A meta-analysis comparing the efficacy of mineralized collagen-polymethylmethacrylate and polymethylmethacrylate bone cements in the treatment of vertebral compression fractures.

PURPOSE: Vertebral compression fractures are often treated with vertebroplasty, and filling the injured vertebrae with bone cement is a key part of vertebroplasty. This meta-analysis was performed to compare the clinical efficacy and safety of mineralized collagen-polymethylmethacrylate (MC-PMMA) and polymethylmethacrylate (PMMA) bone cement in the treatment of vertebral compression fractures by vertebroplasty. METHODS: A computerized search of the published literature on mineralized collagen-polymethylmethacrylate and polymethylmethacrylate bone cement in the treatment of vertebral compression fractures was conducted in the China National Knowledge Infrastructure (CNKI), Wanfang database, PubMed, Embase, and Cochrane Library. The search was carried out from the time the database was created to March 2023 and 2 researchers independently conducted literature searches to retrieve a total of 884 studies, of which 12 were included in this meta-analysis. Cochrane systematic review methods were used to assess the quality of the literature and a meta-analysis was performed using ReviewManager 5.4 software. RESULTS: The results of the present meta-analysis showed that in postoperative adjacent vertebral fractures [OR = 0.25; 95% CI (0.15, 0.41)], postoperative cement leakage [OR = 0.45; 95% CI (0.30, 0.68)], Oswestry Disability Index (ODI) scores in the first 3 days after surgery [OR = -0.22; 95% CI (-0.42, -0.03)], ODI score at 6-12 months postoperatively [OR = -0.65; 95% CI (-0.97, -0.32)], visual analog scale (VAS) score at 6-12 months postoperatively [OR = -0.21; 95% CI (-0.46, 0.04)], and 1-year postoperative CT values [OR = 5.56; 95% CI (3.06, 8.06)], the MC-PMMA bone cement group was superior to the PMMA bone cement group. However, the differences between the two groups were not statistically different in terms of cement filling time, cement filling volume, operation time, intraoperative bleeding, hospitalization time, postoperative (<1 week, 3-6 months) vertebral body posterior convexity Cobb's angle, postoperative (<1 week, 6-12 months) vertebral body anterior margin relative height, postoperative (≤3 days, 1-3 months) pain VAS score and postoperative (1-3 months) ODI score. CONCLUSIONS: Compared with PMMA bone cement, the application of MC-PMMA bone cement is advantageous in reducing postoperative complications (adjacent vertebral fracture rate, cement leakage rate), pain relief, and functional recovery in the long-term postoperative period (>6 months), but there is still a need for more high-quality randomized controlled studies to provide more adequate evidence.

Association between the ESR1 and ESR2 polymorphisms and osteoporosis risk: An updated meta-analysis.

BACKGROUND: Gene polymorphisms of estrogen receptor (ESR) 1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), and RsaI (rs1256049) had been reported to be associated with the risk of osteoporosis. However, these conclusions were inconsistent, therefore, an updated meta-analysis was conducted to further explore these issues. OBJECTIVE: To evaluate the association between gene polymorphisms of ESR1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), RsaI (rs1256049), and osteoporosis risk. MATERIALS AND METHODS: PubMed, Medline, Ovid, Embase, CNKI, and China Wanfang databases were searched. Association was assessed using odds ratio with 95% confidence interval. Moreover, the false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria were used to assess the credibility of statistically significant associations. RESULTS: Overall, ESR1 PvuII (rs2234693) and XbaI (rs9340799) were associated with the risk of osteoporosis in Indians. Moreover, ESR1 G2014A (rs2228480) was associated with the decreased risk of osteoporosis in East Asians. Moreover, ESR2 Alul (rs4986938) was associated with the increased risk of osteoporosis in East Asians and Caucasians. There was a significant association between ESR2 Rsal (rs1256049) and osteoporosis risk in overall population. When only high-quality and Hardy-Weinberg equilibrium studies were included in the sensitivity analysis, all results did not change in the present study. When the credibility was evaluated applying false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria, all significant associations were considered as false positive results. CONCLUSIONS: In summary, this study shows that all substantial associations between gene polymorphisms of ESR1 (PvuII, XbaI, and G2014A) and ESR 2 (AluI and RsaI) and osteoporosis risk are possibly false positive results instead of real associations or biological variables.

Discovery of Novel Mono-Carbonyl Curcumin Derivatives as Potential Anti-Hepatoma Agents.

Curcumin possesses a wide spectrum of liver cancer inhibition effects, yet it has chemical instability and poor metabolic properties as a drug candidate. To alleviate these problems, a series of new mono-carbonyl curcumin derivatives G1-G7 were designed, synthesized, and evaluated by in vitro and in vivo studies. Compound G2 was found to be the most potent derivative (IC50 = 15.39 µM) compared to curcumin (IC50 = 40.56 µM) by anti-proliferation assay. Subsequently, molecular docking, wound healing, transwell, JC-1 staining, and Western blotting experiments were performed, and it was found that compound G2 could suppress cell migration and induce cell apoptosis by inhibiting the phosphorylation of AKT and affecting the expression of apoptosis-related proteins. Moreover, the HepG2 cell xenograft model and H&E staining results confirmed that compound G2 was more effective than curcumin in inhibiting tumor growth. Hence, G2 is a promising leading compound with the potential to be developed as a chemotherapy agent for hepatocellular carcinoma.

Titanium­coated polyetheretherketone cages vs. polyetheretherketone cages in lumbar interbody fusion: A systematic review and meta­analysis.

Fusion material is one of the key factors in the success of lumbar interbody fusion surgery. The present meta-analysis compared the safety and efficacy of titanium-coated (Ti) polyetheretherketone (PEEK) and PEEK cages. Published literature on the use of Ti-PEEK and PEEK cages in lumbar interbody fusion was systematically searched on Embase, PubMed, Central, Cochrane Library, China National Knowledge Infrastructure and Wanfang databases. A total of 84 studies were retrieved and seven were included in the present meta-analysis. Literature quality was assessed using the Cochrane systematic review methodology. After data extraction, meta-analysis was performed using the ReviewManager 5.4 software. Meta-analysis showed that, compared with that in the PEEK cage group, the Ti-PEEK cage group showed a higher interbody fusion rate at 6 months postoperatively (95% CI, 1.09-5.60; P=0.03) and improved Oswestry Disability Index (ODI) scores at 3 months postoperatively [95% CI, -7.80-(-0.62); P=0.02] and visual analog scale (VAS) scores of back pain at 6 months postoperatively [95% CI, -0.8-(-0.23); P=0.0008]. However, there were no significant differences in intervertebral bone fusion rate (12 months after surgery), cage subsidence rate, ODI score (6 and 12 months after surgery) or VAS score (3 and 12 months after surgery) between the two groups. The results of the meta-analysis showed that the Ti-PEEK group had an improved interbody fusion rate and higher postoperative ODI score in the early postoperative period (≤6 months).

Association between OPG polymorphisms and osteoporosis risk: An updated meta-analysis.

Background: Numerous studies have demonstrated an association between osteoprotegerin (OPG) polymorphisms (A163G (rs3102735), T245G (rs3134069), T950C (rs2073617), G1181C (rs2073618)) and osteoporosis risk. However, their conclusions are inconsistent. In addition, some new studies have been updated, and more importantly, previous meta-analyses have not tested for false-positive results. In order to further explore these associations, we recently conducted a meta-analysis. Objectives: To study the relationship between OPG polymorphisms A163G, T245G, T950C, G1181C and the risk of osteoporosis. Methods: PubMed, Medline, International Statistical Institute (ISI), China National Knowledge Infrastructure (CNKI) and China Wanfang Database were used for research searches. Associations were assessed with five genetic models using odds ratios (ORs) with 95% confidence intervals (CIs). In addition, confidence in statistically significant associations was assessed using false-positive report probability (FPRP), Bayesian probability of False discovery (BFDP), and Venice criteria. Results: On the whole, the OPG A163G polymorphism was not significantly associated with risk of osteoporosis. However, in a subgroup analysis, we found that the OPG A163G polymorphism increased the risk of osteoporosis in Caucasians (AG + GG vs AA: OR = 1.35, 95% CI = 1.06-1.73; AA + GG vs AG: OR = 0.64, 95% CI = 0.49-0.82) and the female (G vs A: OR = 1.30, 95% CI = 1.03-1.64; AG + GG vs AA: OR = 1.42, 95% CI = 1.18-1.71). At the same time, the OPG G1181C polymorphism reduces the risk of osteoporosis (C vs G: OR = 0.84, 95% CI = 0.74-0.95; CC vs GG: OR = 0.75, 95% CI = 0.60-0.93; GC + CC vs GG: OR = 0.80, 95% CI = 0.67-0.95; CC vs GG + GC: OR = 0.84, 95% CI = 0.70-1.00). Moreover, a significantly decreased risk of osteoporosis was also discovered in Asian (C vs G: OR = 0.80, 95% CI = 0.66-0.98; CC vs GG: OR = 0.67, 95% CI = 0.47-0.95; GC + CC vs GG: OR = 0.74, 95% CI = 0.58-0.95) and the female (C vs G: OR = 0.85, 95% CI = 0.75-0.97; CC vs GG: OR = 0.77, 95% CI = 0.61-0.96; GC + CC vs GG: OR = 0.79, 95% CI = 0.66-0.95). Finally, we did not find a close association between OPG T245G and T950C polymorphisms and osteoporosis risk. However, when we retained only studies in the control group that was consistent with Hardy-Weinberg equilibrium (HWE) and high-quality scores, we observed that the OPG A163G polymorphism increased the risk of osteoporosis in the overall analysis (G vs A: OR = 1.40, 95% CI = 1.16-1.68; GG vs AA: OR = 1.96, 95% CI = 1.20-3.21; AG + GG vs AA: OR = 1.45, 95% CI = 1.22-1.72). Finally, after the credibility assessment, we concluded that all statistically significant association results in the meta-analysis in this study and those in the previous study were 'positive results with low confidence'. Conclusion: In conclusion, our study concluded that all meaningful results between OPG A163G and G1181C polymorphisms and osteoporosis risk were false-positive results rather than true associations.

Exome sequencing revealed USP9X and COL2A1 mutations in a large family with multiple epiphyseal dysplasia.

Diagnosis of rare skeletal diseases is based primarily on clinical phenotype and radiographic analysis. Genetic etiology of these heterogeneous diseases remains largely unknown. Here, we report the identification of two genomic mutations using exome sequencing from patients with multiple epiphyseal dysplasia (MED) of an unusual family in autosomal dominant and X-linked inheritance. A dominant mutation (c.2224G > A; p.Gly687Ser) in the known causal COL2A1 gene was identified in three patients with MED, deformed femoral heads and vertebral dysplasia. Furthermore, a hemizygous mutation (c.2830G > A; p.Ala944Thr) in the USP9X gene was identified in the fourth patient with short stature, MED, deformed femoral head, thoracic and lumbar platyspondyly, right ankle condyle dysplasia, and subchondral sclerosis. This is the first identification of an X-linked candidate causative gene in a patient with MED, suggesting a new clinical entity. Our findings shed a new light on the role of USP9X in MED-associated disorders.

Evaluation of Association Studies and an Updated Meta-Analysis of VDR Polymorphisms in Osteoporotic Fracture Risk.

Background: Several studies have examined the association between vitamin D receptor (VDR) polymorphisms and osteoporotic fracture risk; however, the results are not uniform. Furthermore, many new articles have been published, and therefore, an updated meta-analysis was performed to further explore these issues. Objectives: The aim of the study was to investigate the association between VDR, BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and osteoporotic fracture risk. Methods: The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between VDR BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and the risk of osteoporotic fracture. We also used the false-positive reporting probability (FPRP) test and the Venice criteria to evaluate the credibility of the statistically significant associations. Results: Overall, this study found that the VDR ApaI and BsmI polymorphisms significantly increased the risk of osteoporotic fracture in European countries and America, respectively. However, when sensitivity analysis was performed after excluding low-quality and Hardy-Weinberg disequilibrium (HWD) studies, it was found that only individuals with the double-mutated genotype have an increased risk of osteoporotic fracture in European countries. In addition, when the credibility of the positive results was assessed, it was found that the positive results were not credible. Conclusion: This meta-analysis indicates that there may be no significant association among the polymorphisms of VDR BsmI, ApaI, TaqI, FokI, and Cdx2 and the risk of osteoporotic fracture. The increased risk of osteoporotic fracture is most likely due to false-positive results.

Association between vitamin D receptor BsmI, FokI, and Cdx2 polymorphisms and osteoporosis risk: an updated meta-analysis.

BACKGROUND: Many studies have reported the association between vitamin D receptor (VDR) polymorphism and osteoporosis risk. However, their results were conflicting. Six previous meta-analyses have been published to analyze VDR BsmI, FokI, and Cdx2 polymorphisms on osteoporosis risk. However, they did not evaluate the reliability of statistically significant associations. Furthermore, a lot of new articles have been published on these themes, and therefore an updated meta-analysis was performed to further explore these issues. OBJECTIVES: To explore the association between VDR BsmI, FokI, and Cdx2 polymorphisms polymorphisms and osteoporosis risk. METHODS: The odds ratios (ORs) and 95% confidence intervals (95% CIs) were pooled to evaluate the association between VDR BsmI, FokI, and Cdx2 polymorphisms and osteoporosis risk. To evaluate the credibility of statistically significant associations, we applied the false-positive report probabilities (FPRPs) test and the Venice criteria. RESULTS: Overall, statistically significantly increased osteoporosis risk was found in Indians and women for VDR FokI polymorphism. Statistically significantly decreased osteoporosis risk was found in West Asians for VDR BsmI polymorphism. However, when we performed a sensitivity analysis after excluding low quality and Hardy-Weinberg Disequilibrium (HWD) studies, significantly decreased osteoporosis risk was only found in overall population for VDR BsmI polymorphism. Further, less-credible positive results were identified when we evaluated the credibility of positive results. CONCLUSION: These positive findings should be interpreted with caution and indicate that significant association may most likely result from less-credible, rather than from true associations or biological factors on the VDR BsmI and FokI polymorphisms with osteoporosis risk.

Association of IL-6 174G/C (rs1800795) and 572C/G (rs1800796) polymorphisms with risk of osteoporosis: a meta-analysis.

BACKGROUND: Several studies have been performed to investigate association between IL-6 174G/C (rs1800795) and 572C/G (rs1800796) gene polymorphisms and osteoporosis predisposition. However, the results were conflicting. So, we performed a meta-analysis designed to provide more reliable results for the association between IL-6 gene polymorphisms and osteoporosis. METHODS: Studies were searched using PubMed, EMBASE, the Cochrane Library and Wanfang electronic databases. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between IL-6 174G/C (rs1800795) and 572C/G (rs1800796) gene polymorphisms and osteoporosis risk. The false-positive report probabilities (FPRP) test and the venice criteria were used to assess the credibility of statistically significant associations. RESULTS: A total of 9 studies with 1891 osteoporosis patients and 2027 healthy controls were included in current meta-analysis. Overall, The IL-6 174G/C (rs1800795) gene polymorphism was insignificantly associated with osteoporosis vulnerability. For IL-6 572C/G (rs1800796), statistically significant elevated osteoporosis vulnerability was found in IL-6 572C/G additive model (OR = 2.25, 95% CI: 1.55-3.26), dominant model (OR = 1.42, 95% CI: 0.78-2.56) and recessive model (OR = 1.96, 95% CI: 1.36-2.83). However, the IL-6 572C/G C allele was found to be associated with reduced susceptibility to osteoporosis (OR = 0.76, 95% CI: 0.56-1.04). When excluding studies that did not conform to HWE, the results did not change significantly. Further, when we evaluated the credibility of the positive results of the current meta-analysis, we identified less credible positive results in IL-6 572C/G recessive and additive model. CONCLUSION: In conclusion, IL-6 572C/G GG genotype may be associated with increased risk of osteoporosis.

Annexin A1 involved in the regulation of inflammation and cell signaling pathways.

With the deepening of research, proteomics has developed into a science covering the study of all the structural and functional characteristics of proteins and the dynamic change rules. The essence of various biological activities is revealed from the perspectives of the biological structure, functional activity and corresponding regulatory mechanism of proteins by proteomics. Among them, phospholipid-binding protein is one of the hotspots of proteomics, especially annexin A1, which is widely present in various tissues and cells of the body. It has the capability of binding to phospholipid membranes reversibly in a calcium ion dependent manner. In order to provide possible research ideas for researchers, who are interested in this protein, the biological effects of annexin A1, such as inflammatory regulation, cell signal transduction, cell proliferation, differentiation and apoptosis are described in this paper.

Treating with besifloxacin for acute bacterial conjunctivitis: a Meta-analysis.

AIM: To evaluate the relative efficacy and safety of besifloxacin for treatment of acute bacterial conjunctivitis. METHODS: A comprehensive search in PubMed, EMBASE Web of Science, Cochrane Central Database and CNKI was undertaken for randomized controlled trials (RCTs) comparing besifloxacin with other treatments or placebo. The primary outcome measures were clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, and bacterial eradication rates of different kinds of pathogens. Safety outcomes were the number of adverse effects (AEs). The final search was performed on August 2018. RESULTS: Six RCTs were included. Four studies compared the efficacy and safety of besifloxacin with placebo, 1 study compared besifloxacin with moxifloxacin, and 1 study compared besifloxacin with gatifloxacin. A total of 2780 patients met the inclusion criteria. Besifloxacin presented higher efficacy and safety than did placebo in clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, bacterial eradication rates of different kinds of pathogens and the number of AEs. There was no significant difference between besifloxacin and moxifloxacin or gatifloxacin in the comparison items mentioned above. CONCLUSION: Besifloxacin is highly effective and safe for treatment of acute bacterial conjunctivitis. Further comparative trials regarding the effect of besifloxacin for treatment of acute bacterial conjunctivitis will aid in treatment decisions.

The Effect of Metformin on Thyroid-Associated Serum Hormone Levels and Physiological Indexes: A Meta-Analysis.

BACKGROUND: Many diseases can be treated with metformin. People with serum thyrotropin (TSH) levels higher than 10 mIU/L are at a risk of cardiovascular events. Some studies have suggested that metformin can lower serum TSH levels to a subnormal level in patients with hyperthyrotropinaemia or hypothyroidism. OBJECTIVE: The objective of this analysis is to evaluate the effect of metformin treatment on serum TSH, free triiodothyronine (FT3), and free thyroxine (FT4) levels and other associated physiological indices. METHODS: A comprehensive search using the PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for controlled trials on the effect of metformin on serum TSH, FT3, and FT4 levels and associated physiological indices. The primary outcome measures were serum TSH, FT3 and FT4 levels, thyroid size, thyroid nodule size, blood pressure, heart rate, body weight, and body mass index (BMI). The final search was conducted in April 2019. RESULTS: Six RCTs were included. A total of 494 patients met the inclusion criteria. Metformin treatment did not significantly lower the serum TSH levels at 3 or 6 months but did at 12 months. Moreover, forest plots also suggested that metformin can significantly lower the serum TSH levels in patients with normal thyroid function but cannot statistically change the serum TSH levels in patients with abnormal thyroid function. In addition, metformin treatment clearly lowered the serum FT3 levels and had no significant effect on serum FT4 levels. Lastly, metformin cannot significantly change the systolic blood pressure (SBP) or BMI but can clearly increase the diastolic blood pressure (DBP). CONCLUSION: Metformin treatment can significantly lower the serum TSH levels, and this effect was much clearer after a 12-month treatment duration and in people with normal thyroid function. However, metformin cannot significantly change the serum FT4 levels or lower serum FT3 levels in people with non-thyroid cancer diseases. In addition, metformin can significantly increase DBP, but it has no clear effect on SBP or BMI.

The efficacy and safety of besifloxacin for acute bacterial conjunctivitis: a Meta-analysis.

AIM: To evaluate the relative efficacy and safety of besifloxacin for treatment of acute bacterial conjunctivitis. METHODS: A comprehensive search in PubMed, EMBASE Web of Science, Cochrane Central Database and CNKI was undertaken for randomized controlled trials (RCTs) comparing besifloxacin with other treatments or placebo. The primary outcome measures were clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, and bacterial eradication rates of different kinds of pathogens. Safety outcomes were the number of adverse effects (AEs). The final search was performed on August 2018. RESULTS: Eight RCTs were included. Five studies compared the efficacy and safety of besifloxacin with placebo, 2 studies compared besifloxacin with moxifloxacin, and 1 study compared besifloxacin with gatifloxacin. A total of 3105 patients met the inclusion criteria. Besifloxacin presented higher efficacy and safety than did placebo in clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, bacterial eradication rates of different kinds of pathogens and the number of AEs. There was no significant difference between besifloxacin and moxifloxacin or gatifloxacin in the comparison items mentioned above. CONCLUSION: Besifloxacin is highly effective and safe for treatment of acute bacterial conjunctivitis. Further comparative trials regarding the effect of besifloxacin for treatment of acute bacterial conjunctivitis will aid in treatment decisions.

Treatment of Glucocorticoid-Induced Osteoporosis with Bisphosphonates Alone, Vitamin D Alone or a Combination Treatment in Eastern Asians: A Meta-Analysis.

BACKGROUND: Glucocorticoid (GC)-induced osteoporosis and fractures have become a serious problem for Eastern Asians. Bisphosphonates (BPs), vitamin D and a combination treatment are effective methods to prevent and treat GC-induced osteoporosis. OBJECTIVE: The study aimed to compare the efficacy of BPs, vitamin D and a combination treatment for preventing and managing GC-induced osteoporosis in Eastern Asians. METHODS: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane CENTRAL databases was undertaken for randomized controlled trials (RCTs) on the effect of BPs, vitamin D and the combination treatment on GCs-induced osteoporosis in Eastern Asian populations. Primary outcome measures were the change in bone mineral density (BMD) and bone turnover markers. The final search was performed in March 2019. RESULTS: Nine RCTs were included. A total of 545 patients met the inclusion criteria. Compared with vitamin D, BPs and the combination treatment significantly alleviated osteoporosis of the spine and femoral neck in Eastern Asians with GC-induced osteoporosis. At the same time, the change in serum bone-specific alkaline phosphatase (BAP) and serum C-telopeptide of type I collagen (CTX) levels was observed to be significantly less with BPs and the combination treatment with vitamin D alone. No significant difference was found between BPs and the combination treatment in the markers mentioned above. CONCLUSION: Compared with vitamin D alone, BPs alone and the combination treatment were significantly effective on Eastern Asians with GC-induced osteoporosis. Compared with the combination treatment, BPs alone were observed to be effective enough to increase the BMDs of the spine and femoral neck on both sides and thus prevent GC-induced osteoporosis in Eastern Asians.

Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice.

Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol 314: R71-R83, 2018. First published September 13, 2017; doi: 10.1152/ajpregu.00157.2017 .-Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS-R1a) in the pancreas has raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signaling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [d-Lys3]-growth hormone-releasing peptide (GHRP)-6, on glucose homeostasis, food intake, and indirect calorimetric parameters in nonobese diabetic MKR mice. Our results showed that [d-Lys3]-GHRP-6 (200 nmol/mouse) reduced pulsatile growth hormone secretion and body fat mass as expected but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and C-peptide levels were observed in MKR mice following long-term [d-Lys3]-GHRP-6 treatment, suggesting a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin-positive cells and a decrease in insulin-positive cells in [d-Lys3]-GHRP-6-treated mice. Furthermore, [d-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of proopiomelanocortin gene expression and antagonized GH secretion via reduced growth hormone-releasing hormone gene expression in hypothalamus. These results demonstrate that [d-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes.

Collagen beta (1-O) galactosyltransferase 1 (GLT25D1) is required for the secretion of high molecular weight adiponectin and affects lipid accumulation.

Secretion of high molecular weight (HMW) adiponectin is dependent on post-translational modification (PTM) of conserved lysines in the collagenous domain. The present study aims to characterize the enzymes responsible for the PTM of conserved lysines which leads to HMW adiponectin secretion, and to define its significance in relation to obesity. Collagen beta (1-O) galactosyltransferase 1 (GLT25D1) was knocked down in HEK cells modified for the stable expression of adiponectin (adiponectin expressing human embryonic kidney cells, Adipo-HEK) as well as in Simpson Golabi-Behmel-Syndrome (SGBS) adipocytes. Knockdown of GLT25D1 caused a significant decrease in HMW adiponectin in Adipo-HEK cells with no change in total adiponectin. Knockdown in the SGBS cells caused an increase in lipid accumulation yet inhibited adipogenesis. Co-immunoprecipitation with adiponectin and mass spectrometry showed that adiponectin formed a protein complex with lysyl hydroxylase 3 (LH3) and GLT25D1. Transient overexpression of GLT25D1 showed that the intracellular retention of LH3 was dependent on GLT25D1. To determine whether changes in GLT25D1 were significant in obesity, mice were fed a standard chow or high-fat diet (HFD) for 5 weeks. GLT25D1 was significantly decreased in mice fed HFD which coincided with a decrease in HMW adiponectin. We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity.

Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice.

Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea. MC4R KO mice were hyperphagic, obese, hyperglycemic, hyperinsulinemic and demonstrated insulin resistance and hepatic steatosis. Irregular estrous cycles and significant changes in the LH secretion profiles were observed in sexually matured 16- to 28-week MC4R KO mice, without any difference in testosterone levels. In addition, MC4R KO mice at 16 weeks of age had significantly fewer corpora lutea than same age WT LM mice. The ovary examinations of MC4R KO mice at 28 weeks of age showed predominantly antral and preovulatory follicles with no corpora lutea. These findings were consistent with the decrease in total, pulsatile, mass and basal LH releases in MC4R KO mice. The characteristics of hormone profiles in obese MC4R KO mice indicate that MC4R plays an important role in regulating LH release, ovulation and reproductive ability probably via hyperphagia-induced obesity. Further study of correlation between metabolic and reproductive regulatory hormones is warranted to dissect the pathological mechanism underlying obesity-induced infertility.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction-online.org/content/153/3/267/suppl/DC1.

MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9.

OBJECTIVES: Sox9 has recently been reported to be a key mediator during cartilage degradation in osteoarthritis (OA). Our aim was to clarify the role of microRNA-30a (miR-30a) and its target gene Sox9 in regulation of extracellular matrix (ECM) degradation in OA. MATERIALS AND METHODS: Expression of miR-30a in cartilage tissues and in primary chondrocytes from healthy and OA donors, was determined by real-time PCR, and levels of Sox9 mRNA and protein were analyzed by real-time PCR and western blotting, respectively. Subsequently, the target of miR-30a was predicted by bioinformatics and confirmed using a luciferase assay. Expression of ECM-related genes was determined by tissue-specific staining, immunofluorescence, real-time PCR, and western blotting. The role of miR-30a in OA was examined in vivo using a collagenase-induced OA rat model. RESULTS: miR-30a was significantly upregulated and Sox9 was downregulated in primary chondrocytes from cartilage taken from OA donors compared to healthy controls. We showed that miR-30a specifically bound to the 3' UTR of Sox9, and overexpression of miR-30a downregulated expression levels of Sox9, proteoglycan aggrecan, and Col II compared to those induced by small interfering RNA transfection to knockdown Sox9. miR-30a inhibition reversed the effects of ECM degradation in vitro and in vivo. CONCLUSIONS: miR-30a acts as a virulence MRA in OA, promoting ECM degradation by targeting Sox9 and by modulating activity of its downstream effectors Col II and proteoglycan aggrecan.