BackgroundSirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1α induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.ResultsHere we show that PGC-1α strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1α led to decreased Sirt3 gene expression. PGC-1α activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (−407/−399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRα bound to the identified ERRE and PGC-1α co-localized with ERRα in the mSirt3 promoter. Knockdown of ERRα reduced the induction of Sirt3 by PGC-1α in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1α-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1α in C2C12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1α on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1α on mitochondrial biogenesis in C2C12 myotubes.ConclusionOur results indicate that Sirt3 functions as a downstream target gene of PGC-1α and mediates the PGC-1α effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease.

Background Systematic data on discontinuation of statins in routine practice of medicine are limited. Objective To investigate reasons for statin discontinuation and the role of statin-related events (clinical events / symptoms thought to have been caused by statins) in routine care settings. Design A retrospective cohort study Setting Practices affiliated with one of two academic hospitals. Patients Adults who received a statin prescription between 01/01/2000 and 12/31/2008. Measurements Information on reasons for statin discontinuations was obtained from a combination of structured electronic medical record (EMR) entries and analysis of electronic provider notes by validated software. Results Statins were discontinued at least temporarily for 57,292 out of 107,835 patients. Statin-related events were documented for 18,778 (17.4%) patients. Statins were discontinued at least temporarily by 11,124 of these patients, 6,579 (59.1%) of whom were rechallenged with a statin over the subsequent 12 months. Most patients who were rechallenged (92.2%) were still taking a statin 12 months after the statin-related event. Among the 2,721 patients who were rechallenged with the same statin to which they had a statin-related event, 1,295 (47.6%) were on the same statin 12 months later, including 996 on the same or higher dose. Limitation Statin discontinuations and statin-related events were assessed in practices affiliated with two academic medical centers. Utilization of secondary data could have led to missing or misinterpreted data as a result of incomplete documentation. Natural language processing tools used to compensate for the low (30%) proportion of reasons for statin discontinuation documented in structured EMR fields are not perfectly accurate. Conclusion Statin-related events are commonly reported and often lead to their discontinuation. However, most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other etiologies, are tolerable or may be specific to individual statins rather than the entire drug class.

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010 in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ( 99 Tc m -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99 Tc m -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99 Tc m -OCT. The gender distribution was equal (M/F ¼ 19/20). Average age was 42 AE 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 AE 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. 99 Tc m -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up. ß

Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirusmediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.

Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. Conclusion: Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. (HEPATOLOGY 2011;54:509-521)

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Context Synchronous distance education (SDE) has been widely used for health science students in recent years. This study examined the effectiveness and acceptance of SDE compared with traditional education for health science students and explored the potential moderators that could impact the pooled results. Methods A systematic review and meta‐analysis was conducted of randomised controlled trials (RCTs) from January 2000 to March 2020 searched on nine electronic databases, including Web of Science, PubMed, Cochrane Library, Scopus, EMBASE, CINAHL, ERIC, PsycINFO, and ProQuest Dissertations and Theses. The outcomes measured were knowledge, skills with objective assessments and overall satisfaction with subjective evaluations. The pooled results were calculated using random‐model effects, and moderators were explored through meta‐regression. Results A total of seven RCTs with 594 participants were included. At the post‐test level, the pooled effect size of knowledge acquisitions (SMD 0.12, 95% CI −0.07‐0.32) showed insignificant difference between the SDE and traditional education groups (P = .207), with low heterogeneity (I2 = 17.6%). Subgroup analyses observed no factors that significantly impacted the pooled results of knowledge acquisition at the post‐test levels (P for interaction > 0.05). Knowledge gains from pretest to post‐test in SDE groups also did not differ significantly between groups (SMD 0.15, 95% CI −0.22‐0.53; P = .428). The pooled effect size of skills (SMD 0.02, 95% CI −0.24‐0.28; P = .735) was similarly insignificant. The pooled effect size of overall satisfaction (SMD 0.60, 95% CI 0.38‐0.83; P < .001) significantly favoured SDE over traditional education. Incorporating two‐group studies without randomisations did not significantly change the overall results of knowledge acquisition at the post‐test level (SMD −0.002, 95% CI −0.11‐0.10; P = .994), with moderate heterogeneity (I2 = 61.9%). Conclusions Synchronous distance education was not significantly different from traditional education in effectiveness and had higher satisfaction ratings. Our findings might provide indications for adoptions of online remote education in health science education centres.

Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The function of M-cells in systemic inflammatory responses are still unclear. Here we show that epithelial non-canonical NFkB signaling mediated by NFkB-inducing kinase (NIK) is highly active in intestinal lymphoid follicles, and is required for M-cell maintenance. Intestinal NIK signaling modulates M-cell differentiation and elicits both local and systemic IL-17A and IgA production. Importantly, intestinal NIK signaling is active in mouse models of colitis and patients with inflammatory bowel diseases; meanwhile, constitutive NIK signaling increases the susceptibility to inflammatory injury by inducing ectopic M-cell differentiation and a chronic increase of IL-17A. Our work thus defines an important function of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis.