Inflammation in Cardiovascular Disease: Current Status and Future Perspectives

Abstract Atherosclerosis has been defined as an inflammatory disease. Three decades of research have pointed to a pivotal role of interleukin 6 for many aspects of cardiovascular disease, not the least of which is atherosclerosis. In this review, experimental and clinical studies are reported on a timeline, exploring mechanisms and possible explanations that form the basis of current knowledge. Some successful clinical trials were proof of concept studies, showing that not only inflammatory biomarkers are related to cardiovascular outcomes, but also that decreasing inflammation can reduce cardiovascular events. Great advances have been made in the management of residual cardiovascular risk due to cholesterol, thrombosis, and metabolic diseases, but the next frontier now seems to be targeting inflammation. In the upcoming years, the importance of inflammation will be evaluated in high-risk patients with chronic kidney disease, after acute coronary heart disease or heart failure with preserved ejection fraction. Inflammation seems to precede the development of cardiovascular risk factors. Moreover, counseling for a heathy lifestyle and, when necessary, the use of cardiometabolic therapies capable of decreasing inflammation, might be important.

Metabolic regulation of Nod-like receptor protein 3 inflammasome and its role in renal diseases / 中华肾脏病杂志

In recent years, with the development of metabolic reprogramming research, people have changed their understanding of the biological effects of immune cells. Under the stimulation of inflammatory response, immune cells re-regulate their metabolism and bioenergetics, provide energy and substrates for cell survival, and initiate immune effect functions. Nod-like receptor protein 3 (NLRP3) inflammasome, as an important component of the innate immune system, has been shown to sense metabolites such as uric acid and cholesterol crystals, and can be inhibited by metabolites such as ketones. It is also regulated by mitochondrial reactive oxygen species and glycolytic components (such as hexokinase). Recent studies have shown that a variety of metabolic pathways converge as effective regulators of NLRP3 inflammasome. The paper reviews the metabolic regulatory pathways and specificity of NLRP3 inflammasome activation, and its role in renal diseases.

Role of pyroptosis in nonalcoholic fatty liver disease / 临床肝胆病杂志

As a novel mode of cell death, pyroptosis plays an important role in nonalcoholic fatty liver disease (NAFLD), and the research on pyroptosis may help to explore new therapeutic targets for NAFLD. This article reviews the advances in pyroptosis from the research background and mechanism of pyroptosis and the role of pyroptosis in NAFLD and elaborates on the pyroptosis execution molecules such as GSDME and caspase-11 and the function of inflammasomes including AIM2.

Expresión de los componentes del inflamasoma y su relación con los marcadores de riesgo cardiovascular en personas con infección por HIV-1 / Expression of the inflammasome components and its relationship with cardiovascular risk markers in people living with HIV-1

Introducción. La infección por el HIV-1 induce un estado de inflamación crónico en el que participan los inflamasomas. El incremento de los parámetros inflamatorios es mayor en individuos con replicación viral activa que en aquellos con control de la replicación viral. Este proceso desencadena alteraciones metabólicas relacionadas con cambios en el perfil lipídico, lo cual podría incrementar el riesgo de eventos cardiovasculares, incluso en pacientes con terapia antirretroviral. Objetivo. Establecer si existe correlación entre la expresión de los componentes de los inflamasomas y los marcadores de riesgo cardiovascular en individuos con control de la replicación viral y en aquellos con replicación viral activa con terapia antirretroviral o sin ella. Materiales y métodos. Se estudiaron 13 individuos con control de la replicación viral y 40 con replicación viral activa (19 sin terapia antirretroviral y 31 con terapia). Se evaluaron los marcadores clásicos de riesgo cardiovascular y se cuantificó mediante RT-PCR la expresión de los componentes de los inflamasomas (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18 y caspasa-1), TLR2, TLR4, TGF-ß e IL-10. Resultados. Se observó que los pacientes con replicación viral activa y con terapia antirretroviral presentaron un incremento en la expresión de TLR2, TLR4 e IL-18, comparados con los controladores del HIV-1. Además, mostraron grandes valores de triglicéridos y lipoproteína de muy baja densidad (Very Low Density Lipopretein, VLDL), lo que se correlaciona positivamente con la expresión de los componentes de los inflamasomas NLRP1, NLRP3, NLRC4, AIM2, ASC y caspasa-1. Conclusión. El aumento en la expresión de los componentes de los inflamasomas en los individuos con replicación viral activa y con terapia antirretroviral se correlacionó con las concentraciones de triglicéridos y VLDL, lo que sugiere el papel de la activación inmunitaria y la terapia antirretroviral en el riesgo cardiovascular.

Introduction: HIV-1 infection induces a chronic inflammatory state in which inflammasomes participate. The increase in inflammatory parameters is higher in individuals with active viral replication (progressors) than in those with viral control (HIV-1 controllers). This process triggers metabolic alterations related to changes in the lipid profile, which could increase the risk of cardiovascular events, even in patients with antiretroviral therapy. Objective: To establish whether there was a correlation between the expression of inflammasome components and cardiovascular risk markers in HIV-1 controllers and progressors with or without antiretroviral therapy. Materials and methods: We studied 13 HIV-1 controllers and 40 progressors (19 without antiretroviral therapy and 31 with therapy) and evaluated in them classic markers of cardiovascular risk. Using RT-PCR we quantified the expression of inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18, and caspase-1), TLR2, TLR4, TGF-ß, and IL-10. Results: Progressors with antiretroviral therapy had an increased expression of TLR2, TLR4, and IL-18 compared to HIV-1 controllers. They also showed high levels of triglycerides and VLDL, which positively correlated with the expression of the inflammasome components NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1. Conclusion: Progressors receiving antiretroviral therapy exhibited an increased expression of the inflammasome components, which correlated with the levels of triglycerides and VLDL. This supports the role of inflammation in cardiovascular risk during HIV-1 infection.

Hydrogen sulfide protects against contrast-induced acute kidney injury via regulation of NLRP3 inflammasome / 中华肾脏病杂志

Objective:To investigate the level of endogenous hydrogen sulfide (H 2S) in contrast-induced acute kidney injury (CIAKI), as well as the potential role of H 2S against CIAKI by down-regulating NLRP3 inflammasome. Methods:Twenty-four healthy male Sprague-Dawley rats, weighing 180-220 g, were randomly divided into three groups according to the random number table method: control group, CIAKI group (iopromide 2.9 g/kg) and CIAKI+NaHS group (NaHS 4 mg/kg for three days before 2.9 g/kg iopromide injection). Kidneys were collected for whole-genome sequencing and bioinformatic analysis. HE and PAS staining were used for kidney histological examination. TUNEL assays were applied to detect renal tubular epithelial injury. Expressions of NLRP3 inflammasome (NLRP3, ASC and caspase-1) were evaluated by immunofluorescence staining. The role of H 2S in contrast (iopromide 200 mgI/kg)-induced injury on human renal tubular epithelium (HK-2 cells) was investigated, and CCK-8 assay was used to detect cellular viability. Results:Compared with the control group, the expression of endogenous H 2S synthetases-related genes [cystathionine β-synthase ( CBS), cystathionine-γ-lyase ( CSE) and 3-mercaptopyruvate sulfurtransferase ( 3- MST)] was lower in CIAKI group (all P<0.05). The gene expression levels of CBS, CSE and 3- MST were negatively correlated with renal function biomarkers serum creatinine, blood urea nitrogen and cystatin-C (all P<0.05). Compared with the CIAKI group, CIAKI+NaHS group showed alleviated creatinine, blood urea nitrogen and cystatin-C, improved histological changes, reduced apoptosis. Moreover, the expression levels of NLRP3, ASC and caspase-1 in CIAKI+NaHS group were lower than those in CIAKI group (all P<0.05). In HK-2 cells, compared with the contrast group, the cellular viability was higher in the contrast+NaHS group; reducing endogenous H 2S by CBS inhibitor could enhance contrast-induced cell viability ( P<0.05). Conclusions:Injury of endogenous H 2S system is pivotal to CIAKI pathogenesis. Up-regulation of H 2S ameliorates renal injury of CIAKI rats, which may be related to regulation of NLRP3 inflammasome.

NLRP3 inflammasome and its role in age-related macular degeneration / 中华实验眼科杂志

Age-related macular degeneration (AMD), the leading cause of central vision loss among people aged 50 years and older, is one of the major eye diseases causing blindness in the world.Clinically, advanced AMD is divided into two types, non-exudative AMD with manifestation of geographic atrophy and exudative AMD with manifestation of choroidal neovascularization.The pathogenesis of AMD is complex, and the para-inflammation is recognized as an important risk factor.Nucleotide-binding oligomerization domain like receptors 3 (NLRP3) inflammasome is a cytoplasmic pattern recognition receptor and is expressed in several kings of cells, including retinal pigment epithelium (RPE) cells, microglial cells, Müller glia cells and retinal vascular endothelial cells.Recent studies have suggested that NLRP3 inflammasome plays an important role in the pathophysiology of both non-exudative and exudative AMD.The role of the NLRP3 inflammasome and its effector cytokines interleukin (IL)-1β and IL-18 in AMD were reviewed in this article to provide guidance on future prevention and therapy of AMD.

Effect of ROS/NLRP3/Caspase-1 signaling pathway on the apoptosis of retinal pigment epithelial cells induced by high glucose / 中华实验眼科杂志

Objective:To investigate the effect of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 (NLRP3) inflammasome on the proliferation and apoptosis of human retinal pigment epithelial cell line ARPE-19 exposed to high glucose and its mechanism.Methods:ARPE-19 cells cultured in vitro were divided into normal control group and high-glucose group, and were cultured in conventional medium and medium containing 30 mmol/L glucose for 48 hours, respectively.The content of reactive oxygen species (ROS) were detected by fluorescent probe, and the activity of superoxide dismutase (SOD) and the concentration of malondialdehyde (MDA) were tested by biochemical assay.The cells of the two groups were cultured with 0, 2, 5, 10, 15 and 20 μmol/L NLRP3 inhibitor CY-09 for 48 hours, respectively.The proliferation rate of ARPE-19 cells under various concentrations of CY-09 treatment was detected by cell counting kit-8, and the appropriate concentration of CY-09 was determined.ARPE-19 cells were divided into normal control group, normal+ CY-09 group, high-glucose group and high glucose+ CY-09 group.The culture medium in the normal+ CY-09 group and high glucose+ CY-09 group was supplemented with 15 μmol/L CY-09.Flow cytometry was used to detect the apoptosis rate of each group, and Western blot was used to detect the relative expression levels of NLRP3, apoptosis-associated point protein (ASC), Caspase-1 precursor (pro-Caspase-1) and active fragments (cleaved-Caspase-1), B lymphocytoma-2 protein (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3 precursor (pro-Caspase-3) and active fragments (cleaved-Caspase-3). Results:The intensity of ROS fluorescence and MDA concentration were 120 020±3 245, (4.92±0.09) nmol/mg in the high-glucose group, which were both significantly higher than 35 426±811 and (1.78±0.03) nmol/mg in the normal control group, and the SOD activity was (35.65±1.22) μmol/(min·mg) in the high-glucose group, which was significantly lower than (74.96±1.41) μmol/(min·mg) in the normal control group, showing statistically significant differences between the two groups ( t=35.760, 46.960, 29.830; all at P<0.05). The proliferation rate of RPE cells in high-glucose group was significantly lower than that in normal control group, and the difference was statistically significant ( t=18.820, P<0.05). With the increase of CY-09 concentration, the proliferation rate of cells in the high-glucose group was gradually increased.The proliferation rates of cells treated with 10, 15 and 20 μmol/L CY-09 were all significantly higher than those treated with 0 μmol/L CY-09, showing statistically significant differences between them (all at P<0.05). The proliferation rates of cells treated with 15 μmol/L and 0 μmol/L CY-09 were not significantly different in the normal control group ( P>0.05). The apoptosis rate of cells in the high-glucose group was (21.68±0.41)%, which was significantly higher than (6.67±1.05)% in the normal control group and (13.96±0.07)% in the high-glucose+ CY-09 group, and the differences were statistically significant (both at P<0.05). The relative expression levels of NLRP3, ASC, cleaved-Caspase-1, cleaved-Caspase-3 and Bax proteins were significantly higher and the relative expression levels of Bcl-2 protein was significantly lower in the high-glucose group compared with the normal control group, and the differences were statistically significant (all at P<0.05). The relative expression levels of NLRP3, ASC, the active fragment of cleaved-Caspase-1, Bax and cleaved-Caspase-3 proteins were decreased and the relative expression levels of Bcl-2 protein were increased in the normal+ CY-09 group and high glucose+ CY-09 group compared with the normal control group and high glucose group, and the differences were statistically significant (all at P<0.05). Conclusions:NLRP3 inflammasome mediates the high glucose induced RPE cells apoptosis through ROS/NLRP3/Caspase-1 signaling pathway.

Role of NLRP3 inflammasome signaling pathway in the occurrence and development of diabetic keratopathy / 中华实验眼科杂志

Diabetic keratopathy is a chronic complication of diabetes caused by abnormal metabolites accumulation, oxidative stress, abnormal inflammation and corneal neuropathy.It can result in delayed corneal epithelial healing and decreased corneal sensitivity under the stimulation of ocular trauma or surgery which bring great challenges to clinicians.Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammatory is one of the factors that cause chronic complications of diabetes, and is also an important factor for delaying the healing of diabetic wounds.The NLRP3 inflammatory signaling pathway is closely related to corneal oxidative stress, delayed epithelium healing and development of corneal neuropathy.In this paper, the research status and prospects of NLRP3 inflammatory signaling pathway and diabetic keratopathy were reviewed to provide new ideas for studying the mechanism and treatment of diabetic keratopathy.

PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis

Abstract Background: Phospholipase C-like 1 (PLCL1), a protein that lacks catalytic activity, has similar structures to the PLC family. The aim of this research was to find the function and underlying mechanisms of PLCL1 in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA). Methods: In this study, we first analyzed the expression of PLCL1 in the synovial tissue of RA patients and K/BxN mice by immunohistochemical staining. Then silencing or overexpressing PLCL1 in FLS before stimulating by TNF-α. The levels of IL-6, IL-1β and CXCL8 in FLS and supernatants were detected by Western Blot (WB), Real-Time Quantitative PCR and Enzyme Linked Immunosorbent Assay. We used INF39 to specifically inhibit the activation of NLRP3 inflammasomes, and detected the expression of NLRP3, Cleaved Caspase-1, IL-6 and IL-1β in FLS by WB. Result: When PLCL1 was silenced, the level of IL-6, IL-1β and CXCL8 were down-regulated. When PLCL1 was overexpressed, the level of IL-6, IL-1β and CXCL8 were unregulated. The previous results demonstrated that the mechanism of PLCL1 regulating inflammation in FLS was related to NLRP3 inflammasomes. INF39 could counteract the release of inflammatory cytokines caused by overexpression of PLCL1. Conclusion: Result showed that the function of PLCL1 in RA FLS might be related to the NLRP3 inflammasomes. We finally confirmed our hypothesis with the NLRP3 inhibitor INF39. Our results suggested that PLCL1 might promote the inflammatory response of RA FLS by regulating the NLRP3 inflammasomes.

Expression mechanism and clinical significance of absent in melanoma 2 in liver diseases / 临床肝胆病杂志

Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA (dsDNA) sensing protein that can recognize the dsDNA released during cell disturbance and pathogen invasion and trigger the activation of inflammasome cascade. Activation of inflammasomes leads to the maturation and release of inflammatory cytokines (interleukin-1β and interleukin-18), induces pyroptosis, and initiate innate immune response. Among these inflammasomes, AIM2 and its mechanism of action and clinical significance in liver diseases has become a research hotspot at present. This article summarizes and discusses the importance of AIM2 in the pathogenesis of various liver diseases including nonalcoholic fatty liver disease, hepatitis B virus infection, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, so as to provide new ideas and a reference for clinical treatment.

Expression mechanism and clinical significance of absent in melanoma 2 in liver diseases / 临床肝胆病杂志

Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA (dsDNA) sensing protein that can recognize the dsDNA released during cell disturbance and pathogen invasion and trigger the activation of inflammasome cascade. Activation of inflammasomes leads to the maturation and release of inflammatory cytokines (interleukin-1β and interleukin-18), induces pyroptosis, and initiate innate immune response. Among these inflammasomes, AIM2 and its mechanism of action and clinical significance in liver diseases has become a research hotspot at present. This article summarizes and discusses the importance of AIM2 in the pathogenesis of various liver diseases including nonalcoholic fatty liver disease, hepatitis B virus infection, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, so as to provide new ideas and a reference for clinical treatment.

The role of inflammatory molecules related to pyroptosis pathway in the pathogenesis of atopic dermatitis / 国际儿科学杂志

Atopic dermatitis(AD)is a common skin disease in pediatrics.It is a chronic inflammatory skin disease related to allergic diathesis that interacts with genetic and environmental factors.In about 60% of patients, the onset is before the age of one.With the deepening of research on the pathogenesis of AD, current research shows that pyroptosis-related inflammatory molecules may be involved in the occurrence and development of AD.Pyroptosis is a kind of regulated cell death accompanied by the release of inflammatory cytokines.It has been proven to play an important role in diseases such as atherosclerosis, diabetes, asthma, and inflammatory bowel disease.This article summarizes the role of inflammatory molecules related to pyroptosis pathway in the pathogenesis of atopic dermatitis, in order to deepen the understanding of the pathogenesis of atopic dermatitis and explore new therapies for it.

Danggui Shaoyaosan Inhibits Neuroinflammation in AD Rats by Regulating NLRP3/Caspase-1 Pathway / 中国实验方剂学杂志

Objective:To investigate the neuroprotective effect of Danggui Shaoyaosan （DSS） in a rat model of amyloid-<italic>β</italic>-peptide_1-42 （A<italic>β</italic>_1-42）-induced Alzheimer's disease （AD） as well as its regulatory effect on NOD-like receptor protein 3 （NLRP3）/cysteinyl aspartate-specific protease-1 （Caspase-1） signaling pathway. Method:The AD animal model was established via intracerebral injection of A<italic>β</italic>_1-42 and treated with different concentrations of DSS after the division of rats into the sham operation group， model group， as well as the high-， medium-， and low-dose DSS groups. Morris water maze test was conducted to determine the learning and memory abilities of rats. The morphology and function of neurons were detected by hematoxylin-eosin （HE） staining and Golgi staining， followed by immunofluorescence co-localization of NLRP3 inflammasome activation. The mRNA expression levels of interleukin （IL）-1<italic>β</italic> and IL-18 were measured by Real-time polymerase chain reaction （Real-time PCR）， and the protein expression levels of NLRP3， Caspase-1， and IL-1<italic>β </italic>were assayed by Western blot. Result:Compared with the sham operation group， the model group exhibited significantly decreased learning and memory abilities （<italic>P</italic><0.01）， impaired neuronal morphology and function， up-regulated IL-1<italic>β</italic> and IL-18 mRNA expression， enhanced NLRP3 inflammasome activation， and elevated NLRP3， Caspase-1， and IL-1<italic>β</italic> protein expression （<italic>P</italic><0.01）. Compared with the model group， DSS at both medium and high doses remarkably improved the learning and memory abilities of AD rats （<italic>P</italic><0.05， <italic>P</italic><0.01）， restored neuronal morphology and function， down-regulated the mRNA expression levels of inflammatory factors IL-1<italic>β</italic> and IL-18， reduced the activation of NLRP3 inflammasomes， and lowered the protein expression levels of NLRP3， Caspase-1， and IL-1<italic>β</italic> （<italic>P</italic><0.01）. Conclusion:DSS inhibits inflammasome activation and neuroinflammatory response possibly by regulating the NLRP3/Caspase-1 signaling pathway， thus exerting the neuroprotective effect.

Inhibitory effect of pills against diethylnitrosamine-induced hepatocarcinogenesis in rats / 南方医科大学学报

OBJECTIVE@#To study the inhibitory effect of pills (BJJ) agaisnt diethylnitrosamine (DEN)-induced hepatocarcinogenesis and explore the relation between this effect and the inflammasome signaling pathway.@*METHODS@#Sixty-five male SD rats were randomly divided into control group, DEN model group, and 3 BJJ treatment groups at low, medium and high dose (with daily dose of 0.55, 1.1 and 2.2 g/kg, respectively, for 12 consecutive weeks starting from the 5th week after modeling). The pathological changes of the liver tissue were observed with HE and Masson staining, and serum levels of alanine transaminase (ALT), glutamic oxaloacetic transaminase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL) of the rats were detected using ELISA. Oxidation stress in the liver tissue was assessed with ELISA, and Western blotting and ELISA were used to detect the molecular expressions of inflammasome-related pathway.@*RESULTS@#BJJ significantly inhibited tumor growth in the liver of the rats. HE and Masson staining showed that BJJ treatment obviously ameliorated liver fibrosis and reduced cancer cell and inflammatory cell infiltration in the liver. BJJ significantly reduced elevations of serum ALT, AST, ALP and TBIL levels, increased the contents of superoxide dismutase, catalase and glutathione peroxidase in the liver and suppressed malondialdehyde in Den-treated rats. BJJ also dose-dependently decreased the expressions of NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1, pro-IL-1β, pro-IL-18, IL-1β and IL-18 in the liver of Den-treated rats.@*CONCLUSIONS@#BJJ treatment can dose-dependently inhibit DEN-induced hepatocarcinogenesis by enhancing antioxidant capacity and down-regulating inflammatory-related pathways in rats.

Discussion of the promising effect of electroacupuncture on cognitive improvement in D-galactose-induced aging rats based on NLRP3-ASC-Caspase-1 signaling pathway / 针灸推拿医学（英文版）

Objective: To investigate the effect of electroacupuncture (EA) on cognitive function in D-galactose (D-gal)-induced aging rats, and the correlation between the effect and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3)-ASC-Caspase-1 signaling pathway. Methods: Forty-six male Sprague-Dawley (SD) rats were randomly divided into a control group (n=10), a model group (n=12), an EA-7 d group (n=12) and an EA-21 d group (n=12). Except the control group, the other three groups received 42 consecutive days of intraperitoneal injection of D-gal to establish aging rat models with cognitive dysfunction. The control group received the same amount of normal saline via intraperitoneal injection. Two EA groups were given EA therapy for 21 consecutive days (began from the 22nd day of modeling) or 7 consecutive days (began from the 36th day of modeling) accordingly at Dazhui (GV 14), Baihui (GV 20), Shenshu (BL 23) and Zusanli (ST 36). After modeling/ intervention, all four groups received behavioral evaluations by Morris water maze (MWM) test, novel object recognition (NOR) test and step-down passive avoidance (SDPA) test followed by the Western blot (WB) detection of the expression levels of hippocampal NLRP3 inflammasome-associated proteins NLRP3, ASC and Caspase-1. Results: MWM (place navigation test, PNT) results showed that the escape latency in the model group was significantly longer than that in the other three groups (P<0.05), and there was no significant difference among the other three groups on the 1st day of the test (P>0.05). From the 2nd day to the 4th day of the test, there was no significant difference between the EA-21 d group and the control group (P>0.05) in the escape latency; the escape latency was significantly shorter in the EA-21 d group than in the model group and the EA-7 d group (P<0.05). MWM (spatial probe test, SPT) results showed that the time spent in the target quadrant was significantly shorter and platform crossover number was significantly lower in the model group than in the other three groups (P<0.05). The time spent in the target quadrant was longer in the EA-7 d group than in the model group (P<0.05), but was shorter than that in the control group and the EA-21 d group (P<0.05). There was no significant difference in the swimming speed among the four groups (P>0.05). NOR results showed that there was no significant difference in the recognition ratio between the EA-7 d group and the EA-21 d group (P>0.05), and the recognition ratio was significantly higher in the two EA groups than in the model group (P<0.05), but was lower than in the control group (P<0.05). SDPA results showed that the electric shock number was higher in the model group than in the other three groups (P<0.05), and the differences among the other three groups were statistically insignificant (P>0.05). The model group had the shortest step-down latency, followed by the EA-7 d group, the EA-21 d group and the control group in order (P<0.05). The WB results indicated that the expression level of NLRP3 was significantly lower in the control group and the EA-21 d group than in the model group and the EA-7 d group (P<0.05). The expression levels of ASC and Caspase-1 were significantly higher in the model group than in the other three groups (P<0.05), and there was no significant difference among these three groups (P>0.05). Conclusion: NLRP3 inflammasome may be involved in the development of cognitive decline in aging rats; 7 consecutive days of EA intervention can partially improve the cognitive impairment in aging rats though the effect is rather limited; 21 consecutive days of EA intervention may improve the learning and memory abilities in aging rats via downregulating the expression levels of NLRP3 inflammasome-associated proteins in hippocampus.

NLRP3 inflammasomes and skin diseases / 中华皮肤科杂志

NOD-like receptor protein 3 (NLRP3) inflammasomes play an important role in innate immunity.It can induce the maturation and release of cytokines interleukin (IL)-1β and IL-18 by activating caspase-1,and participate in a variety of host immunoinflammatory responses.Once the regulation of NLRP3 inflammasomes is unbalanced,excessive IL-1β and IL-18 may be produced,triggering a series of inflammatory diseases.NLRP3 inflammasome activation plays important roles in skin diseases such as acne,psoriasis,pyoderma gangrenosum,polymyositis/dermatomyositis and bullous pemphigoid.This review summarizes research progress in NLRP3 inflammasomes in skin diseases.

Role of pyroptosis in the pathogenesis of acute pancreatitis / 临床肝胆病杂志

Acute pancreatitis (AP) is a common gastrointestinal disease and may lead to local complications and even multiple organ failure, and the pathogenesis of AP involves self-digestion of trypsin, inflammatory response, and microcirculation disturbance. This article introduces the role of pyroptosis in the pathogenesis of AP and briefly describes the activation pathway of pyroptosis, inflammasome, and the mechanism of action of effector molecules in inducing damage to the pancreas and extra-pancreatic organs. It is believed that the regulation of pyroptosis plays an important role in the pathogenesis of AP, which provides new ideas for the prevention and treatment of AP.

Epithelial PI3K-δ Promotes House Dust Mite-Induced Allergic Asthma in NLRP3 Inflammasome-Dependent and -Independent Manners

PURPOSE: Phosphoinositide 3-kinase (PI3K)-δ-dependent Akt activation is known to play critical roles in various immune responses of white blood cells in which PI3K-δ isoform is mostly expressed in contrast to the classes IA PI3Ks p110α and p110β. However, the immunological role of PI3K-δ isoform is still controversial in airway epithelium under house dust mite (HDM)-induced allergic response. This study aimed to evaluate the role of PI3K-δ isoform in HDM-induced allergic responses, focusing on NLRP3 inflammasome activation in airway epithelium.METHODS: We used wild-type mice and PI3K-δ knock-out (KO) mice for HDM-induced asthma animal model and also performed in vitro experiments using primary cultured murine tracheal epithelial cells and human airway epithelial cells.RESULTS: PI3K-δ activated HDM-induced NLRP3 inflammasome and epithelial cell-derived cytokines in the lung including airway epithelial cells. PI3K-δ KO mice or knock-down of PI3K-δ using siRNA exhibited the significant reduction in allergic asthmatic features and the suppression of NLRP3 inflammasome assembly as well as epithelial cell-derived cytokines. Interestingly, significantly increased expression of PI3K-δ isoform was observed in stimulated airway epithelial cells and the increases in epithelial cell-derived cytokines were markedly suppressed by blocking PI3K-δ, while these cytokine levels were independent of NLRP3 inflammasome activation.CONCLUSIONS: The results of this study suggest that PI3K-δ-isoform can promote HDM-induced allergic airway inflammation via NLRP3 inflammasome-dependent response as well as via NLRP3 inflammasome-independent epithelial cell activation.

Factores inmunológicos relacionados con VIH-1 en pacientes colombianos / Immunological Factors Related to HIV-1 in Colombian Patients / Fatores imunológicos relacionados com HIV-1 em pacientes colombianos

Resumen Introducción : los inflamasomas dirigen la maduración de las citoquinas IL-1b e IL-18, las cuales contribuyen en la patogénesis de la infección por VIH-1. Dada la complejidad de la infección, se hace necesaria la búsqueda de marcadores que permitan identificar nuevos blancos terapéuticos o hacer seguimiento del estado inmunológico de los pacientes. Por lo tanto, el objetivo del presente trabajo fue explorar el efecto independiente de los principales componentes inflamatorios sobre la infección por VIH-1. Materiales y métodos : estudio analítico con 36 pacientes VIH+ y 36 controles sanos, pareados por edad y sexo. Se cuantificó la carga viral, los linfocitos T CD4+/CD8+, el perfil lipídico, la proteína C reactiva y las concentraciones séricas de IL-1-ß, IL-6 e IL-18. El HIRNA de los genes relacionados con los inflamasomas fue cuantificado por RT-PCR en tiempo real. El análisis estadístico se basó en medidas de resumen, pruebas de hipótesis y regresión logística binaria multivariante. Resultados : se encontraron menores valores de HDL y HIRNA IL-18 y mayores de HIRNA NLRPI y HIRNA ASC en los pacientes con VIH-1, comparados con los controles. Los valores de HDL y HIRNA IL-18 se correlacionaron con los recuentos de linfocitos. En el análisis multivariado se encontró que la relación CD4/CD8, el mRNA IL-18 y el HIRNA ASC pueden constituir las principales variables que tienen un potencial explicativo sobre la infección por VIH-1 en la población de estudio. Conclusión : se evidenció la importancia de estudiar los inflamasomas, dado que en la población de estudio constituyen potenciales blancos terapéuticos para disminuir la respuesta inflamatoria.

Abstract Introduction : Inflammasomes direct the maturation of the cytokines IL-1ß and IL-18, which contribute to the pathogenesis of HIV-1 infection. Given its complexity, it is necessary to search for markers that can identify new therapeutic targets or monitor the immunological status of patients. Therefore, the objective of the present work was to explore the independent effect of the main inflammatory components on HIV-1 infection. Materials and Methods : Researchers conducted an analytical study with 36 HIV+ patients and 36 healthy controls, matched by age and sex. Viral load, CD4+/CD8+ T lymphocytes, lipid profile, C-reactive protein and serum concentrations of IL-1ß, IL-6, and IL-18 were quantified. RT-PCR in real time quantified the ITIRNA of the genes related to the inflammasomes. The statistical analysis based on summary measures, hypothesis tests, and multivariate binary logistic regression. Results : Lower values of HDL and ITIRNA IL-18 and higher ITIRNA NLRPI and ITVRNA ASC presented in patients with HIV-1 compared with controls. The values of HDL and ITIRNA IL-18 correlated with lymphocyte counts. The multivariate analysis shows that the CD4 / CD8 ratio, the IL-18 ITIRNA and the ASC ITIRNA can be the main variables that have an explanatory potential on HIV-1 infection in the study population. Conclusion : The importance of studying inflammasomes was evidenced, given that in the study population they are potential therapeutic targets to reduce the inflammatory response.

Resumo Introdução : os inflamassomas dirigem a maduração das citocinas IL-1ß e IL-18; as quais contribuem nas patogêneses da infeção por HIV-1. Dada a complexidade da infeção se faz necessária a busca de marcadores que permitam identificar novos alvos terapêuticos ou fazer seguimento do estado imunológico dos pacientes. Portanto, o objetivo do presente trabalho foi explorar o efeito independente os principais componentes inflamatórios sobre a infeção por HIV-1. Materiais e métodos : estudo analítico com 36 pacientes HIV+ e 36 controles saudáveis, pareados por idade e sexo. Se quantificou a carga viral, os linfócitos T CD4+/CD8+, o perfil lipídico, a proteína C reativa e as concentrações séricas de IL-1ß, IL-6 e IL-18. O ITIRNA dos genes relacionados com os inflamassomas foi quantificado por RT-PCR em tempo real. A análise estatística se baseou em medidas de resumo, provas de hipótese e regressão logística binaria multivariado. Resultados : se encontraram menores valores de HDL e TÍTRNA IL-18 e maiores de TÍIRNA NLRPI e TÍTRNA ASC nos pacientes com HIV-1, comparados com os controles. Os valores de HDL e TÍTRNA IL-18 se correlacionaram com os recontos de linfócitos. Na análise multivariada encontrou-se que a relação CD4/CD8, o TÍIRNA IL-18 e o TÍTRNA ASC podem constituir as principais variáveis que têm um potencial explicativo sobre a infeção por HIV-1 na população de estudo. Conclusão : se evidenciou a importância de estudar os inflamassomas, dado que na população de estudo constituem potenciais brancos terapêuticos para diminuir a resposta inflamatória.

Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome

BACKGROUND: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.METHODS: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.RESULTS: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with thein vivoresults, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.CONCLUSION: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.