GVS-12 attenuates non-alcoholic steatohepatitis by suppressing inflammatory responses via PPARγ/STAT3 signaling pathways

Non-alcoholic steatohepatitis (NASH), a type of fatty liver disease, is characterized by excessive inflammation and fat accumulation in the liver. Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone has great potential in protecting against the development of NASH. However, long-term usage of rosiglitazone probably leads to many adverse reactions. In this research, GVS-12 was designed and synthesized as a PPARγ agonist with high selectivity, evidenced by increasing the activity of the PPARγ reporter gene and promoting the mRNA expression of the PPARγ responsive gene cluster of differentiation 36 (CD36). It was noteworthy that GVS-12 could ameliorate dysfunction and lipid accumulation by down-regulating the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the liver of high fat diet (HFD)-induced rats and palmitic acid (PA)-stimulated hepatocellular carcinoma G2 (HepG2) cells. Moreover, PPARγ siRNA (siPPARγ) markedly diminished GVS-12 induced the down-regulation of mRNA expression of IL-1β, IL-6 and TNF-α in PA-stimulated HepG2 cells. Additionally, GVS-12 could reduce the phosphorylation level of STAT3 and up-regulate the protein expression of a suppressor of cytokine signaling 3 (SOCS3), which could be reversed by siPPARγ. In detail, SOCS3 siRNA (siSOCS3) diminished the inhibitory effect of GVS-12 on the mRNA expression of IL-1β, IL-6 and TNF-α. In conclusion, GVS-12 suppressed the development of NASH by down-regulating the mRNA expression of IL-1β, IL-6 and TNF-α via PPARγ/STAT3 signaling pathways.

Non-alcoholic steatohepatitis (NASH), a type of fatty liver disease, is characterized by excessive inflammation and fat accumulation in the liver.     

Lemon Polyphenols Suppress Diet-induced Obesity by Up-Regulation of mRNA Levels of the Enzymes Involved in β-Oxidation in Mouse White Adipose Tissue

The aim of this study was to investigate the effect of dietary lemon polyphenols on high-fat diet-induced obesity in mice, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. Mice were divided into three groups and fed either a low fat diet (LF) or a high fat diet (HF) or a high fat diet supplemented with 0.5% w/w lemon polyphenols (LP) extracted from lemon peel for 12 weeks. Body weight gain, fat pad accumulation, the development of hyperlipidemia, hyperglycemia, and insulin resistance were significantly suppressed by lemon polyphenols. Supplementation with lemon polyphenols also significantly up-regulated the mRNA level of the peroxisome proliferator activated receptor-α (PPARα) compared to the LF and HF groups in the liver. Furthermore, the mRNA level of acyl-CoA oxidase (ACO) was up-regulated in the LP group compared to the LF group, but not HF group in the liver, and was also significantly increased in the epididymal white adipose tissue. Thus, feeding with lemon polyphenols suppressed body weight gain and body fat accumulation by increasing peroxisomal β-oxidation through up-regulation of the mRNA level of ACO in the liver and white adipose tissue, which was likely mediated via up-regulation of the mRNA levels of PPARα.     

Exploring potential serum levels of Homocysteine,interleukin‐1 beta,and apolipoprotein B 48 as new biomarkers for patients with ischemic stroke

BackgroundStroke is the second leading cause of death worldwide with heterogeneous characteristics. The subtypes of stroke are due to different pathophysiological regulations and causes. This study aimed to investigate the correlation of serum levels of apolipoprotein B 48, interleukin‐1β and Homocysteine with BMI in patients with ischemic stroke (IS).MethodsOver one hundred controls (120) and an equal number of IS patients, including 31 women and 89 men, were recruited to participate in the case‐control study conducted at Imam Reza Hospital (Tabriz, Iran) from February 2019 to March 2020. We measured serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine. Receiver operating characteristic analysis (ROC) was performed to evaluate the diagnostic value of these indices in patients and control groups.ResultsThe mean serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine, were significantly increased in the experimental group compared to the control group with a p‐value of 0.001. The ROC curve analysis showed that the area under the curve for apo B48, IL −1β, hs‐CRP, and Homocysteine serum levels were 0.94, 0.98, 0.99, and 1, respectively.ConclusionsThe results of our current study show that the determination of serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine can potentially be used to monitor and diagnose IS patients. However, there was no statistically significant correlation between serum levels of apolipoprotein B 48, interleukin 1β and Homocysteine and BMI in the patient group. However, there was a statistically significant inverse correlation between serum levels of high‐sensitivity C‐reactive protein (hs‐CRP) and BMI in the patient group.     

川崎病并冠状动脉损害危险因素相关研究

目的探讨川崎病（Kwasaki disease,KD）合并冠状动脉损害（coronary artery lesions,CAL）的危险因素。方法参照KD及CAL诊断标准,回顾性分析124例KD患儿,分成两组,CAL组50例和非冠状动脉损害组（not coronary artery lesions,NCAL）74例。应用统计学方法分析两组患儿的白细胞（WBC）、血小板（PLT）血红蛋白（Hb）、血沉（ESR）、C反应蛋白（CRP）、免疫球蛋白（IgG、IgA、IgM）、血清钠、血清钾的变化。结果与NCAL组患儿相比,CAL组患儿WBC、PLT、CRP、IgGI、gAI、gM明显增高（P〈0.05）,血清钠明显降低,差异有统计学意义（P〈0.05）。血清钾、Hb、ESR差异无统计学意义（P〉0.05）;多因素loistic回归分析显示PLT、CRPI、gGI、gM、血清钠与KD合并CAL密切相关。结论 PLT、CRPI、gGI、gM及血清钠可作为KD患儿并CAL的可靠预测指标。     

Protective role of fenofibrate in sepsis-induced acute kidney injury in BALB/c mice

Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the associated high mortality rate. Fenofibrate, a peroxisome proliferator activated receptor α (PPARα) agonist, has received considerable attention because of its effects related to renal damage-related energy metabolism and inflammation. The present study investigated the effects of fenofibrate on sepsis-associated AKI in BALB/c mice subjected to caecal ligation and puncture (CLP). Eight-week-old male BALB/c mice were divided into four groups: control group, fenofibrate group, caecal ligation and puncture (CLP) group, and fenofibrate + CLP group. CLP was performed after mice were gavaged with fenofibrate for 2 weeks. After 48 hours, we measured the histopathological alterations of the kidney tissue and plasma levels of serum creatinine (CRE), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), ATP, and ADP. We evaluated PPARα and P53 protein levels as well as interleukin (IL)-1β, IL-6, and tumour necrosis factor-α mRNA levels. Our results showed that administering fenofibrate significantly reduced kidney histological alterations caused by CLP. Fenofibrate inhibited the plasma levels of ROS, CRE, NGAL, and increased the ATP/ADP ratio. Fenofibrate significantly inhibited elevations in P53, IL-1β, IL-6, and tumour necrosis factor-α expression. The results suggest that fenofibrate administration effectively modulates energy metabolism and may be a novel approach to treat sepsis-induced renal damage.

Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the associated high mortality rate.     

PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation

Excess lipid accumulation in the heart is associated with decreased cardiac function in humans and in animal models. The reasons are unclear, but this is generally believed to result from either toxic effects of intracellular lipids or excessive fatty acid oxidation (FAO). PPARγ expression is increased in the hearts of humans with metabolic syndrome, and use of PPARγ agonists is associated with heart failure. Here, mice with dilated cardiomyopathy due to cardiomyocyte PPARγ overexpression were crossed with PPARα-deficient mice. Surprisingly, this cross led to enhanced expression of several PPAR-regulated genes that mediate fatty acid (FA) uptake/oxidation and triacylglycerol (TAG) synthesis. Although FA oxidation and TAG droplet size were increased, heart function was preserved and survival improved. There was no marked decrease in cardiac levels of triglyceride or the potentially toxic lipids diacylglycerol (DAG) and ceramide. However, long-chain FA coenzyme A (LCCoA) levels were increased, and acylcarnitine content was decreased. Activation of PKCα and PKCδ, apoptosis, ROS levels, and evidence of endoplasmic reticulum stress were also reduced. Thus, partitioning of lipid to storage and oxidation can reverse cardiolipotoxicity despite increased DAG and ceramide levels, suggesting a role for other toxic intermediates such as acylcarnitines in the toxic effects of lipid accumulation in the heart.     

miRNA-145和miRNA-143在川崎病患儿血浆中的表达及意义

目的 探讨miRNA-145和miRNA-143在儿童川崎病(kawasaki disease,KD)中表达水平及其辅助诊断价值。方法 共纳入45例确诊为川崎病的患儿,并依据心超结果分为:伴有冠状动脉损伤组(CAL组)19例,无冠状动脉损伤组(NCAL组)26例。同期匹配30例健康儿童作为对照组(NC组)。采用实时荧光定量PCR方法检测miRNA-145和miRNA-143在川崎病患儿发病急性期和治疗缓解期及正常儿童血浆中的表达水平。应用ROC曲线及AUC(95%CI)评估其作为诊断指标的效能。结果 miRNA-145及miRNA-143在CAL组患儿急性期的相对表达量为2.33±1.26和1.64±0.50,高于正常对照组,差异具有统计学意义(t=5.108,5.072,P<0.01); miRNA-145在CAL组缓解期相对表达量为1.55±0.49,高于NC组,差异具有统计学意义(t=3.837,P<0.01); miRNA-143在CAL组缓解期相对表达量为1.17±0.33,与NC组相比,差异无统计学意义(t=1.033,P>0.05); NCAL组急性期miRNA-145和miRNA-143的相对表达量分别为2.02±1.00和1.63±0.50,与NC组相比差异有统计学意义(t=4.746,5.261,P<0.01),缓解期两者表达量分别为1.07±0.18和1.12±0.16,与NC组相比,差异均无统计学意义(t=0.264 9,0.584 9,P>0.05)。miRNA-145用于KD急性期诊断的最佳临界值为1.697,敏感度为64.44%,特异度为90%,AUC为0.773 3,95%CI为0.667 0～0.879 7; miRNA-143的最佳临界值为1.361,敏感度为64.44%,特异度为86.67%,AUC为0.816 3,95%CI为0.722 5～0.910 0。结论 该研究表明,miRNA-145和miRNA-143可作为儿童川崎病急性期诊断的辅助指标。     

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β⁺ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.     

Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model

BackgroundFibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor’s (PPAR’s) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-γ was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders.ObjectiveTo investigate the potential effect of PPAR-γ agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model.Materials and methodsThirty-six male Wistar rats were divided into negative control (n = 9) and reserpine-induced FM (n = 27) groups. The latter was subdivided into three equal subgroups (n = 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1.ResultsPioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant’s activity, while GW9662, a known PPAR-γ antagonist, aggravated the FM manifestations in the rat model.ConclusionPPAR-γ agonists show a promising role against FM-associated motor dysfunctions.     

MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation

Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre–miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223–regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.     

双源CT诊断川崎病冠状动脉病变

目的 探讨双源CT(DSCT)诊断川崎病冠状动脉病变的临床应用价值。方法 对16例川崎病冠状动脉病变患者进行DSCT冠状动脉成像,将获得的数据进行容积再现(VR)、多平面重建(MPR)、最大密度投影(MIP)、曲面重建(CPR),观察冠状动脉病变的部位、数目、形态和大小,并和同期超声心动图(ECHO) 进行比较分析。结果 16例川崎病患者共累及22支血管,表现为单纯性冠状动脉扩张4例、单纯性冠状动脉狭窄2例、冠状动脉瘤10例(共28个),其中2例冠状动脉瘤伴钙化、4例冠状动脉瘤伴冠状动脉扩张。ECHO未显示的病变为小冠状动脉瘤4个(右冠状动脉远段2个、左前降支远段及左回旋支中段各1个)、冠状动脉钙化2例、冠状动脉狭窄1例、冠状动脉轻度扩张1例。结论 DSCT能清晰全面显示冠状动脉病变及程度,是川崎病冠状动脉病变患儿诊断和随访的重要评估方法。     

PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.     

Plasma Levels of Alpha and Gamma Synucleins in Autism Spectrum Disorder: An Indicator of Severity

ObjectivesThe aim of this study was to correlate plasma levels of the synaptic proteins α-synuclein and γ-synuclein in autism spectrum disorder (ASD) children in order to elucidate their possible contribution to the pathogenesis of ASD and to study their association with the severity of the disorder.Subjects and MethodsPlasma levels of α-synuclein and γ-synuclein were measured in 38 male children diagnosed with ASD and 40 healthy age-matched male children by ELISA.ResultsOur results showed that plasma levels of α-synuclein (18.02 ± 5.3 pg/mL) were significantly higher in ASD children than in control children (14.39 ± 2 pg/mL), and plasma levels of γ-synuclein were decreased in the ASD group (23.74 ± 7.7 pg/mL) compared to the control group (32.40 ± 6.8 pg/mL) (p < 0.0001). Our data also indicate that plasma levels of both α-synuclein and γ-synuclein are significantly associated with the severity of ASD.ConclusionsOur study showed that alteration in α-synuclein and γ-synuclein might be associated with ASD pathogenesis and could be an indicator of the severity of the disorder.     

PPARγ agonists promote the resolution of myelofibrosis in preclinical models

Myelofibrosis (MF) is a non–BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.     

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg^flox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg^flox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.