Liquiritigenin Attenuated Collagen-Induced Arthritis and Cardiac Complication via Inflammation and Fibrosis Inhibition in Mice.

Rheumatoid arthritis (RA) is a common autoimmune disease with increased cardiovascular disease risk. Liquiritigenin (LG) is a triterpene with anti-inflammatory properties. Our study aimed to explore the effect of LG on RA and the cardiac complication. Collagen-induced arthritis (CIA) mice with LG treatment exhibited obvious alleviation in histopathological changes, accompanied by the decreased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-17A in synovium and serum. LG attenuated cartilage destruction by reducing matrix metalloproteinase (MMP)-3 and MMP-13 expression in the synovium of CIA mice. The echocardiography results proved the alleviation of cardiac dysfunction in CIA mice. The electrocardiogram, biochemical, and histochemical analysis proved the cardioprotection effect of LG against RA. The decreased expression of inflammatory factors (TNF-α, IL-1ß, and IL-6) and fibrotic markers (fibronectin, Collagen I, and Collagen III) in cardiac tissues of CIA mice further corroborated the attenuation of myocardial inflammation and fibrosis by LG. Mechanistic studies showed that LG could inhibit transforming growth factor ß-1 (TGF-ß1) and phos-Smad2/3 expression in cardiac tissues of CIA mice. Our study suggested that LG could relieve RA and its cardiac complication probably by inhibiting the TGF-ß1/Smad2/3 pathway. All these suggested that LG might be a potential candidate for RA and its cardiac complication therapy.

Loss of AKAP12 aggravates rheumatoid arthritis-like symptoms and cardiac damage in collagen-induced arthritis mice.

A-kinase anchoring protein 12 (AKAP12) has been identified as an anti-inflammatory and anti-fibrotic regulator in chronic inflammation and cardiovascular disease. However, the potential of AKAP12 in autoimmune disorders, rheumatoid arthritis (RA) and associated cardiac complications remains elusive. Here, a murine model of collagen-induced arthritis (CIA) was successfully induced, followed by adenovirus-mediated AKAP12 short hairpin RNA (shRNA) treatment. AKAP12 silenced mice displayed elevated clinical arthritis scores and significant ankle joint swelling. AKAP12 loss in CIA mice increased inflammatory cell infiltration and cartilage erosion, increased the levels of anti-IIC IgG and inflammatory cytokines IL-1ß, IL-6, tumor necrosis factor (TNF)-α in serum, and upregulated the expression of cartilage-degrading enzymes MMP-1, MMP-3, MMP-13 in synovium, but reduced IL-10. The number of M1 macrophages and the expression of the markers (CCR7, IL-6, TNF-α and iNOS) was enhanced in synovial tissues, while M2 polarized macrophages and the makers (IL-10 and arginase-1) were reduced in response to AKAP12 loss. Moreover, low expression of AKAP12 was detected in the hearts of CIA mice. Loss of AKAP12 results in increased cardiac inflammation and fibrosis. This work suggests that AKAP12 loss aggravates joint inflammation likely through the promotion of M1 macrophage polarization and exacerbates inflammation-caused cardiac fibrosis.

Magnetic resonance imaging for acute pancreatitis in type 2 diabetes patients.

Type 2 diabetes mellitus (T2DM) and its complications have significantly increased the burden of mortality and disability globally, making diabetes one of the most dangerous and prevalent chronic diseases. Acute pancreatitis (AP) is one of the most frequent gastrointestinal causes for hospital admission, which is a common exocrine pancreatic inflammatory disease that can cause severe abdominal pain and multiple organ dysfunction. There is an inseparable relationship between AP and diabetes. Diabetes is a high risk factor of AP, and patients with AP can develop pancreatogenic diabetes. In T2DM patients, the incidence rate of AP is significantly higher than that of the general population, and the clinical symptoms are more severe, with the majority of cases being moderate to severe AP. This review briefly introduces the pathogenesis and clinical features of AP in T2DM patients, focusing on the magnetic resonance imaging (MRI) manifestations of AP in T2DM patients. Our aim is to evaluate the severity of AP in patients with T2DM by MRI, so as to help clinicians assess the patient's condition and prognosis.

[Interleukin-8 monoclonal antibody attenuates smooth muscle cell proliferation and balloon inflation-induced abdominal aorta stenosis in rabbits].

OBJECTIVE: To observe the effects of interleukin-8 monoclonal antibody on smooth muscle cell proliferation and balloon inflation-induced abdominal aorta stenosis in rabbits. METHODS: Thirty-six New Zealand white rabbits were randomly assigned to balloon inflation group (group A, n = 12), interleukin-8 monoclonal antibody pre-treated rabbits (2 mg/kg for 3 days before balloon inflation, group B, n = 12) and sham-operated control group (group C, n = 12). Peripheral blood was collected before experiment and at 4 h, 1, 3, 7, 14, and 28 days post balloon inflation or sham operation and the levels of IL-8 were measured by enzyme linked immunosorbent assay (ELISA). The ratio of positive and negative masculine cells in the high power microscopic field was determined in proliferating cell nuclear antigen (PCNA) stained slide. Histopathologic examination was performed in abdominal aorta and luminal area, intima and tunica media area were measured. RESULTS: Plasma interleukin-8 began to rise at 4 h and peaked at 1 day and remained increased up to 28 days after balloon inflation in rabbits of group A, plasma interleukin-8 level in group A was significantly higher than in group B and C at 4 h and thereafter post operation. The ratio of positive and negative masculine cells was significantly increased in group A compared to group C and was significantly lower in group B than in group A. Abdominal aorta stenosis, luminal area, intima and tunica media area were significantly reduced in group B than in group A. Correlation analysis indicated that there were positive relations between plasma IL-8 level and intima thickness, area of intima and tunica media, respectively (r = 0.894, 0.783, 0.801, 0.912, all P < 0.01). CONCLUSIONS: Plasma IL-8 level is increased in this abdominal aorta stenosis model and is positively correlated to the severity of abdominal aorta stenosis. IL-8 monoclonal antibody could significantly reduce abdominal aorta stenosis in this abdominal aorta stenosis model.

Wedelolactone ameliorates synovial inflammation and cardiac complications in a murine model of collagen-induced arthritis by inhibiting NF-κB/NLRP3 inflammasome activation.

INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disorder associated with joint damage and attendant cardiovascular complications. Wedelolactone (Wed), derived from Eclipta alba, possesses anti-inflammatory activity. Whether Wed regulates RA inflammation and related heart damage remains unknown. MATERIAL AND METHODS: A murine model of collagen-induced arthritis (CIA) was well-established by two subcutaneous injections of type II collagen (days 0 and 21). Wed was then administered via intraperitoneal injection every other day from day 28 to day 48. Joint swelling was monitored and paw thickness was calculated. Histopathological changes in synovial tissues or ankle cartilage were evaluated by hematoxylin and eosin (H&E) and Safranin O-Fast Green staining. The concentrations of inflammatory factors in serum and synovial tissues were detected by ELISA. The qRT-PCR, Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) were performed to assess receptor activator of nuclear factor kappa ligand (RANKL), matrix metalloprotease (MMP)-3, NLRP3, caspase-1 (pro- and cleaved forms), p-p65, IκBα, p-IκBα, p65, αsmooth-actin 2 (ACTA2), collagen type I and E-cadherin expression. H&E and Masson staining were used to assess the pathological alterations in the heart. RESULTS: Treatment with Wed ameliorated ankle joint swelling and cartilage degradation. Wed decreased the infiltration of inflammatory cells, the release of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IL-18), and the expression of RANKL and MMP-3 in serum and synovial tissues of CIA mice. Moreover, Wed increased the expression of NLRP3 and cleaved-caspase-1 in the synovium, leading to IL-1ß and IL-18 secretion. Nuclear factor-kappaB (NF-κB) activation in synovial tissues was suppressed by Wed, as manifested by reduced phosphorylation of p65 and IκBα and nuclear translocation of p65. Furthermore, Wed reduced in CIA mice heart weight/body weight ratio and dampened cardiac inflammation and fibrosis that was accompanied at the mRNA level by down-regulation of ACTA2 and collagen I and up-regulation of E-cadherin. CONCLUSIONS: These findings suggested that Wed attenuated synovial inflammation and joint damage in a mouse model of RA via inhibiting NF-κB/NLRP3 inflammasome activation, and ameliorated RA-induced cardiac complications.

Inhibition of Kruppel-like factor 7 attenuates cell proliferation and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis through nuclear factor κB and mitogen-activated protein kinase signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease, which can lead to joint inflammation and progressive joint destruction. Kruppel-like factor 7 (KLF7) is the member of KLF family and plays an important role in multiple biological progresses. However, its precise roles in RA have not been described. Present study aimed to investigate the role of KLF7 in RA-fibroblast-like synoviocytes (FLSs). Data showed that KLF7 expression was obviously upregulated in synovial tissues of rats with adjuvant-induced arthritis. Functional studies demonstrated that the loss of KLF7 may suppress cell proliferation and the expression of pro-inflammatory factors (IL-6, IL-1ß, IL-17A) and matrix metalloproteinase (MMP-1, MMP-3, MMP-13) in FLSs through the inhibition of phosphorylation of nuclear factor κB (NF-κB) p65 and JNK. We further showed that miR-9a-5p specifically interacts with KLF7 to negatively regulate the expression of KLF7 in RA-FLSs. Taken together, our results demonstrated that KLF7 which targeted by miR-9a-5p might participate in the pathogenesis of RA by promoting cell proliferation, pro-inflammatory cytokine release and MMP expression through the activation of NF-κB and JNK pathways in RA-FLSs. Hence, KLF7 could be a novel target for RA therapy.

PPARG Silencing Improves Blood Pressure Control and Alleviates Renal Damage by Modulating RAS Circadian Rhythm in Hypertensive Rats.

OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPARG) polymorphisms are associated with hypertension, but the role of PPARG in hypertensive nephropathy is poorly understood. METHODS: Male Sprague-Dawley rats were applied to construct renovascular hypertension model by 2-kid-ney, 1-clip (2K1C) method. Tail vein bolus injection of adeno-associated virus (rAAV)-shPPARG was performed to knockout PPARG in 2K1C rats. The heart rate (HR), systolic pressure (SBP), diastolic pressure (DBP) and activity of rats were monitored after treatments. The role of PPARG in hypertension, renal damage, and circadian rhythm of renin-angiotensin system (RAS) was explored by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot, Masson staining, hematoxylin eosin (HE) staining, Sirius red staining and enzyme-linked immunosorbent assay. RESULTS: PPARG was over-expressed in thoracic aortas of 2K1C rats. 2K1C treatment enhanced DBP and SBP in rats, which was reversed by PPARG silencing. PPARG silencing alleviated 2K1C-induced renal damage. 2K1C treatment reduced angiotensin II and increased angiotensin converting enzyme (ACE) and plasma renin activity (PRA) concentrations in rat plasma during the light period and decreased plasma PRA concentration during the dark period, which were all overturned by PPARG silencing. PPARG silencing effectively improved the RAS circadian rhythm in hypertension. CONCLUSION: PPARG silencing improved blood pressure control and alleviated renal damage by regulating RAS circadian rhythm in hypertensive rats.

Pentraxin 3 depletion (PTX3 KD) inhibited myocardial fibrosis in heart failure after myocardial infarction.

BACKGROUND: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. METHODS: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. RESULTS: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. CONCLUSIONS: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.

High-dose vitamin C intravenous infusion in the treatment of patients with COVID-19: A protocol for systematic review and meta-analysis.

BACKGROUND: Patients infected with a virus usually lack vitamin C. High-dose vitamin C has an antiviral effect, and has been used by several researchers to treat COVID-19 by intravenous infusion, achieving good results. However, the efficacy and safety of vitamin C in the treatment of patients with COVID-19 remain unclear. Thus, the aim of the present study was to investigate the efficacy of high-dose vitamin C infusion in the treatment of patients with COVID-19. METHODS: Electronic databases were searched, including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, China National Knowledge Infrastructure database, Chinese Wanfang database, and Chinese Biomedical Literature database. The aim was to collect randomized controlled trials of high-dose vitamin C infusion in the treatment of patients with COVID-19, with the retrieval time being from the establishment of the database to March 2021. In accordance with the pre-designed inclusion/exclusion criteria, all data were extracted independently by 2 researchers. To assess the risk bias in the studies, the Cochrane collaboration's tool for assessing risk of bias was used to assess the risk bias in the studies, while meta-analysis was performed using Revman 5.3 software. RESULTS: In the present study, a high-quality comprehensive evaluation is provided of high-dose vitamin C infusion in the treatment of patients with COVID-19. CONCLUSION: Further convincing evidence for the clinical treatment of COVID-19 is provided, in addition to evidence-based guidance for clinical practice. PROSPERO REGISTRATION NUMBER: CRD42021246342.