S100a8/9 (S100 Calcium Binding Protein a8/9) Promotes Cardiac Hypertrophy Via Upregulation of FGF23 (Fibroblast Growth Factor 23) in Mice.

BACKGROUND: S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy. METHODS AND RESULTS: Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice. CONCLUSIONS: In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.

Isthmin-1 alleviates cardiac ischaemia/reperfusion injury through cGMP-PKG signalling pathway.

AIMS: Ischaemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of revascularization; however, specific and efficient treatment for cardiac I/R injury is still lacking. Isthmin-1 (ISM1) is a novel adipokine and plays indispensable roles in regulating glycolipid metabolism and cell survival. The present study aims to investigate the potential role and molecular mechanism of ISM1 in cardiac I/R injury using gain- and loss-of-function approaches. METHODS AND RESULTS: Cardiac-specific ISM1 overexpression and silence were achieved using an adeno-associated virus serotype 9 system, and then these mice were subjected to I/R surgery, followed by biochemical test, echocardiography and histopathologic examinations, etc. Meanwhile, neonatal rat cardiomyocytes (NRCMs) with ISM1 silence or overexpression also received simulated I/R (sI/R) injury to further verify its role in vitro. The potential downstream pathways and molecular targets of ISM1 were screened by RNA sequencing. We also treated injured mice and NRCMs with recombinant ISM1 (rISM1) to explore whether supplementation with ISM1 was sufficient to protect against I/R injury. Furthermore, acute myocardial infarction patients with percutaneous coronary intervention (PCI) and paired healthy controls were included to reveal the clinical relevance of circulating ISM1. Cardiac-specific ISM1 silencing aggravated while ISM1 overexpression alleviated I/R-induced acute cardiac injury and cardiac remodelling and dysfunction. Mechanistically, ISM1 targeted αvß5 integrin to facilitate the nuclear accumulation of nuclear transcription factor Y subunit alpha, transcriptionally increased soluble guanylyl cyclase beta subunit expression, and eventually enhanced cGMP generation. Besides, we confirmed that treatment with rISM1 before or after reperfusion could confer cardioprotective effects in mice. Clinically, lower ISM1 levels post-PCI was associated with worse outcome in patients. CONCLUSION: ISM1 can protect against cardiac I/R injury through cGMP-PKG signalling pathway, and it is a promising therapeutic and predictive target of cardiac I/R injury.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Safety and Effectiveness of Baricitinib in Chinese Patients with Moderate-to-Severe Rheumatoid Arthritis: 24-Week Results from a Post-Marketing Safety Study.

INTRODUCTION: Baricitinib, a JAK1/JAK2 inhibitor, is approved for treatment of moderate-to-severe rheumatoid arthritis (RA) in China. This single-arm, prospective, multi-center, post-marketing safety study (PMSS) evaluated the safety and effectiveness of baricitinib in Chinese patients. METHODS: This study included adult patients with moderate-to-severe active RA who received baricitinib over periods of approximately 12 and 24 weeks. The primary endpoint was safety, defined as week 12 adverse event (AE)/serious AE incidence. Secondary endpoints were week 24 safety and effectiveness (disease activity score with 28 joints/C-reactive protein [DAS28-CRP] and simplified/Clinical Disease Activity Index [SDAI/CDAI]). RESULTS: Safety analyses included 667 patients (female, 82.3%; mean age, 53.3 years; mean RA duration, 86.9 months); 106/667 (15.9%) were 65-74 years old and 19/667 (2.8%) were ≥ 75 years old; 87.0% received baricitinib 2 mg QD. Total exposure was 262.1 patient-years (PY). At week 12, AEs had occurred in 214 (32.1%; exposure-adjusted incidence rate [EAIR], 172.5 per 100 PY) patients (serious AEs: 22 [3.3%; EAIR, 15.0]). At week 24, AEs had occurred in 250 (37.5%; EAIR, 125.9) patients (serious AEs: 28 [4.2%; EAIR, 10.9]). Two patients (0.3%) died (of pneumonia and unknown cause); EAIR for death, 0.77. Serious infection occurred in 1.2% of patients (EAIR, 3.1). Hepatotoxicity occurred in 3.4% of patients (EAIR, 9.0). No patients met potential Hy's law laboratory criteria (alanine/aspartate aminotransferases ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN). Malignancy occurred in one patient. No patients experienced venous thromboembolism (VTE) or major adverse cardiovascular events (MACE). At week 24, 52.4%, 27.5%, and 27.6% of patients achieved remission per DAS28-CRP, SDAI, and CDAI, respectively. CONCLUSIONS: This PMSS investigated the safety and effectiveness of baricitinib in clinical practice in China. No VTE/MACE or new safety signals were reported and there was promising effectiveness, supporting the use of baricitinib in Chinese patients with moderate-to-severe active RA. TRIAL REGISTRATION: EU PAS Register: EUPAS34213.

Effect of smoking on thrombotic antiphospholipid syndrome: a 10-year prospective cohort study.

OBJECTIVES: Cigarette smoking is an established risk factor for autoimmune diseases. However, whether smoking plays a clear role in thrombotic antiphospholipid syndrome (TAPS) has not been determined. We aimed to investigate the effects of smoking on clinical characteristics and prognosis of TAPS. METHODS: This was a prospective cohort study from 2013 to 2022. During the study period, 297 patients were diagnosed with TAPS, including 82 smokers and 215 non-smokers. After propensity score matching, 57 smokers and 57 non-smokers matched by age and sex were analysed. RESULTS: Overall, smokers with TAPS had more cardiovascular risk factors (CVRFs) than non-smokers, including hypertension (36.59% vs. 14.42%, P<0.001), obesity (15.85% vs. 7.44%, P=0.029), dyslipidaemia (64.63% vs. 48.37%, P=0.012), and hyperhomocysteinaemia (62.20% vs. 36.28%, P<0.001). Arterial thrombotic events were more common in smokers at diagnosis (62.20% vs. 46.05%, P=0.013), especially myocardial infarction, visceral thrombosis, and peripheral vascular thrombosis. After matching, smokers showed balanced CVRFs with non-smokers at baseline, but retained a higher prevalence of arterial thrombosis (59.65% vs. 33.33%, P=0.005), mainly distributed in cerebral vascular, cardiovascular, and retinal vascular territories. During follow-up, smokers presented a tendency for more recurrent arterial thrombosis and less recurrent venous thrombosis. Smokers had significantly poorer outcomes for organ damage with higher DIAPS (median, 2.00 vs. 1.00, P=0.008), especially in the cardiovascular (26.32% vs. 3.51%, P=0.001), gastrointestinal (15.79% vs. 1.75%, P=0.016), and ophthalmologic (10.53% vs. 00.00%, P=0.027) systems. CONCLUSION: Smoking is related to increased arterial events and poor prognosis in TAPS patients. Patients with TAPS should be fully encouraged to avoid smoking.

Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population: a retrospective genotype-phenotype analysis of 105 patients.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients. METHODS: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis. RESULTS: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027). CONCLUSIONS: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.

Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways.

Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg-1· d-1, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 µg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and ß-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.

Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs.

BACKGROUND: This study aims to evaluate the efficacy and safety of the iguratimod (IGU) as monotherapy or combined therapy in patients with rheumatoid arthritis (RA) by using meta-analysis. METHODS: We searched Medline, EMBASE, Cochrane library, CNKI, Wanfang medical network from initial to 30 June, 2020, for randomized clinical trials (RCTs). Two authors independently screened the studies via reading the title, abstract, and full text. The risk of bias in individual studies was assessed using the Cochrane Risk of Bias tool. STATA 12.0 was used for pooled analysis of all included studies. RESULTS: A total of 23 RCTs were included in this analysis. Meta-analysis showed that patients in the IGU monotherapy or combined therapy group had significantly higher ACR20 (OR = 1.97, 95% CI 1.29 to 3.00, P = 0.002), lower DAS28-CRP (SMD = -3.49, 95% CI -5.40 to -1.58, P < 0.001) and DAS28-ESR (SMD = -2.61, 95% CI -3.64 to -1.57, P < 0.001), as well as shorter duration of morning stiffness (SMD = -2.06, 95% CI -2.86 to -1.25, P < 0.001) and lower HAQ score (SMD = -0.91, 95% CI -1.61 to -0.21, P = 0.011), than those received other disease-modifying antirheumatic drugs (DMARDs) monotherapy (primarily comprising methotrexate). For the safety profile, IGU monotherapy had similar risks for gastrointestinal reactions (P = 0.070), leucopenia (P = 0.309), increment in transaminase (P = 0.321), increase of ALT (P = 0.051), and liver damage (P = 0.182) to methotrexate monotherapy, and IGU combined with other DMARDs therapy did not increase the risks of these AEs (P > 0.05). CONCLUSIONS: Our evidence suggests that IGU is effective and tolerant as monotherapy or combined therapy especially with methotrexate in patients with active RA. IGU may be regarded as a potential alternative to methotrexate, and a preferable choice when combined with other DMARDs for the treatment of RA.

Ideal physical activity in association with incident ankylosing spondylitis: a community-based, prospective cohort study.

OBJECTIVES: Only limited risk factors for ankylosing spondylitis (AS) have been identified to date. Therefore, we aimed to explore whether cardiovascular health (CVH) behaviours and factors are associated with the risk of developing AS. METHODS: Patients with incident AS were identified in cohorts from two ongoing prospective studies. Assessments were made of the association of AS with individual baseline cardiovascular health lifestyle behaviours (including smoking status, body mass index, physical activity and diet) and cardiovascular health factors (including total cholesterol levels, blood pressure levels and fasting plasma glucose levels), and with a cardiovascular health metric determined by the number of ideal behaviours and factors. Cox regression analysis was used for the estimation of hazard ratios (HRs) for AS. RESULTS: Among 124,303 participants, incident AS was identified in 53 individuals within the 8 years of follow-up. For participants with ideal physical activity (>80 min/week) the HR was 0.21 (95% CI 0.05-0.89) compared with participants without ideal physical activity after adjusting for potential confounders. No signi cant risk of developing AS was associated with baseline smoking, diet, body mass index, blood pressure, fasting blood glucose or total cholesterol status, nor did cardiovascular health metrics. CONCLUSIONS: Adherence to ideal physical activity may reduce the risk of developing AS.

Circadian Clock and Sirtuins in Diabetic Lung: A Mechanistic Perspective.

Diabetes-induced tissue injuries in target organs such as the kidney, heart, eye, liver, skin, and nervous system contribute significantly to the morbidity and mortality of diabetes. However, whether the lung should be considered a diabetic target organ has been discussed for decades. Accumulating evidence shows that both pulmonary histological changes and functional abnormalities have been observed in diabetic patients, suggesting that the lung is a diabetic target organ. Mechanisms underlying diabetic lung are unclear, however, oxidative stress, systemic inflammation, and premature aging convincingly contribute to them. Circadian system and Sirtuins have been well-documented to play important roles in above mechanisms. Circadian rhythms are intrinsic mammalian biological oscillations with a period of near 24 h driven by the circadian clock system. This system plays an important role in the regulation of energy metabolism, oxidative stress, inflammation, cellular proliferation and senescence, thus impacting metabolism-related diseases, chronic airway diseases and cancers. Sirtuins, a family of adenine dinucleotide (NAD+)-dependent histone deacetylases, have been demonstrated to regulate a series of physiological processes and affect diseases such as obesity, insulin resistance, type 2 diabetes (T2DM), heart disease, cancer, and aging. In this review, we summarize recent advances in the understanding of the roles of the circadian clock and Sirtuins in regulating cellular processes and highlight the potential interactions of the circadian clock and Sirtuins in the context of diabetic lung.

The Potential Role of PKA/CREB Signaling Pathway Concerned with Gastrodin Administration on Methamphetamine-Induced Conditioned Place Preference Rats and SH-SY5Y Cell Line.

To investigate the effects of gastrodin (GAS) on methamphetamine (MA)-induced conditioned place preference (CPP) in rats and explore its potential mechanisms. MA (10 mg/kg) was initially injected intraperitoneally (i.p.) in rats, after which they were administered either MA or saline alternately from day 4 to 13 (D4-13) for 10 days, followed by treatment with GAS (10 or 20 mg/kg, i.p.) on D15-21 for 7 days. The rats underwent CPP testing after MA and GAS treatment. In vitro, SH-SY5Y cells were exposed to MA (2.0 mM) for 24 h, followed by treatment with GAS (2.0 or 4.0 mM) for 24 h. The expression levels of PKA, P-PKA, CREB, and P-CREB proteins in the prefrontal cortex, nucleus accumbens, and ventral tegmental area of MA-induced CPP rats and in SH-SY5Y cells were detected by Western blot analysis. The MA-induced CPP rat model was successfully established. The administration of MA stimulated a significant alteration in behavior, as measured by the CPP protocol. After treatment with GAS, the amount of time rats spent in the MA-paired chamber was significantly reduced. Results also showed that MA increased the expression levels of PKA, P-PKA, CREB, and p-CREB proteins in the prefrontal cortex, nucleus accumbens, and ventral tegmental area of CPP rats and in SH-SY5Y cells (p < 0.05). GAS attenuated the effect of MA-induced CPP in rats and decreased the expression levels of proteins in vivo and in vitro. Our study suggests that GAS can attenuate the effects of MA-induced CPP in rats by regulating the PKA/CREB signaling pathway.

[Clinical Features of Relapsing Polychondritis Patients Presented with Arthropathy].

Objective To explore the clinical characteristics of relapsing polychondritis(RP)patients presented with arthropathy. Methods We retrospectively analyzed the clinical data of 201 RP patients who were hospitalized in our center between December 2005 and February 2019.After 16 patients with co-existing other autoimmune diseases and malignancies were ruled out,185 RP patients entered the final analysis,among whom 16 RP patients were presented with arthropathy and 169 without arthropathy.The demographic data,clinical manifestations,laboratory findings,and prognosis were compared between these two groups. Results Five of the 16 RP patients with arthropathy at presentation were misdiagnosed as rheumatoid arthritis.Compared with RP patients without arthropathy at presentation,RP patients with arthropathy at presentation had a longer disease course[(37.50±66.50)months vs.(9.00±11.00)months,z=-3.186,P =0.001],longer time of diagnostic delay[(24.00±41.25)months vs.(7.00±9.00)months,z=-2.890,P=0.004],and higher incidence of eye(62.50% vs. 36.09%,χ2=4.309,P=0.038)and nervous system involvements(43.75% vs. 15.38%,χ2=6.205,P=0.013). Conclusions RP patients with arthropathy at presentation are most likely to be misdiagnosed as rheumatoid arthritis.These patients are characterized by longer disease course and diagnostic delay and more frequrent eye and nervous system involvements.

Patterns of renal pathology in Chinese patients with systemic sclerosis undergoing renal biopsy at a tertiary medical center.

OBJECTIVE: We investigated renal injury characteristics in Chinese patients with systemic sclerosis (SSc) who had undergone renal biopsy. METHODS: We searched the medical records of patients with SSc who were hospitalized at Peking Union Medical College Hospital between January 1990 and August 2019. We analyzed the clinical characteristics and pathological results of these patients. RESULTS: We identified 25 patients who had undergone renal biopsy. Of these patients, 10 had scleroderma renal crisis (SRC); one underwent renal biopsy twice (for diffuse mesangial proliferative glomerulonephritis and for SRC); two had antineutrophil cytoplasmic antibody-associated glomerulonephritis; one had immunoglobulin M nephropathy; one had minimal change nephropathy; seven had lupus nephritis; one had scleroderma renal crisis with comorbid lupus nephritis; and two had drug-related kidney injury (caused by aristolochic acid in one and D-penicillamine in the other). Acute tubular necrosis was observed in the patient taking oral aristolochic acid, while minimal change nephropathy was observed in the patient with D-penicillamine-induced renal injury. CONCLUSIONS: SRC was the most commonly encountered renal damage in patients with SSc. We recommend biopsy for patients undergoing treatment for SRC who have persistent renal injury with proteinuria, regardless of hematuria. Rheumatologists in Eastern countries should be aware of aristolochic acid nephropathy.

[The Expression and Significance of c-myc and bcat1 in Cervical Cancer].

OBJECTIVE: To explore the relationship between c-myc and bcat1 expression and the occurrence, development and clinical features of cervical cancer. METHODS: The expression level of c-myc and bcat1 were detected in 30 cases of normal cervical tissues, 30 cases of CIN tissues, 40 cases of cervical squamous carcinoma tissues and 40 cases of cervical adenocarcinoma tissues by immunohistochemistry; Conduct a Spearman rank correlation analysis between c-myc and bcat1 expressions; Analyze the relationship between the expression of both genes and clinicopathological factors of cervical cancer. RESULTS: The positive rates of c-myc expression were 16.7% (5/30) in normal cervical tissues, 43.3% (13/30) in CIN tissues and 73.8% (59/80) in cervical cancer tissues, the positive rates of bcat1 expression were 10.0% (3/30) in normal cervical tissues, 23.3% (7/30) in CIN tissues and 52.5% (42/80) in cervical cancer tissues. The rank correlation index between c-myc and bcat1 is respectively 0.773 (P=0.000) in cervical squamous carcinoma and 0.369 (P=0.019) in adenocarcinoma. The positive expression rate of c-myc was related to the pathological type of cancer tissue (adenocarcinoma/squamous cell carcinoma), the degree of tumor tissue differentiation, the depth of interstitial infiltration, and the presence or absence of vascular invasion (P<0.05). The positive expression rate of bcat1 was related to the degree of tumor differentiation, vascular invasion and Ki67 index (P<0.05). CONCLUSION: The high expression of c-myc may promote the invasion and metastasis of cervical cancer, and the high expression of bcat1 may promote the proliferation, invasion and metastasis of cervical cancer, which may have a synergistic effect in the pathogenesis of cervical cancer.

HIV-1 Tat and methamphetamine co-induced oxidative cellular injury is mitigated by N-acetylcysteine amide (NACA) through rectifying mTOR signaling.

Methamphetamine (Meth) is an addictive psychostimulant whose abuse is intimately linked to increased risks for HIV-1 infection. Converging lines of evidence indicate that Meth also aggravates the symptoms of HIV-associated neurocognitive disorders (HAND), though the underlying mechanisms remain poorly understood. By using the lipophilic antioxidant N-acetylcysteine amide (NACA) as an interventional agent, we examined the roles of oxidative stress in autophagy and apoptosis induced by HIV-Tat (the transactivator of transcription), Meth or their combined treatment in human SH-SY5Y neuroblastoma cells and in the rat striatum. Oxidative stress was monitored in terms of the production of intracellular reactive oxygen species (ROS) and antioxidant reserves including glutathione peroxidase (GPx) and Cu,Zn-superoxide dismutase (SOD). NACA significantly reduced the level of ROS and restored GPx and SOD to levels comparable to that of normal control, implying a cytoprotective effect of NACA against oxidative stress elicited by Tat- and/or Meth. Protein expression of mammalian target of rapamycin (mTOR) was measured in SH-SY5Y cells and in the rat striatum to further explore the underlying mechanism of NACA protect against oxidative stress. The results support a beneficial effect of NACA in vivo and in vitro through rectification of the mTOR signaling pathway. Collectively, our study shows that NACA protects against Meth and/or Tat-induced cellular injury in vitro and in the rat striatum in vivo by attenuating oxidative stress, apoptosis and autophagy, at least in part, via modulation of mTOR signaling.

Overexpression of CTRP3 protects against sepsis-induced myocardial dysfunction in mice.

C1q/tumor necrosis factor-related protein-3 (CTRP3) shows striking homologies of genomic structure to the adiponectin. In this study, we aimed to investigate the protective role of CTRP3 against sepsis-induced cardiomyopathy. Here, we overexpressed CTRP3 in myocardium by direct intramyocardial injection and constructed a model of lipopolysaccharide (LPS)-induced sepsis in mice. Our results demonstrated that cardiac-specific overexpression of CTRP3 remarkably attenuated myocardial dysfunction and increased the phosphorylation level of AMPKα during LPS-induced sepsis. The anti-inflammatory effects of CTRP3, as determined by decreased mRNA levels of TNF-α, IL-6 and a lower protein expression of phosphorylated NF-κB p65 and IκBα, was detected in mice following LPS treatment. Additionally, CTRP3 suppressed cardiac apoptosis induced by LPS in mice as indicated by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining and western blot for Cleaved-caspase3, Bax and Bcl-2. In conclusion, CTRP3 could protect against sepsis-induced myocardial dysfunction in mice. The cardioprotective effects of CTRP3 might be mediated by activating AMPKα signaling pathway and blunting inflammatory response and apoptosis.

CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1.

BACKGROUND: Inflammation and myocytes apoptosis play critical roles in the development of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that C1q/tumour necrosis factor-related protein-3 (CTRP3) could inhibit cardiac inflammation and apoptosis of myocytes but its role in DOX-induced heart injury remains largely unknown. Our study aimed to investigate whether CTRP3 protected against DOX-induced heart injury and the underlying mechanism. METHODS: We overexpressed CTRP3 in the hearts using an adeno-associated virus system. The mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to induce short-term model for cardiomyopathy. The morphological examination and biochemical analysis were used to evaluate the effects of CTRP3. H9C2 cells were used to verify the protective role of CTRP3 in vitro. RESULTS: Myocardial CTRP3 protein levels were reduced in DOX-treated mice. Cardiac specific-overexpression of CTRP3 preserved heart dysfunction, and attenuated cardiac inflammation and cell loss induced by DOX in vivo and in vitro. CTRP3 could activate silent information regulator 1 (Sirt1) in vivo and in vitro. Moreover, specific inhibitor of Sirt1 and the silence of Sirt1 could abolish the protective effects of CTRP3 against DOX-induced inflammation and apoptosis. CONCLUSION: CTRP3 protected against DOX-induced heart injury via activation of Sirt1. CTRP3 has therapeutic potential for the treatment of DOX cardiotoxicity.

Acacetin protects against cardiac remodeling after myocardial infarction by mediating MAPK and PI3K/Akt signal pathway.

Since inhibiting cardiac remodeling is a critical treatment goal after myocardial infarction (MI), many drugs have been evaluated for this purpose. Acacetin is a flavonoid compound that has been shown to have anti-cancer, anti-mutagenic, anti-inflammatory and anti-peroxidative effects. In this study, we investigated whether acacetin is able to exert a protective effect against MI. One week after anterior wall standard MI surgeries or sham surgeries were performed in mice, acacetin was administered via gavage for two weeks. The results of echocardiographic and hemodynamic evaluation revealed that cardiac dysfunction significantly improved after acacetin treatment. H&E staining indicated that the ratio of the infarct size and the cardiomyocyte cross-sectional area was decreased by acacetin. Masson's staining detected that the fibrotic area ratio was evidently lower in the acacetin-treated MI group. TUNEL assays showed that acacetin ameliorated cardiomyocyte apoptosis after MI. RT-qPCR analysis showed that levels of hypertrophic and fibrotic markers were significantly decreased after acacetin treatment. Western blot analysis of various signaling pathway proteins showed that acacetin targets the MAPK and PI3K/Akt signaling pathways. Collectively, acacetin improves mouse left ventricular function and attenuates cardiac remodeling by inhibiting of the MAPK and PI3K/Akt signaling pathway.

Arctiin protects against cardiac hypertrophy through inhibiting MAPKs and AKT signaling pathways.

PURPOSE: The mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) pathways have emerged as essential intracellular signaling pathways in eukaryotic cells, particularly as regulators of cardiac hypertrophy. Previous studies indicated that arctiin, an active ingredient of biennial dried ripe burdock, could exhibit potent anti-inflammatory and anti-allergic activities via down-regulating the activation of MAPKs and AKT pathways. However, little is known about its effects on cardiac hypertrophy. Therefore, the present study aimed to explore whether arctiin could attenuate cardiac hypertrophy. GENERAL METHODS: Arctiin (80 mg/kg) was administered by oral gavage once daily for 3 weeks from 1 week after surgery. Then, the mice were subjected to either chronic pressure overload generated by aortic banding (AB) or sham surgery (control group). Cardiac function was assessed by echocardiography. FINDINGS: The results indicated that arctiin attenuated cardiac hypertrophy induced by AB, and suppressed cardiac fibrosis and accumulation of collagen in vivo. Arctiin also inhibit the activation of MAPKs and AKT occurs in response to hypertrophic stimuli. Arctiin attenuated phenylephrine-induced hypertrophy of myocytes in vitro. CONCLUSIONS: In conclusion, arctiin can improve cardiac function and prevent the development of cardiac hypertrophy by blocking the MAPKs and AKT signaling pathways.