation, and inflammation in mesangial cells via TLR4/NF‐κB pathway.
2.
HMGB1 was identified and confirmed to be the target of miR‐205, and miR‐205 played a protective role against HG‐induced cell injure via targeting HMGB1.
3.
circLRP6 regulates HG‐induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via sponging miR‐205, upregulating HMGB1 and activating TLR4/NF‐κB pathway.
The toll‐like receptor (TLR) family consists of vital receptors responsible for pattern recognition in innate immunity, making them the core proteins involved in pathogen detection and eliciting ...immune responses. The most studied member of this family, TLR4, has been the center of attention regarding its contributory role in many inflammatory diseases including sepsis shock and asthma. Notably, mounting pieces of evidence have proved that this receptor is aberrantly expressed on the tumor cells and the tumor microenvironment in a wide range of cancer types and it is highly associated with the initiation of tumorigenesis as well as tumor progression and drug resistance. Cancer therapy using TLR4 inhibitors has recently drawn scientists’ attention, and the promising results of such studies may pave the way for more investigation in the foreseeable future. This review will introduce the key proteins of the TLR4 pathway and how they interact with major growth factors in the tumor microenvironment. Moreover, we will discuss the many aspects of tumor progression affected by the activation of this receptor and provide an overview of the recent therapeutic approaches using various TLR4 antagonists.
Toll‐like receptor‐4 is often overexpressed in various cancer cells which leads to cancer progression through different mechanisms such as metastasis and drug‐resistance induction. Moreover, this receptor shows cross‐talks with different growth factors in the tumor microenvironment that further affects the malignant cells.
Scope
In this study, it has been investigated whether the neuroprotective efficacy of epigallocatechin‐3‐gallate (EGCG) is mediated by inhibition of canonical and noncanonical inflammasome activation ...via toll‐like receptor 4 (TLR4)/NF‐κB pathway both in LPS+Aβ‐induced microglia in vitro and in APP/PS1 mice in vivo.
Methods and results
In BV2 cells, EGCG inhibits the expressions of Iba‐1, cleaved IL‐1β, and cleaved IL‐18 induced by LPS+Aβ. Then, the supernatants are used to treat SH‐SY5Y cells, and EGCG treatment significantly recovers the neurotoxicity from LPS+Aβ‐induced microglial conditioned media. Subsequently, it has been found that EGCG reduces the microglial expressions of caspase‐1 p20, NLRP3, and caspase‐11 p26. Furthermore, the expression levels of Toll‐like receptor 4 (TLR4), p‐IKK/IKK, and p‐NF‐κB/NF‐κB were decreased after EGCG treatment. As expected, when a caspase‐1 specific inhibitor Z‐YVAD‐FMK, and an IKK and caspase‐11 inhibitor wedelolactone are used for blocking, Z‐YVAD‐FMK and wedelolactone exacerbate the inhibitory efficacy than using EGCG alone. Finally, consistent with the results obtained in BV2 cells, EGCG treatment reduces microglial inflammation and neurotoxicity by suppressing the activation of canonical NLRP3 and noncanonical caspase‐11‐dependent inflammasome via TLR4/NF‐κB pathway in LPS+Aβ‐induced rat primary microglia and hippocampus of APP/PS1 mice.
Conclusion
EGCG attenuates microglial inflammation and neurotoxicity by inhibition of canonical NLRP3 and noncanonical caspase‐11‐dependent inflammasome activation via TLR4/NF‐κB pathway.
Epigallocatechin‐3‐gallate (EGCG) inhibits LPS and Aβ‐induced activation of canonical NLRP3 inflammasome and noncanonical caspase‐11‐mediated inflammasome via TLR4/NF‐κB signaling pathway, thereby attenuating the microglial inflammation and neurotoxicity in Alzheimer's disease.
Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative ...bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of
E. coli.
In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.
Inflammatory bowel disease (IBD) is a lifelong and recurrent disease of the gastrointestinal tract that afflicts many people in the world. Growing evidence has currently indicated that dysfunction of ...immune system, particularly toll‐like receptors 4 (TLR4) signaling pathway dysfunction plays a pivotal part in the pathogenesis of IBD. TLR4 signaling is involved both in the pathogenesis and in the efficacy of treatment of IBD. There are some medicinal products and herbal medicines, which their role in the treatment of IBD through modulation of TLR4 signaling has been implicated. The purpose of this review article is to summarize those medicinal products and herbal medicines.
The vital roles of some circular RNA (circRNA) have been reported to be associated with atherosclerosis (AS). In this paper, we explored the function of circ_0005699 in AS.
The 3-(4, ...5-dimethyl-2-thiazolyl)−2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2′-deoxyuridine (EdU) assay were applied to evaluate cell proliferation. The flow cytometry assay uncovered cell apoptosis. The ELISA and tube formation assay were implemented to assess cell inflammatory response and angiogenesis. The circ_0005699, microRNA-636 (miR-636) and toll-like receptor 4 (TLR4) abundances were measured by qRT-PCR and western blot in serum specimens and HUVECs. The Bcl2-associated X, apoptosis regulator (Bax), Cleaved-caspase-3, p-P65, P65, p-lkBα, and lkBα levels were quantified by western blot. The binding sites of miR-636 and circ_0005699 or TLR4 were uncovered by dual-luciferase reporter assay and RNA Binding Protein Immunoprecipitation (RIP) assay.
Circ_0005699 and TLR4 abundances were up-regulated but miR-636 abundance was down-regulated in AS serum specimens and HUVECs with ox-LDL treatment. Circ_0005699 knockdown impaired ox-LDL-mediated repression of proliferation and angiogenesis, as well as promotion of apoptosis and inflammatory response in HUVECs. Circ_0005699 activated the NF-κB signaling via up-regulating TLR4 by functioning as a miR-636 sponge molecular.
Circ_0005699 participated in ox-LDL-induced HUVEC injury via miR-636/TLR4/NF-κB axis, which might provide different thinking to cure AS.
•The abundance of circ_0005699 was enhanced in serum of AS cases.•Circ_0005699 silencing lessened ox-LDL-induced HUVEC injury.•Circ_0005699 participated in ox-LDL-induced HUVEC injury via targeting the miR-636/TLR4/NF-κB axis.
Atherosclerosis is one type of cardiovascular disease (CVD) in which activation of the NLRP3 inflammasome and toll-like receptor (TLR) pathways is implicated. One of the most effective treatments for ...atherosclerosis is the use of statin medications. Recent studies have indicated that statins, in addition to their lipid-lowering effects, exert inhibitory and/or stimulatory effects on the NLRP3 inflammasome and TLRs. Some of the statins lead to activation of the inflammasome and subsequently cause secretion of IL-1β and IL-18. Thus, these actions may further aggravate the disease. On the other hand, some statins cause inhibition of the inflammasome or TLRs and along with lipid-lowering, help to improve the disease by reducing inflammation. In this article, we discuss these contradictory studies and the mechanisms of action of statins on the NLRP3 inflammasome and TLR pathways. The dose-dependent effects of statins on the NLRP3 complex are related to their chemistry, pharmacokinetic properties, and danger signals. Lipophilic statins have more pleiotropic effects on the NLRP3 complex in comparison to hydrophilic statins. Statins can suppress TLR4/MyD88/NF-ĸB signaling and cause an immune response shift to an anti-inflammatory response. Furthermore, statins inhibit the NF-ĸB pathway by decreasing the expression of TLRs 2 and 4. Statins are cost-effective drugs, which should have a continued future in the treatment of atherosclerosis due to both their immune-modulating and lipid-lowering effects.
Lipopolysaccharide (LPS), commonly known as endotoxin, is ubiquitous and the most-studied pathogen-associated molecular pattern. A component of Gram-negative bacteria, extracellular LPS is sensed by ...our immune system via the toll-like receptor (TLR)-4. Given that TLR4 is membrane bound, it recognizes LPS in the extracellular milieu or within endosomes. Whether additional sensors, if any, play a role in LPS recognition within the cytoplasm remained unknown until recently. The last decade has seen an unprecedented unfolding of TLR4-independent LPS sensing pathways. First, transient receptor potential (TRP) channels have been identified as non-TLR membrane-bound sensors of LPS and, second, caspase-4/5 (and caspase-11 in mice) have been established as the cytoplasmic sensors for LPS. Here in this review, we detail the brief history of LPS discovery, followed by the discovery of TLR4, TRP as the membrane-bound sensor, and our current understanding of caspase-4/5/11 as cytoplasmic sensors.
Sepsis‐induced myocardial dysfunction (SIMD) causes high mortality in seriously ill patients. Ginsenoside Rg1 has been proven to have effective anti‐inflammatory and antiapoptotic properties. ...However, the specific role of Rg1 in SIMD and the molecular mechanism remain unclear. Hence, we aimed to investigate the latent effects of ginsenoside Rg1 against SIMD and explore its underlying mechanisms. Male C57BL/6J mice and neonatal rat cardiomyocytes (NRCMs) were used as in vivo and in vitro models, respectively. Western blot analysis was used to detect the level of protein expression, and reverse transcription polymerase chain reaction was conducted to determine the messenger RNA expression of inflammatory factors. The terminal deoxynucleotidyl transferase‐mediated nick end labeling assay and flow cytometry were used to determine the apoptosis rate. Echocardiography was performed to assess cardiac function. The results showed that Rg1 improved cardiac function and attenuated lipopolysaccharide (LPS)‐induced apoptosis and inflammation in mice. In addition, in NRCMs, Rg1 downregulated the expression of LPS‐induced inflammatory cytokines and reversed the increased expression of Toll‐like receptor 4 (TLR4), nuclear factor‐κB (NF‐κB), and NOD‐like receptor 3 (NLRP3). In addition, treatment with TLR4 small interfering RNA (siRNA), a p‐NF‐κB inhibitor, or NLRP3 siRNA suppressed LPS‐induced apoptosis and inflammation. In conclusion, Rg1 can attenuate LPS‐induced inflammation and apoptosis both in NRCMs and septic mice and restore impaired cardiac function. Moreover, Rg1 may exert its effect via blocking the TLR4/NF‐κB/NLRP3 pathway.
Via experiments, we found that Rg1 could attenuate lipopolysaccharide induced inflammation and apoptosis both in neonatal rat cardiomyocytes and septic mice and restore the impaired cardiac function. Moreover, Rg1 exerted its role may via blocking Toll‐like receptor 4 TLR4/nuclear factor‐κB/NOD‐like receptor 3 pathway.
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