HMBA ameliorates obesity by MYH9- and ACTG1-dependent regulation of hypothalamic neuropeptides.

The global epidemic of obesity remains a daunting problem. Here, we report hexamethylene bisacetamide (HMBA) as a potent anti-obesity compound. Peripheral and central administration of HMBA to diet-induced obese mice regulated the expression of hypothalamic neuropeptides critical for energy balance, leading to beneficial metabolic effects such as anorexia and weight loss. We found that HMBA bound to MYH9 and ACTG1, which were required for the anti-obesity effects of HMBA in both NPY-expressing and POMC-expressing neurons. The binding of HMBA to MYH9 and ACTG1 elevated the expression of HEXIM1 and enhanced its interaction with MDM2, resulting in the dissociation of the HEXIM1-p53 complex in hypothalamic cells. Subsequently, the free HEXIM1 and p53 translocated to the nucleus, where they downregulated the transcription of orexigenic NPY, but p53 and acetylated histone 3 upregulated that of anorexigenic POMC. Our study points to a previously unappreciated efficacy of HMBA and reveals its mechanism of action in metabolic regulation, which may propose HMBA as a potential therapeutic strategy for obesity.

Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ Signaling.

BACKGROUND & AIMS: The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. METHODS: We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. RESULTS: Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. CONCLUSIONS: Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.

Immediate arthroscopy following ORIF for tibial plateau fractures provide early diagnosis and treatment of the combined intra-articular pathologies.

PURPOSE: To evaluate the effectiveness of immediate arthroscopy and clinical outcomes following open reduction and internal fixation (ORIF) of tibial plateau fractures. METHODS: Sixty patients (36 men and 24 women, median age 56 (20-78) years) were divided into Group I (ORIF only: 26 patients, median age 58 (25-78) years) or Group II (ORIF with immediate arthroscopy: 34 patients, median age 55 (20-75) years) in tibial plateau fractures (Schatzker Type II-VI fractures). In the first part of this study, ORIF only was performed without arthroscopic treatment. In the second part, ORIF with immediate arthroscopic examination and treatment was performed. Clinical outcomes, utilizing range of motion (ROM), International Knee Documentation Committee (IKDC) score and hospital for special knee score (HSS) were assessed. RESULTS: At the final follow-up, HSS score was 81 ± 11 points in Group I and 83 ± 9 points in Group II. The IKDC score was 85 ± 8 points in Group I and 86 ± 6 points in Group II. In Group II, concomitant intra-articular lesions in 10 patients (29%) were found and treated simultaneously. However, there were no significant differences in clinical scores or ROM between the two groups. CONCLUSION: Immediate arthroscopy following ORIF for tibial plateau fracture is an effective procedure that provides accurate information for fracture reduction, leading to immediate treatment of concomitant intra-articular lesions without complications. LEVEL OF EVIDENCE: III.

Delayed Lateral Row Anchor Failure in Suture Bridge Rotator Cuff Repair: A Report of 3 Cases.

Compared to single row repair, use of lateral row anchors in suture bridge rotator cuff repair enhances repair strength and increases footprint contact area. If a lateral knotless anchor (push-in design) is inserted into osteoporotic bone, pull-out of the lateral row anchor can developed. However, failures of lateral row anchors have been reported at several months after surgery. In our cases, even though complete cuff healing occurred, delayed pull-out of the lateral row anchor in the suture bridge repair occurred. In comparison to a conventional medial anchor, further biomechanical evaluation of the pull-out force, design, and insertion angle of the lateral anchor is needed in future studies. We report three cases with delayed pull-out of lateral row anchor in suture bridge rotator cuff repair with a literature review.

Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1.

Scopoletin (6-methoxy-7-hydroxycoumarin) is a coumarin compound and a pharmacologically active agent that has been isolated from several plant species. However, as yet there is no clear explanation of how scopoletin affects the production of inflammatory cytokine. We therefore used cells from the human mast cell line (HMC-1) to investigate this effect. Scopoletin significantly and dose-dependently inhibits the way in which phorbol 12-myristate 13-acetate (PMA) plus A23187 induces the production of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 (P<0.05). The maximal rates at which scopoletin (0.2 mM) inhibited the production of TNF-alpha, IL-6, and IL-8 were 41.6%+/-4.2%, 71.9%+/-2.5%, and 43.0%+/-5.7%, respectively. In activated HMC-1 cells, the expression level of nuclear factor (NF)-kappaB/Rel A protein was increased in the nucleus whereas the level of NF-kappaB/Rel A in nucleus was decreased by treatment with scopoletin. Scopoletin decreased PMA plus A23187-induced luciferase activity. Scopoletin also inhibits IkappaBalpha phosphorylation and degradation in cytoplasm. These results indicate that scopoletin has a potential regulatory effect on inflammatory reactions that are mediated by mast cells.