Thioredoxin interacting protein,a key molecular switch between oxidative stress and sterile inflammation in cellular response

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

Polypeptide from Moschus Suppresses Lipopolysaccharide-Induced Inflammation by Inhibiting NF-κB-ROS/NLRP3 Pathway

Objective To examine the anti-inflammatory effects and potential mechanisms of polypeptide from Moschus(PPM)in lipopolysaccharide(LPS)-induced THP-1 macrophages and BALB/c mice.Methods The polypeptide was extracted from Moschus and analyzed by high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE).Subsequently,LPS was used to induce inflammation in THP-1 macrophages and BALB/c mice.In LPS-treated or untreated THP-1 macrophages,cell viability was observed by cell counting kit 8 and lactate dehydrogenase release assays;the proinflammatory cytokines and reactive oxygen species(ROS)were measured by enzyme-linked immunosorbent assay and flow cytometry,respectively;and protein and mRNA levels were measured by Western blot and real-time quantitative polymerase chain reaction(qRT-PCR),respectively.In LPS-induced BALB/c mice,the proinflammatory cytokines were measured,and lung histology and cytokines were observed by hematoxylin and eosin(HE)and immunohistochemical(IHC)staining,respectively.Results The SDS-PAGE results suggested that the molecular weight of purified PPM was in the range of 10–26 kD.In vitro,PPM reduced the production of interleukin 1β(IL-1β),IL-18,tumor necrosis factorα(TNF-α),IL-6 and ROS in LPS-induced THP-1 macrophages(P<0.01).Western blot analysis demonstrated that PPM inhibited LPS-induced nuclear factorκB(NF-κB)pathway and thioredoxin interacting protein(TXNIP)/nucleotide-binding oligomerization domain,leucine-rich repeat and pyrin domain containing 3(NLRP3)inflammasome pathway by reducing protein expression of phospho-NF-κB p65,phospho-inhibitors of NF-κB(IκBs)kinaseα/β(IKKα/β),TXNIP,NLRP3,apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),and pro-caspase-1(P<0.05 or P<0.01).In addition,qRT-PCR revealed the inhibitory effects of PPM on the mRNA levels of TXNIP,NLRP3,ASC,and caspase-1(P<0.05 or P<0.01).Furthermore,in LPS-induced BALB/c mice,PPM reduced TNF-αand IL-6 levels in serum(P<0.05 or P<0.01),decreased IL-1βand IL-18 levels in the lungs(P<0.01)and alleviated pathological injury to the lungs.Conclusion PPM could attenuate LPS-induced inflammation by inhibiting the NF-κB-ROS/NLRP3 pathway,and may be a novel potential candidate drug for treating inflammation and inflammation-related diseases.