Perioperative outcomes of laparoscopic low anterior resection using ArtiSential® versus robotic approach in patients with rectal cancer: a propensity score matching analysis.

BACKGROUND: Total mesorectal excision using conventional straight fixed devices may be technically difficult because of the narrow and concave pelvis. Several laparoscopic articulating tools have been introduced as an alternative to robotic systems. The aim of this study was to compare perioperative outcomes between laparoscopic low anterior resection using ArtiSential® and robot-assisted surgery for rectal cancer. METHODS: This retrospective study included 682 patients who underwent laparoscopic or robotic low anterior resection  for rectal cancer from September 2018 to December 2021. Among them, 82 underwent laparoscopic surgery using ArtiSential® (group A) and 201 underwent robotic surgery (group B). A total of 73 [group A; 66.37 ± 11.62; group B 65.79 ± 11.34] patients were selected for each group using a propensity score matching analysis. RESULTS: There was no significant difference in the baseline characteristics between group A and B. Mean operative time was longer in group B than A (163.5 ± 61.9 vs 250.1 ± 77.6 min, p < 0.001). Mean length of hospital stay was not significantly different between the two groups (6.2 ± 4.7 vs 6.7 ± 6.1 days, p = 0.617). Postoperative complications, reoperation, and readmission within 30 days after surgery were similar between the two groups. Pathological findings revealed that the circumferential resection margins were above 10 mm in both groups (11.00 ± 7.47 vs 10.17 ± 6.25 mm, p = 0.960). At least 12 lymph nodes were sufficiently harvested, with no significant difference in the number harvested between the groups (20.5 ± 9.9 vs 19.7 ± 7.3, p = 0.753). CONCLUSIONS: Laparoscopic low anterior resection using ArtiSential® can achieve acceptable clinical and oncologic outcomes. ArtiSential®, a multi-joint and articulating device, may serve a feasible alternative approach to robotic surgery in rectal cancer.

Risk factors and mortality associated with multi-drug-resistant Gram-negative bacterial infection in adult patients following abdominal surgery.

BACKGROUND: Multi-drug-resistant (MDR) Gram-negative bacterial (GNB) infection remains a significant cause of morbidity and mortality among surgical patients. The objective of this study was to recognize the risk factors for MDR GNB infection in patients following abdominal surgery, and determine the predictors independently associated with death. METHODS: From 2010 to 2017, a retrospective cohort study was conducted among patients with abdominal surgery admitted to the surgical intensive care unit (ICU). Patients with GNB infection were included for analyses. RESULTS: In total, 364 patients experienced GNB infection following abdominal surgery. Of these, 117 (32.1%) were MDR GNB infection. Of 133 MDR GNB isolates, the most common isolate was Escherichia coli (45.1%). Patients with MDR GNB infection had significantly longer ventilator-days and hospital stay, as well as higher 30-day and in-hospital mortality compared with non-MDR GNB patients. Multi-variable analysis showed that longer length of pre-ICU stay, surgical re-exploration, receipt of group 2 carbapenems (e.g. imipenem, meropenem and doripenem) and fluoroquinolones, and higher total bilirubin were independent risk factors for the acquisition of MDR GNB infection. Predictors for 30-day mortality among patients with MDR GNB infection were chronic kidney disease, receipt of group 2 carbapenems and inappropriate empirical antimicrobial therapy. CONCLUSIONS: This study provides important information about the risk factors for MDR GNB infection and 30-day mortality among patients following abdominal surgery.

Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes.

BACKGROUND: In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. METHODS: Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. RESULTS: More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease. CONCLUSION: Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.

Pre-stroke glycemic control is associated with early neurologic deterioration in acute atrial fibrillation-related ischemic stroke.

BACKGROUND: It has been suggested that AF-related ischemic stroke (IS) that is accompanied by atherosclerotic burden have poorer outcomes. The aim of this study was to investigate the importance of pre-stroke glycemic control (PSGC) on the early neurologic deterioration (END) of patients with acute AF-related IS. METHODS: We retrospectively recruited 121 patients with AF-related IS who also had Diabetes mellitus (DM). The HbA1C level was measured in all subjects. END was defined as an increase in the National Institute of Health Stroke Scale (NIHSS) score of 4 NIHSS points within 7 days of symptom onset compared to the initial NIHSS score. RESULTS: In this study, 20.7% (25 patients) were classified as having a poor PSGC status with a HbA1C level above 8.0%. In the univariate analysis, a poor PSGC status (p < 0.01), smoking (p = 0.01), severe neurologic deficits at admission (p = 0.01), and a larger size of ischemic lesions on DWI (p < 0.01) were associated with the occurrence of END. In the multivariate model, a poor PSGC status (p = 0.02) and larger size of ischemic lesions on MRI (p < 0.01) were independent predictors of END in acute AF-related IS. CONCLUSION: The HbA1c level upon admission was independently associated with significant prediction of END in acute AF-related IS.

Increase in resting heart rate over 2 years predicts incidence of diabetes: A 10-year prospective study.

OBJECTIVE: The association between resting heart rate (RHR) and the development of diabetes has yet to be fully elucidated, and the relationship between changes in RHR and incidence of diabetes also remains unclear. Our study aimed to investigate the association between changes in RHR over 2 years and the risk of diabetes. METHODS: A total of 7416 adults without diabetes were included. All had participated in the Korean Genome and Epidemiology Study, a community-based, 10-year prospective study in which RHR was measured at baseline and 2 years later. Incident diabetes was defined as fasting blood glucose ≥126mg/dL, 2-h post-load glucose ≥200mg/dL during a 75-g oral glucose tolerance test or current use of diabetes medication. The relative risk of diabetes associated with the 2-year change in RHR was calculated using Cox models. RESULTS: During the 10-year follow-up, 1444 (19.5%) developed diabetes. Compared with RHR increases <5 beats per minute (bpm) over 2 years, increases >10bpm were significantly associated with development of diabetes (adjusted hazard ratio: 1.31, 95% confidence interval: 1.06-1.60), even after adjusting for glycometabolic parameters and baseline RHR. This significant association was attenuated in people who exercised regularly (P=0.650), but remained significant in those not doing any regular exercise (P=0.010). CONCLUSION: An increase in RHR over a 2-year follow-up period is significantly associated with a risk of diabetes, independently of baseline RHR and glycometabolic parameters. Further investigations into ways to control RHR as a potential preventative measure against the development of diabetes are now needed.

Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.

BACKGROUND: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. METHODS: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. RESULTS: Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. CONCLUSIONS: Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Single-port versus conventional three-port laparoscopic totally extraperitoneal inguinal hernia repair: a randomized controlled trial.

BACKGROUND: Single-port laparoscopic surgery (SPLS) has been introduced for totally extraperitoneal (TEP) inguinal hernia repair. Clinically, however, the benefits of single-port TEP (SP TEP) are unclear. This study aimed to compare short-term surgical outcomes between SP TEP and conventional laparoscopic TEP(CL TEP) inguinal hernia repair. METHODS: Between January 2013 and February 2015, 99 men with primary unilateral inguinal hernia were randomized to the single-port or conventional 3-port TEP procedures. The primary end point was postoperative pain. Secondary end points were complications, postoperative hospital stay, days to return to daily normal activities, cosmesis, and quality of life (QOL). RESULTS: We randomized 50 patients to SP TEP and 49 to CL TEP repair. The SP TEP group patients had significantly lower pain scores (visual analog scale) 7 days postoperation (p = 0.017). However, there were no significant differences between the two groups in postoperative pain scores 24 h (p = 0.44) and 4 weeks (p = 0.677) after operation and analgesic requirements on the operation day (p = 0.303) and 7 days after the operation (p = 0.204). Operation time, postoperative hospital stay, and complications were comparable between the two groups. The days to return to daily normal activities, QOL, and cosmetic satisfaction were not different between the two groups. CONCLUSION: The outcomes of SP TEP hernia repair for operation time and morbidities were comparable to CL TEP, and postoperative pain was lower at 7 days than in CL TEP hernia repair. The SP TEP technique can be recommended as an alternative treatment for inguinal hernia repair in experienced hands.

Effects of Ambient Temperature on Growth Performance, Blood Metabolites, and Immune Cell Populations in Korean Cattle Steers.

Exposure to cold may affect growth performance in accordance with the metabolic and immunological activities of animals. We evaluated whether ambient temperature affects growth performance, blood metabolites, and immune cell populations in Korean cattle. Eighteen Korean cattle steers with a mean age of 10 months and a mean weight of 277 kg were used. All steers were fed a growing stage-concentrate diet at a rate of 1.5% of body weight and Timothy hay ad libitum for 8 weeks. Experimental period 1 (P1) was for four weeks from March 7 to April 3 and period 2 (P2) was four weeks from April 4 to May 1. Mean (8.7°C) and minimum (1.0°C) indoor ambient temperatures during P1 were lower (p<0.001) than those (13.0°C and 6.2°C, respectively) during P2. Daily dry matter feed intake in both the concentrate diet and forage groups was higher (p<0.001) during P2 than P1. Average daily weight gain was higher (p<0.001) during P2 (1.38 kg/d) than P1 (1.13 kg/d). Feed efficiency during P2 was higher (p = 0.015) than P1. Blood was collected three times; on March 7, April 4, and May 2. Nonesterified fatty acids (NEFA) were higher on March 7 than April 4 and May 2. Blood cortisol, glucose, and triglyceride concentrations did not differ among months. Blood CD4+, CD8+, and CD4+CD25+ T cell percentages were higher, while CD8+CD25+ T cell percentage was lower, during the colder month of March than during May, suggesting that ambient temperature affects blood T cell populations. In conclusion, colder ambient temperature decreased growth and feed efficiency in Korean cattle steers. The higher circulating NEFA concentrations observed in March compared to April suggest that lipolysis may occur at colder ambient temperatures to generate heat and maintain body temperature, resulting in lower feed efficiency in March.

Association between prolonged breastfeeding and bone mineral density and osteoporosis in postmenopausal women: KNHANES 2010-2011.

UNLABELLED: This study showed that a negative correlation between duration of breastfeeding and bone mineral density (BMD) in the lumbar spine and prolonged breastfeeding is an independent risk for osteoporosis in postmenopausal women. The present study suggests that postmenopausal women with a history of prolonged breastfeeding require more careful screening for osteoporosis. INTRODUCTION: Several studies suggest that breastfeeding and childbirth lead to maternal calcium loss and a decline in BMD. While the association between breastfeeding and BMD immediately after weaning is well-established, the effects of breastfeeding on postmenopausal women have been controversial. The aim of this study was to examine the effects of breastfeeding on bone mineral density (BMD) and the prevalence of osteoporosis in postmenopausal women. METHODS: The present study was a cross-sectional survey based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2010 and 2011 data. The association between breastfeeding and BMD and osteoporosis was examined in 1222 postmenopausal women. RESULTS: The duration of breastfeeding and BMD in the lumbar spine showed a negative correlation. The association between duration of breastfeeding and BMD remained significant after adjustment for reproductive factors and other confounding factors (P = 0.008). However, the number of deliveries and age at the time of delivery did not correlate with BMD at any site after adjustment. Moreover, the prevalence of osteoporosis in postmenopausal women with a history of prolonged breastfeeding was significantly higher than that in women with a short history of breastfeeding (≥37 months, OR = 3.292; 95 % CI 1.485-7.299). The prevalence of lumbar spine fracture showed a significant increasing trend with the increase in the duration of breastfeeding. CONCLUSION: Prolonged breastfeeding was significantly associated with low BMD in the lumbar spine and higher prevalence of osteoporosis. However, the number of deliveries or age at the time of childbirth did not influence BMD.

Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress.

Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca(2+) increase due to depletion of luminal ER Ca(2+). Palmitate-induced ER Ca(2+) depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca(2+) pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca(2+) depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca(2+) loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca(2+) depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca(2+) depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury.

A self-amplified transistor immunosensor under dual gate operation: highly sensitive detection of hepatitis B surface antigen.

Ion-sensitive field-effect transistors (ISFETs), although they have attracted considerable attention as effective immunosensors, have still not been adopted for practical applications owing to several problems: (1) the poor sensitivity caused by the short Debye screening length in media with high ion concentration, (2) time-consuming preconditioning processes for achieving the highly-diluted media, and (3) the low durability caused by undesirable ions such as sodium chloride in the media. Here, we propose a highly sensitive immunosensor based on a self-amplified transistor under dual gate operation (immuno-DG ISFET) for the detection of hepatitis B surface antigen. To address the challenges in current ISFET-based immunosensors, we have enhanced the sensitivity of an immunosensor by precisely tailoring the nanostructure of the transistor. In the pH sensing test, the immuno-DG ISFET showed superior sensitivity (2085.53 mV per pH) to both standard ISFET under single gate operation (58.88 mV per pH) and DG ISFET with a non-tailored transistor (381.14 mV per pH). Moreover, concerning the detection of hepatitis B surface antigens (HBsAg) using the immuno-DG ISFET, we have successfully detected trace amounts of HBsAg (22.5 fg mL(-1)) in a non-diluted 1× PBS medium with a high sensitivity of 690 mV. Our results demonstrate that the proposed immuno-DG ISFET can be a biosensor platform for practical use in the diagnosis of various diseases.

Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function.

AIM: To investigate the effects of LY2405319, an analogue of fibroblast growth factor 21 (FGF21), on glucose homeostasis in streptozotocin (STZ)-induced insulin-deficient mice (STZ mice). METHODS: Nine-week-old male C57BL/6J mice were administered a single intraperitoneal injection of STZ (150 mg/kg). One week later, after confirmation of hyperglycaemia, saline or LY2405319 (5 mg/kg) was injected subcutaneously daily for 4 weeks. Changes in glucose homeostasis, energy metabolism and brown adipose tissue (BAT) function were assessed. RESULTS: The STZ mice had elevated blood glucose and reduced plasma FGF21 levels, impaired glucose uptake in the BAT, and BAT mitochondria with absent or swollen cristae and fewer lipid vacuoles. LY2405319 significantly reduced blood glucose levels and this was associated with increased BAT glucose uptake and changes in gene expression and morphology, indicating improved mitochondrial lipid metabolism in the BAT. Importantly, the ability of LY2405319 to lower blood glucose in STZ mice was compromised after removing interscapular BAT. CONCLUSIONS: Our results show that LY2405319 reduces blood glucose levels in insulin-deficient diabetes by improving BAT metabolism. Additional studies investigating the therapeutic potential of FGF21 for the treatment of type 1 diabetes are warranted.

Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension.

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

Phospholipase D1 decreases type I collagen levels in hepatic stellate cells via induction of autophagy.

Hepatic stellate cells (HSCs) are major players in liver fibrogenesis. Accumulating evidence shows that suppression of autophagy plays an important role in the development and progression of liver disease. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA) and choline, was recently shown to modulate autophagy. However, little is known about the effects of PLD1 on the production of type I collagen that characterizes liver fibrosis. Here, we examined whether PLD1 regulates type I collagen levels in HSCs through induction of autophagy. Adenovirus-mediated overexpression of PLD-1 (Ad-PLD1) reduced type I collagen levels in the activated human HSC lines, hTERT and LX2. Overexpression of PLD1 in HSCs led to induction of autophagy as demonstrated by increased LC3-II conversion and formation of LC3 puncta, and decreased p62 abundance. Moreover, inhibiting the induction of autophagy by treating cells with bafilomycin or a small interfering (si)RNA for ATG7 rescued Ad-PLD1-induced suppression of type I collagen accumulation in HSCs. The effects of PLD on type I collagen levels were not related to TGF-ß/Smad signaling. Furthermore, treatment of cells with PA induced autophagy and inhibited type I collagen accumulation. The present study indicates that PLD1 plays a role in regulating type I collagen accumulation through induction of autophagy.

The physiological roles of apolipoprotein J/clusterin in metabolic and cardiovascular diseases.

Several isoforms of apolipoprotein J/clusterin (CLU) are encoded from a single gene located on chromosome 8 in humans. These isoforms are ubiquitously expressed in the tissues, and have been implicated in aging, neurodegenerative disorders, cancer progression, and metabolic/cardiovascular diseases including dyslipidemia, diabetes, atherosclerosis and myocardial infarction. The conventional secreted form of CLU (sCLU) is thought to be a component of high density lipoprotein-cholesterol. sCLU functions as a chaperone for misfolded proteins and it is thought to promote survival by reducing oxidative stress. Nuclear CLU, a truncated CLU formed by alternative splicing, is responsible for promoting apoptosis via a Bax-dependent pathway. There are putative regulatory sites in the promoter regions of CLU, which are occupied by transcription factors such as transforming growth factor (TGF)-ß inhibitory element, activator protein-1, CLU-specific elements, and carbohydrate response element. However, the molecular mechanisms underlying the distinct roles of CLU in a variety of conditions remain unclear. Although the function of CLU in cancer or neurological disease has been studied intensively for three decades, physiological roles of CLU seem unexplored in the cardiovascular system and metabolic diseases. In this review, we will discuss general characteristics and regulations of CLU based on previous literature and assess the recent findings associated with its physiological roles in different tissues including the vasculature, heart, liver, kidney, adipose tissue, and brain.

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models.

AIMS/HYPOTHESIS: The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction. METHODS: We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction. RESULTS: miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3'-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice. CONCLUSIONS/INTERPRETATION: Our data demonstrate that miR-30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicity-induced beta cell dysfunction.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

Anti-inflammatory effect of pachymic acid promotes odontoblastic differentiation via HO-1 in dental pulp cells.

OBJECTIVES: Heme oxygenase-1 (HO-1) is contributed to odontoblast differentiation in human dental pulp cells (HDPCs). In this study, pachymic acid from mushroom Formitopsis niagra is examined to determine whether it affects pulpal inflammation and promotes odontogenesis via HO-1 gene expression. MATERIALS AND METHODS: The HDPCs were given H2O2 for inflammation. The anti-inflammatory character and odontoblast differentiation by pachymic acid were analyzed by Western blotting, alkaline phosphatase activity, and alizarin red S staining. To understand the mechanism of pachymic acid via HO-1 induction, the cells were treated with zinc protoporphyrin IX (ZnPP: HO-1 inhibitor). RESULTS: H2O2 induced pulp inflammation and disturbed odontoblast differentiation. However, the HDPCs treated with pachymic acid affected anti-inflammatory effect and induction of odontoblast differentiation through increasing HO-1 expression. In addition, pachymic acid has potent cytoprotection and mineralization under H2O2 treatment. Furthermore, pachymic acid significantly suppressed nuclear factor-kappa B (NF-κB) translocation into nucleus and induced NE-E2-related factor-2 (Nrf2) translocation into nucleus. Overall, NF-κB and Nrf2 translocation were regulated by the HO-1 pathway. CONCLUSIONS: The pachymic acid showed anti-inflammatory function and odontoblast differentiation via HO-1 pathway. These results suggested that pachymic acid may be applicable for prevention of oral inflammation or to improve dentin mineralization against several stresses.

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis.

AIMS/HYPOTHESIS: Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis. METHODS: The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production. RESULTS: Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, Ad-Crebh inhibited insulin- and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo. CONCLUSIONS/INTERPRETATION: These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.