Predictive value of the inconsistency between the residual and post-PCI QFR for prognosis in PCI patients.

Introduction: To investigate the prognostic value of the consistency between the residual quantitative flow ratio (QFR) and postpercutaneous coronary intervention (PCI) QFR in patients undergoing revascularization. Methods: This was a single-center, retrospective, observational study. All enrolled patients were divided into five groups according to the ΔQFR (defined as the value of the post-PCI QFR minus the residual QFR): (1) Overanticipated group; (2) Slightly overanticipated group; (3) Consistent group; (4) Slightly underanticipated group; and (5) Underanticipated group. The primary outcome was the 5-year target vessel failure (TVF). Results: A total of 1373 patients were included in the final analysis. The pre-PCI QFR and post-PCI QFR were significantly different among the five groups. TVF within 5 years occurred in 189 patients in all the groups. The incidence of TVF was significantly greater in the underanticipated group than in the consistent group (P = 0.008), whereas no significant differences were found when comparing the underanticipated group with the other three groups. Restricted cubic spline regression analysis showed that the risk of TVF was nonlinearly related to the ΔQFR. A multivariate Cox regression model revealed that a ΔQFR≤ -0.1 was an independent risk factor for TVF. Conclusions: The consistency between the residual QFR and post-PCI QFR may be associated with the long-term prognosis of patients. Patients whose post-PCI QFR is significantly lower than the residual QFR may be at greater risk of TVF. An aggressive PCI strategy for lesions is anticipated to have less functional benefit and may not result in a better clinical outcome.

LncRNA SNHG8 regulates the migration and angiogenesis of pHUVECs induced by high glucose via the TRPM7/ERK1/2 signaling axis.

This study aimed to evaluate the regulatory effect and molecular mechanism of long noncoding RNA small nucleolus RNA host gene 8 (LncRNA SNHG8) in the migration and angiogenesis of primary human umbilical vein endothelial cells (pHUVECs) under high-glucose (HG) conditions. The HG-induced endothelial injury model was established in vitro.The cell model of silencing SNHG8, overexpressing SNHG8, and silencing TRPM7 was established by transfecting SNHG8-siRNA, SNHG8 plasmid and TRPM7-siRNA into cells with liposomes.The SNHG8 level was determined through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of transient receptor potential melastatin 7 (TRPM7), endothelial nitric oxide synthase (eNOS), p-eNOS, extracellular signal-regulated kinase 1/2(ERK1/2), and p-ERK1/2 were assessed through western blot. Nitric oxide (NO) levels were measured with DAF-FM. pHUVEC migration was examined through wound healing and Transwell assay, and pHUVEC angiogenesis was observed through a tube formation assay. Results showed that HG promoted the expression of lncRNA SNHG8 and TRPM7 and decreased the ratio of p-eNOS/eNOS and p-ERK1/2/ERK1/2 in pHUVECs . NO production, migration , and angiogenesis were inhibited in pHUVECs under HG conditions. Silencing lncRNA SNHG8 and TRPM7 could significantly reverse the HG-induced decrease in eNOS activation, NO production , migration, and angiogenesis . SNHG8 and U0126 (ERK pathway inhibitor) overexpression enhanced the HG effects, whereas using U0126 did not affect the TRPM7 expression. In conclusion, lncRNA SNHG8 participates in HG-induced endothelial cell injury and likely regulates NO production, migration, and angiogenesis of pHUVECs via the TRPM7/ERK1/2 signaling axis.

[Retracted] Acetylsalicylic acid combined with diclofenac inhibits cartilage degradation in rabbit models of osteoarthritis.

[This retracts the article DOI: 10.3892/etm.2016.3560.].

Impact of PIWIL1 Single Nucleotide Polymorphisms on Gastric Cancer Risk in a Chinese Population.

Background: PIWI-like proteins contribute to the onset and progression of carcinogenesis. Whether single nucleotide polymorphisms (SNPs) in the PIWI-like 1 (PIWIL1) gene affect the morbidity and mortality of gastric cancer (GC) remains unclear. To investigate the efficacy of PIWIL1 SNPs genotype on the morbidity and mortality of GC and its interaction within PIWIL1 gene SNPs variation and between elevated plasma glucose. Materials and Methods: We conducted a case-control study that contained 216 GC patients and 204 cancer-free controls to compare differential expression of PIWIL1 SNPs. Results: PIWIL1 gene rs1106042 AA and AG genotypes were associated with significantly reduced GC risk (odds ratio [OR]: 0.15 and 0.26, p < 0.001 and p = 0.016), and rs10773771 CT+CC type significantly increased cancer risk (OR: 1.54 p = 0.037). We observed strong associations between rs10773771 and pathological type (p = 0.012), rs11703684, and invasion depth (p = 0.012). We noticed significant gene-gene interaction between rs1106042 and rs10773771 (p = 0.0107). Interaction between the copresence of rs1106042 GG plus hyperglycemia was also significant (relative excess risk due to interaction: 28.78, attributable proportion due to interaction: 68.2%, synergy index: 3.32). Patients with rs1892723 TT and rs1892722 GG+GA type had better survival (p = 0.030 and p = 0.048). Conclusion: rs10773771 CT+CC was associated with GC risk increase, rs1106042 AA and AG function as a protective factor. rs1892723 CT+TT and rs1892722 AA type may portend a poor prognosis. Elevated fasting plasma glucose will significantly increase the risk of PIWIL gene rs1106042 GG carcinogenesis by multiplicative interaction.

Prognostic value of long-term antidiabetic and antihypertensive therapy in postoperative gastric cancer patients: the FIESTA study.

BACKGROUND: Gastric cancer is often comorbid with hypertension and diabetes mellitus and increases the mortality risk. MATERIALS AND METHODS: We conducted this prospective cohort study to investigate antidiabetics and antihypertensives' impact on gastric cancer survival. 3012 patients with gastric carcinoma undergoing radical gastrectomy were enrolled since January 2000 and followed up until July 2020. RESULTS: Hypertension and diabetes patients had worse survival than patients without hypertension and diabetes [median survival time (MST): 48 versus 112.5 months, p < 0.001 for hypertension, MST: 32.7 versus 183+ months, p < 0.001 for diabetes]. Compared to untreated patients, treated patients had better survival (MST: 109.7 months versus 39.1 months, p < 0.001 for antihypertensives, MST: 120.9 months versus 22.3 months, p < 0.001 for antidiabetics). Antihypertensives and antidiabetics were related to 42% (HR 0.58, 95% CI 0.47-0.73, p < 0.001) and 70% (HR 0.30, 95% CI 0.24-0.38, p < 0.001) reduced mortality risk relative to those without medications. metformin and Calcium channel blockers can better-improved prognosis compared to others (p = 0.00029 and p = 0.015). CONCLUSION: Post-surgical gastric cancer patients could benefit substantially from anti-diabetes and antihypertensive therapy. Metformin and Calcium channel blockers may be superior to other medications.

Dexamethasone Sensitizes Acute Monocytic Leukemia Cells to Ara-C by Upregulating FKBP51.

In this study, we demonstrated that the expression of FK506 binding protein 51 (FKBP51) is upregulated in acute monocytic leukemia (AML-M5) cells by dexamethasone and aimed to investigate the possible effects of FKBP51 on the growth and cytarabine sensitivity of AML-M5 cells. THP-1 and U937cells were used to establish AML-M5 cell models with FKBP51 overexpression and knockdown, respectively. Cell proliferation, apoptosis and response to cytarabine were investigated by cell cycle, CCK-8 and Flow cytometry analyses. The mice experiment was conducted to detect the role of FKBP51 on AML-M5 cells proliferation and antileukemia effect of Ara-C/Dexamethasone co-therapy in vivo. Western blots were employed to determine protein expression levels. FKBP51 upregulation significantly attenuated THP-1 cell proliferation and sensitized the cells to cytarabine treatment which was further enhanced by dexamethasone. These effects were indicated by decreases in cell viability, S-G2/M phase cell cycle distribution, cytarabine 50% inhibitory concentration (IC50) values and increases in apoptosis and were supported by decreased phosphorylation levels of AKT, GSK3ß and FOXO1A and decreased levels of BCL-2 and increased levels of P21 and P27. In contrast, FKBP51 knockdown led to excessive U937 cell proliferation and cytarabine resistance, as indicated by increased cell viability and S-G2/M phase cell cycle distribution, decreased apoptosis, increased phosphorylation levels of AKT, GSK3ß and FOXO1A, and increased BCL-2 and decreased P21 and P27 expression. In addition, an AKT inhibitor blocked cell cycle progression and reduced cell viability in all groups of cells. Furthermore, SAFit2, a specific FKBP51 inhibitor, increased U937 cell viability and cytarabine resistance as well as AKT phosphorylation. In conclusion, FKBP51 decelerates proliferation and improves the cytarabine sensitivity of AML-M5 cells by inhibiting AKT pathways, and dexamethasone in combination with Ara-C improves the chemosensitivity of AML-M5.

Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway.

Diabetes is a potential risk factor for gastric cancer (GC). Pin1, a peptidyl-prolyl cis/trans isomerase, promotes GC cell proliferation and migration. The role and underlying mechanism of the Pin1/BRD4 axis in hyperglycemia-induced proliferation and migration of GC cells were analyzed in vivo and in vitro. Proliferation and migration of GC cells were measured; Pin1 and BRD4 expression of the cell cycle were determined. Pin1 and BRD4 were downregulated by transfecting Pin1 shRNA lentivirus into GC cells and JQ1-intervention GC cells. Tumor formation and lung metastasis were assessed in vivo. Inhibition of Pin1 and BRD4 significantly suppressed high-glucose (HG)-induced GC cell proliferation and migration. HG enhanced G1/S cell-cycle transition, associated with increased Pin1 and BRD4 expression. Silencing Pin1 significantly downregulated the expression of BRD4 and NAP1L1 and upregulated that of P21 in GC cells. In vivo studies indicated that hyperglycemia promotes tumor growth and lung metastasis by inducing Pin1 and BRD4 expression. Thus, Pin1/BRD4 plays an important role in hyperglycemia-promoted tumor growth. The significance of these findings toward improved prognosis of diabetic patients with GC cannot be underestimated.

Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.

Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14+ monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene (FCGR3A) is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.

The Impact of Bariatric Surgery Versus Non-Surgical Treatment on Blood Pressure: Systematic Review and Meta-Analysis.

The purpose of this study was to compare bariatric surgery versus non-surgical treatment on blood pressure for patients with obesity. Nineteen RCTs (1353 total patients) were included. In the pooled analyses, bariatric surgery reduces more systolic blood pressure (WMD: - 3.937 mmHg, CI95%: - 6.000 to - 1.875, p < 0.001, I2 = 0%), diastolic blood pressure (WMD: - 2.690 mmHg, CI95%: - 3.994 to - 1.385, P < 0.001, I2 = 0%) and more antihypertensives. In subgroup analyses, patients after Roux-en-Y gastric bypass, with poor control of hypertension (BP > 130/80 mmHg) and diabetes mellitus (HbA1C > 7.0%, FPG > 7.0 mmol/L), elder patients (> 45 years), non-severe obesity (BMI < 40 kg/cm2, body weight < 120 kg), less waist circumference (< 115 cm) tend to decrease more blood pressure. Besides, patients after surgery also lost more weight (p < 0.001), decreased more waist circumference (p < 0.001), fasting plasma glucose (p < 0.001), glycosylated hemoglobin (p < 0.001), triglycerides (p < 0.001), hsCRP (p = 0.001), increased more high-density lipoprotein cholesterol (p < 0.001), and had better remission of metabolic syndrome (p < 0.001). Changes in total cholesterol, low-density lipoprotein cholesterol, renal function, resting heart rate, and 6-min walking test were not significantly different. Therefore, bariatric surgery is more effective than non-surgical treatment in controlling patients' blood pressure.

FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling.

FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKß, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. Collectively, FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate the transcriptional activity and nuclear translocation of NF-κB, thereby promoting LUAD progression. Our findings suggest that FKBP4 may function as a prognostic biomarker of LUAD and provide a newly mechanistic insight into modulating IKK/NF-κB signaling.

Virucidal activity and the antiviral mechanism of acidic polysaccharides against Enterovirus 71 infection in vitro.

Enterovirus 71 (EV71) is the predominant pathogen for severe hand, foot, and mouth disease (HFMD) in children younger than 5 years, and currently no effective drugs are available for EV71. Thus, there is an urgent need to develop new drugs for the control of EV71 infection. In this study, LJ04 was extracted from Laminaria japonica using diethylaminoethyl cellulose-52 with 0.4 mol/l NaCl as the eluent, and its virucidal activity was evaluated based on its cytopathic effects on a microplate. LJ04 is composed of fucose, galactose, and mannose and mainly showed good virucidal activity against EV71. The antiviral mechanisms of LJ04 were the direct inactivation of the virus, the blockage of virus binding, disruptions to viral entry, and weak inhibitory activity against the nonstructural protein 3C. The two most important findings from this study were that LJ04 inhibited EV71 proliferation in HM1900 cells, which are a human microglia cell line, and that LJ04 can directly inactivate EV71 within 2 hr at 37°C. This study demonstrates for the first time the ability of a polysaccharide from L. japonica to inhibit viral and 3C activity; importantly, the inhibition of 3C might have a minor effect on the antiviral effect of LJ04. Consequently, our results identify LJ04 as a potential drug candidate for the control of severe EV71 infection in clinical settings.

Lnc-NA inhibits proliferation and metastasis in endometrioid endometrial carcinoma through regulation of NR4A1.

Endometrioid endometrial carcinoma (EEC) is the most common gynaecologic malignancy worldwide. Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, particularly cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in EEC have not been extensively studied. Here, we describe the discovery of Lnc-NA from the promoter of the transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) gene. The role and function of Lnc-NA in EEC remain unknown. In this study, we used quantitative real-time polymerase chain reactions to confirm that Lnc-NA expression was down-regulated in 30 EEC cases (90%) and in EEC cell lines compared with that in the paired adjacent tissues and normal endometrial cells. In vitro experiments further demonstrated that overexpressing Lnc-NA decreased EEC cell proliferation, migration and invasion and promoted apoptosis via inactivation of the apoptosis signalling pathway. Moreover, the results show that Lnc-NA expression was positively correlated with NR4A1. Furthermore, Lnc-NA regulated NR4A1 expression and activated the apoptosis signalling pathway to inhibit tumour progression. In summary, our results demonstrate that the Lnc-NA-NR4A1 axis could be a useful tumour suppressor and a promising therapeutic target for EEC.

Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques.

Subclinical hypothyroidism is associated with cardiovascular diseases, yet the underlying mechanism remains largely unknown. Herein, in a common population (n = 1,103), TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness. Consistently, TSH receptor ablation in ApoE -/- mice attenuated atherogenesis, accompanied by decreased vascular inflammation and macrophage burden in atherosclerotic plaques. These results were also observed in myeloid-specific Tshr-deficient ApoE -/- mice, which indicated macrophages to be a critical target of the proinflammatory and atherogenic effects of TSH. In vitro experiments further revealed that TSH activated MAPKs (ERK1/2, p38α, and JNK) and IκB/p65 pathways in macrophages and increased inflammatory cytokine production and their recruitment of monocytes. Thus, the present study has elucidated the new mechanisms by which TSH, as an independent risk factor of atherosclerosis, aggravates vascular inflammation and contributes to atherogenesis.

A FKBP5 mutation is associated with Paget's disease of bone and enhances osteoclastogenesis.

Paget's disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. Herein, we report a case of Chinese familial PDB without mutations in known genes and identify a novel c.163G>C (p.Val55Leu) mutation in FKBP5 (encodes FK506-binding protein 51, FKBP51) associated with PDB using whole-exome sequencing. Mutant FKBP51 enhanced the Akt phosphorylation and kinase activity in cells. A study of osteoclast function using FKBP51V55L KI transgenic mice proved that osteoclast precursors from FKBP51V55L mice were hyperresponsive to RANKL, and osteoclasts derived from FKBP51V55L mice displayed more intensive bone resorbing activity than did FKBP51WT controls. The osteoclast-specific molecules tartrate-resistant acid phosphatase, osteoclast-associated receptor and transcription factor NFATC1 were increased in bone marrow-derived monocyte/macrophage cells (BMMs) from FKBP51V55L mice during osteoclast differentiation. However, c-fos expression showed no significant difference in the wild-type and mutant groups. Akt phosphorylation in FKBP51V55L BMMs was elevated in response to RANKL. In contrast, IκB degradation, ERK phosphorylation and LC3II expression showed no difference in wild-type and mutant BMMs. Micro-CT analysis revealed an intensive trabecular bone resorption pattern in FKBP51V55L mice, and suspicious osteolytic bone lesions were noted in three-dimensional reconstruction of distal femurs from mutant mice. These results demonstrate that the mutant FKBP51V55L promotes osteoclastogenesis and function, which could subsequently participate in PDB development.

Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.

Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis.

Hepatitis B Virus e Antigen Regulates Monocyte Function and Promotes B Lymphocyte Activation.

Hepatitis B virus (HBV) e (HBe) antigen is a nonstructural virus component with great immune regulation roles. It regulates adaptive immunity response and participates in persistent infection development. However, its roles on monocytes and B lymphocytes were rarely studied. Herein, we studied HBe roles on U937 and Hmy2.CIR by creating HBe stably transfected cells using lentivirus. We detected the motility of HBe-U937 through transwell migration assay. Cytokines that primarily produced by monocytes, including BAFF, B-cell activating factor (BAFF), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and A proliferation inducing ligand (APRIL), were measured in culture supernatants of transfected U937, and serum BAFF, IL-6, and IL-10 were detected in HBe-positive and HBe-negative HBV-infected patients. Among these, BAFF mRNA and membrane-bound BAFF were further detected. Activation and inhibition markers of B lymphocytes on HBe-Hmy2.CIR and proliferation of transfected Hmy2.CIR after coculture with transfected U937 were also detected. We found that U937 migration was inhibited by HBe. BAFF expression was increased in HBe-U937, however, membrane-bound BAFF on HBe-U937 was decreased. In addition, Serum BAFF in HBe-positive patients was higher than in HBe-negative patients. IL-6 and IL-10 were increased in HBe-U937 after being stimulated by lipopolysaccharide (LPS), however, serum IL-6 and IL-10 were not associated with HBe status in patients. Besides, TNF-α and APRIL expression were basically the same in GV166-U937 and HBe-U937. B lymphocyte activation markers CD86 and Tspan33 were raised in HBe-Hmy2.CIR. However, inhibition markers Lyn and CD32b had no differences between HBe-Hmy2.CIR and control. Proliferation of transfected Hmy2.CIR was not affected by coculture with transfected U937, however, HBe transfection itself enhanced Hmy2.CIR proliferation. Altogether, these revealed that HBe can inhibit U937 migration and promote cytokines, including BAFF, IL-6, and IL-10, production in U937. Besides, HBe enhances BAFF release from U937 and increases BAFF concentration in vivo. In addition, HBe antigen facilitates Hmy2.CIR activation and proliferation through direct induction.

Acetylsalicylic acid combined with diclofenac inhibits cartilage degradation in rabbit models of osteoarthritis.

The present study aimed to investigate the effect of different concentrations of acetylsalicylic acid combined with diclofenac on the articular cartilage of a rabbit model of osteoarthritis (OA). A total of 40 New Zealand white rabbits were divided into 5 groups. Group A was a sham-operated control group, which was treated with normal saline. Groups B-E were OA models and were treated with normal saline and acetylsalicylic acid combined with diclofenac at concentrations of 5, 10 and 20 mg/kg, respectively. A cartilage macroscopic examination and a pathological observation were performed to analyze the structure of the articular cartilage in all of the treated groups. The nitric oxide (NO) content and interleukin 1ß (IL-1ß) levels were detected by an enzyme-linked immunosorbent assay. In addition, the protein expression of matrix metalloproteinase 3 (MMP)-3 and MMP-13 were detected by western blot analysis. The mRNA expression of tissue inhibitor of metalloproteinases 1 (TIMP1) was detected by polymerase chain reaction (PCR). The results revealed that different concentrations of the drugs significantly reduced the scores of cartilago articularis, the NO and IL-1ß levels and the protein expression of MMP-3 and MMP-13. Furthermore, PCR revealed that the mRNA expression of TIMP1 was significantly upregulated, and the effects increased with increasing drug concentration. Thus, the administration of different concentrations of acetylsalicylic acid combined with diclofenac demonstrates preventive or therapeutic effects against OA progression.

Endoplasmic Reticulum Stress May Play a Pivotal Role in Lipid Metabolic Disorders in a Novel Mouse Model of Subclinical Hypothyroidism.

Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSH in vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI, and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.

Association of IL-1R2 genetic polymorphisms with the susceptibility of ankylosing spondylitis in Northern Chinese Han population.

OBJECTIVES: Previous Genome-wide association studies (GWAS) have demonstrated Interleukin-1 receptor 2 (IL-1R2) was strongly associated with susceptibility to ankylosing spondylitis (AS). The aim of this study was to replicate the association of IL-1R2 single-nucleotide polymorphisms (SNPs) with AS in the northern Han Chinese. METHODS: A total of 490 AS patients and 580 matched healthy controls were enrolled in our study. Six tagSNPs in IL-1R2: rs4851526, rs4851527, rs2302589, rs2072476, rs2072472, and rs2310173 were selected and genotyped by Taqman SNP genotyping method. The differences of allele and genotype frequencies were analyzed by use of PLINK 1.07. RESULTS: Logistic regression analysis showed that one tagSNP rs2302589 in IL-1R2 was significantly associated with AS susceptibility (OR 0.77, 95% CI = 0.64-0.92, P = 0.005). However, no significant association was observed on the other tagSNPs for AS risk. The haplotype analysis further showed that the haplotype "GCGCGG" of IL-1R2 was also associated with the increased risk of AS (OR 1.362, P = 0.0207). CONCLUSIONS: This is the first detection that the genetic variation rs2302589 in IL-1R2 gene was associated with AS in Northern Han Chinese. This result confirmed that IL-1R2 may be genetic biomarker for susceptibility to AS.