Robert G. Dorfman

Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2

Phosphoenolpyruvate carboxykinase 1 (PEPCK1) is the critical enzyme for gluconeogenesis and is linked with type II diabetes. Previous studies have found that SIRT2, a deacetylase, plays an important role in deacetylating PEPCK1 and little is known about the anti-diabetic activity of SIRT2 inhibitors. In this study, we investigated the anti-diabetic effects of sirtinol, a SIRT2 inhibitor, on cell gluconeogenesis in vivo and in vitro. Immunoblotting analysis revealed that sirtinol significantly decreased the protein level of PEPCK1, and was accompanied by the hyperacetylation of PEPCK1 as well as decreased glucose output in a dose-dependent manner. Furthermore, sirtinol exerted little impact on endogenous PEPCK1 levels in SIRT2-knockdown cells. The in vitro experiments further confirmed the in vivo data; sirtinol decreased liver PEPCK1 protein level and prevented pyruvate-induced blood glucose from increasing. Based on our results, the rate-limiting enzyme PEPCK1 is the primary target of sirtinol, and the inhibition of SIRT2 activity may play an important role in cell gluconeogenesis. Thus, SIRT2 may be a novel molecular target for diabetes therapy and may thus shed light on the underlying diabetes treatment mechanisms of sirtinol.

Butyrate inhibits interleukin-17 and generates Tregs to ameliorate colorectal colitis in rats

BackgroundButyrate is an energy source for colonocytes that is formed by bacterial fermentation of dietary fiber in the colon and that exerts broad anti-inflammatory activities. Although the administration of butyrate improves homeostasis in patients and ameliorates IBD (Inflammatory Bowel Disease)-related lesions and symptoms, the anti-inflammatory mechanisms of butyrate still remain unclear. To explore the impact of butyrate on Treg (Regulatory T cell)/Th17 (T helper 17 cell) differentiation and colitis in rats.MethodsThe effect of butyrate on the expression of markers related to both Tregs and Th17 cells were determined in human monocytes as well as a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid. Rats were treated with butyrate in vivo, whereas the rat splenocytes and human monocytes were treated in vitro.ResultsWe found that butyrate administration increased peripheral blood Treg cell levels as well as plasma levels of anti-Th17 cytokines (IL-10 and IL-12). Butyrate administration further suppressed IL-17 levels in both plasma and colonic mucosa, and ameliorated colonic colitis lesions in rats. This promotion of Treg activity and inhibition of IL-17 release was also observed in human venous monocytes and rat splenocytes in vitro.ConclusionsOur results suggest that butyrate plays a key role in regulating the Treg/Th17 balance and ultimately protects the colon mucosa against the development of IBD.

Mucosa-reparing and microbiota-balancing therapeutic effect of Bacillus subtilis alleviates dextrate sulfate sodium-induced ulcerative colitis in mice

Gut microbiota composition of patients with ulcerative colitis (UC) is markedly altered compared with healthy individuals. There is mounting evidence that probiotic therapy alleviates disease severity in animal models and patients with inflammatory bowel disease (IBD). Bacillus subtilisis, as a probiotic, has also demonstrated a protective effect in IBD. However, the therapeutic mechanism of its action has yet to be elucidated. In the present study, a dextrose sulfate sodium (DSS)-induced UC mouse model was used to investigate the role of B. subtilis in the restoration of gut flora and determine its effective dose. Mucosal damage was assessed by performing alcian blue staining, cytokine levels were analyzed by ELISA and microbiota composition was investigated using 454 pyrosequencing to target hypervariable regions V3-V4 of the bacterial 16S ribosomal RNA gene. The results demonstrated that a higher dose B. subtilisis administration ameliorated DSS-induced dysbiosis and gut inflammation by balancing beneficial and harmful bacteria and associated anti- and pro-inflammatory agents, thereby aiding intestinal mucosa recovery from DSS-induced injuries. These findings indicate that choosing the correct dose of B. subtilis is important for effective UC therapy. The present study also helped to elucidate the mechanisms of B. subtilis action and provided preclinical data for B. subtilis use in UC therapy.

The Ethics of Sharing Plastic Surgery Videos on Social Media: Systematic Literature Review, Ethical Analysis, and Proposed Guidelines

Summary: Recent videos shared by plastic surgeons on social media applications such as Snapchat, Instagram, and YouTube, among others, have blurred the line between entertainment and patient care. This has left many in the plastic surgery community calling for the development of more structured oversight and guidance regarding video sharing on social media. To date, no official guidelines exist for plastic surgeons to follow. Little is known about the ethical implications of social media use by plastic surgeons, especially with regard to video sharing. A systematic review of the literature on social media use in plastic surgery was performed on October 31, 2016, with an emphasis on ethics and professionalism. An ethical analysis was conducted using the four principles of medical ethics. The initial search yielded 87 articles. Thirty-four articles were included for analyses that were found to be relevant to the use of social media in plastic surgery. No peer-reviewed articles were found that mentioned Snapchat or addressed the ethical implications of sharing live videos of plastic surgery on social media. Using the four principles of medical ethics, it was determined that significant ethical concerns exist with broadcasting these videos. This analysis fills an important gap in the plastic surgery literature by addressing the ethical issues concerning live surgery broadcasts on social media. Plastic surgeons may use the guidelines proposed here to avoid potential pitfalls.

AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition

Histone deacetylases (HDACs) play critical roles in apoptosis and contribute to the proliferation of cancer cells. AR-42 is a novel Class I and II HDAC inhibitor that shows cytotoxicity against various human cancer cell lines. The present study aims to identify the target of AR-42 in hepatocellular carcinoma (HCC) as well as evaluate its therapeutic efficacy. We found that HDAC5 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. CCK8 and colony-formation assays showed that HDAC5 overexpression promotes proliferation in HCC cell lines. Treatment with AR-42 decreased HCC cell growth and increased caspase-dependent apoptosis, and this was rescued by HDAC5 overexpression. We demonstrated that AR-42 can inhibit the deacetylation activity of HDAC5 and its downstream targets in vitro and in vivo. Taken together, these results demonstrate for the first time that AR-42 targets HDAC5 and induces apoptosis in human hepatocellular carcinoma cells. AR-42 therefore shows potential as a new drug candidate for HCC therapy.

Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis

Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA .Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA.

Surgical Duration Impacts Venous Thromboembolism Risk in Microsurgical Breast Reconstruction

Background Increased surgical duration can impact patient outcomes and operative efficiency metrics. In particular, there are studies suggesting that increased surgical duration can increase the risk of venous thromboembolism (VTE). One of the longer duration plastic surgery procedures commonly performed is microsurgical breast reconstruction. With the widening indications for multiple and “stacked” free flaps to reconstruct breasts, we endeavored to assess (1) the relationship between duration of microsurgical breast reconstruction and VTE; and (2) determine if a threshold operative time exists that connotes VTE higher risk. Methods Patients from the American College of Surgeons National Surgical Quality Improvement Program (ACS‐NSQIP) between 2005 and 2014 who underwent microsurgical breast reconstruction were identified by Current Procedural Terminology code. Three models of multivariate logistic regression were used to characterize the adjusted risk for VTE by operative duration, bilaterality, the length of stay, and patient demographics. Results A total of 4,782 patients who underwent microsurgical breast reconstruction were identified. Overall VTE incidence was 1.13%. The mean operative duration was 8:31 hours:minutes (standard deviation: 2:59). Operative duration was statistically associated with VTE in continuous, quintile, and dichotomized risk models. Beyond an operative duration of 11 hours, adjusted VTE risk increases fourfold corresponding to a number needed to harm of 45.8. Conclusions Increasing surgical duration heightens the risk of VTE in microsurgical breast reconstruction. Increasing body mass index and age enhances this VTE risk. Moreover, limiting surgical duration to 11 hours or less can decrease VTE risk by fourfold vis‐à‐vis baseline. Level of Evidence Risk, II.

Faecalibacterium prausnitzii Produces Butyrate to Maintain Th17/Treg Balance and to Ameliorate Colorectal Colitis by Inhibiting Histone Deacetylase 1

Background Inflammatory bowel disease (IBD)-associated dysbiosis is characterized by a loss of Faecalibacterium prausnitzii, whose supernatant exerts an anti-inflammatory effect. However, the anti-inflammatory substances in F. prausnitzii supernatant and the mechanism in ameliorating colitis in IBD have not yet been fully investigated. Methods Experimental colitis models were induced and evaluated by clinical examination and histopathology. Levels of cytokines and ratio of T cells were detected by enzyme-linked immunosorbent assay and flow cytometry analysis, respectively. F. prausnitzii supernatant was separated by macroporous resins. After extraction, the substances in supernatant were identified by gas chromatography-mass spectrometer. T-cell differentiation assay was conducted in vitro. Changes in signaling pathways were examined by immunoblot, immunohistochemistry, and immunofluorescent staining. Results We found that the supernatant of F. prausnitzii could regulate T helper 17 cell (Th17)/regulatory T cell (Treg) differentiation. Then, we identified butyrate produced by F. prausnitzii that played the anti-inflammatory effects by inhibiting interleukin (IL)-6/signal transducer and the activator of transcription 3 (STAT3)/IL-17 pathway and promoting forkhead box protein P3 (Foxp3). Finally, we demonstrated that the target of butyrate was histone deacetylase 1 (HDAC1). Conclusions It is butyrate, instead of other substances produced by F. prausnitzii, that maintains Th17/Treg balance and exerts significant anti-inflammatory effects in colorectal colitis rodents, by inhibiting HDAC1 to promote Foxp3 and block the IL-6/STAT3/IL-17 downstream pathway. F. prausnitzii could be an option for further investigation for IBD treatment. Targeting the butyrate-HDAC1-T-cell axis offers an effective novel approach in the treatment of inflammatory disease.

The Effect of Implant Type on Nipple Position Geometry and Aesthetics Following Tissue Expander Reconstruction After Nipple Sparing Mastectomy

Background While recent studies have reported modest to no difference in breast aesthetics for shaped and round implant types in breast augmentations, the anatomy and biomechanics in the setting of breast reconstruction is different. Objectives Accordingly, we endeavored to evaluate whether two implant types impacted nipple position and aesthetic features in prosthetic breast reconstruction. Methods A retrospective chart review was carried out on patients who underwent nipple-sparing mastectomy (NSM) with immediate tissue expander breast reconstruction. Patients were divided into two cohorts: smooth round implants and textured shaped implants. Postoperative photographs were evaluated to assess nipple displacement vis-à-vis a vector of maximal projection and aesthetic outcome for features of breast shape. Results Of 102 breasts meeting the inclusion criteria, 41 had tissue expander-implant reconstruction with anatomical shaped implants, and 61 had reconstruction with smooth round implants. The shaped implant cohort had less nipple deviation from the point of maximal projection (3.69 ± 6.24 vs 7.52 ± 10.50; P < 0.0001). Graded semi-quantitative aesthetic scores were also higher (4.04 ± 0.67 vs 3.72 ± 0.93; P = 0.0044) in the shaped implants than in the round cohort. Conclusions Unlike breast augmentation, there is a paucity of overlying breast tissue and larger dissected spaces in prosthetic breast reconstruction. Our analysis suggests that in this setting, textured anatomic implants result in less nipple deviation from the point of maximum projection and improved aesthetic outcomes compared to round implants. When considering implant choice in NSM reconstruction, the manifold risks of shaped textured implants must thus be informed by potential aesthetic benefits with respect to shape and enhanced nipple sensation. Level of Evidence 4

Downregulation of SIRT2 Inhibits Invasion of Hepatocellular Carcinoma by Inhibiting Energy Metabolism

Hepatocellular carcinoma (HCC) is one of the most common neoplasms, and metastasis is the most important feature for HCC-related deaths. Mounting evidence implies the dynamic regulatory role of SIRT2, a histone deacetylase, in cancer cells. Unfortunately, the role of SIRT2 and the antitumor activity of its inhibition are not known in HCC. The present study aims to evaluate the biological function of SIRT2 in HCC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 inhibiton marginally promotes proliferation in HCC cell lines, SIRT2 knockdown decreased the invasion of HCC cells. We demonstrated that downregulation of SIRT2 could inhibit its downstream target phosphoenolpyruvate carboxykinase 1 and glutaminase, which is related to mitochondrial metabolism and the E-Cadherin pathway. These results demonstrate, for the first time that downregulation of SIRT2 decreases migration as well as invasion in human HCC cells, indicating that inhibiting SIRT2 may be an effective therapeutic strategy for treating HCC.