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Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes.

Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves.

Objective: Adhesion barriers have not traditionally been used during laparoscopic cholecystectomy (lap-chole), and so there are no data confirming the safety of the dextrin hydrogel adhesion barrier (AdSpray®) for the use during lap-chole. The aim of this prospective study is to investigate the safety of AdSpray® for elective lap-chole. Methods: Between July 2019 and March 2021, we conducted a prospective study at Saiseikai Kumamoto Hospital to assess the safety of applying AdSpray® around the hepatoduodenal ligament, liver surface, and port area after extraction of the gallbladder during elective lap-chole. We assessed patient morbidity, mortality, and laboratory data on postoperative day 1 and at the outpatient follow-up visit. Results: A total of 100 patients (43 men, 57 women) received AdSpray® application during elective lap-chole at our institution. The mean patient age was 56.5 ± 14.8 y, and the mean body mass index was 25.1 ± 4.8 kg/m2. Preoperative gallbladder drainage was performed in 3 (3.0%) patients as conservative treatment for acute cholecystitis. The mean operative time was 91.7 ± 35.1 min, and the median blood loss was 5 mL (range, 5–120 mL). Intraoperative gallbladder perforation was observed in 4.0% of patients (n = 4). There was no intraoperative bile duct injury. One (1.0%) patient had a postoperative subhepatic fluid collection without bacterial infection. The mean white blood cell count and C-reactive protein level was significantly elevated on postoperative day 1 but returned to preoperative levels by the time of the follow-up visit. All patients were successfully discharged after surgery, and the median postoperative hospital stay was 2 d (range, 2–9 d). Conclusion: Applying AdSpray® during elective lap-chole is safe, with an acceptable rate of postoperative complications.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-β (TGF-β) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-β signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. Methods and results: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-β signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-β signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-β activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. Conclusions: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-β signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.

Abstract Background Subtotal cholecystectomy in patients with severe acute cholecystitis is considered a “bailout” option when the safety of the bile duct cannot be guaranteed. However, subtotal cholecystectomy has a long-term risk of remnant cholecystitis. The appropriate management of remnant cholecystitis has not been fully elucidated. Case presentation Case 1 was a 66-year-old man who had undergone subtotal cholecystectomy 14 years prior to the development of remnant cholecystitis. We first performed endoscopic gallbladder drainage to minimize inflammation, and then proceeded with elective surgery. We performed a reconstituting procedure for the residual gallbladder due to significant adhesions between the cystic and common bile ducts. Case 2 was a 56-year-old man who had undergone subtotal cholecystectomy for abscess-forming perforated cholecystitis 2 years prior to the development of remnant cholecystitis. He underwent endoscopic drainage followed by complete remnant cholecystectomy 4 months later. Conclusion Endoscopic gallbladder drainage is a useful strategy to improve inflammation and reduce the risk of bile duct injury during remnant cholecystectomy.

Abstract Aim Severe postoperative pleural effusion (sPOPE) after hepatectomy can lead to respiratory distress and may require thoracic drainage, leading to prolonged hospitalization. Preventive chest tube insertion may be useful for patients at high risk for sPOPE. We aimed to develop a predictive model for sPOPE after hepatectomy and evaluate indications for preventive chest tube insertion using our model. Methods We evaluated all patients who underwent hepatectomy from 2013 to 2020. Risk factors for sPOPE were used to develop a predictive model for sPOPE, which was validated in a cohort that received preventative chest tube placement postoperatively. Results A total of 325 patients were analyzed. Thirty‐one (9.5%) patients had a preventive chest tube placed at the end of their operation. Twenty‐one patients out of the remaining 294 patients developed sPOPE. Multivariate analysis identified resection containing segment 8 [relative risk (RR) 3.24, P = .022], intraoperative bleeding ≥ 500 g (RR 4.02, P = .008), intraoperative diaphragmatic incision (RR 6.96, P = .042) and open hepatectomy (RR 7.51, P = .016) as independently associated with sPOPE. The estimated probability of sPOPE ranged from 0.4% in patients with none of these factors to 73.4% in the presence of all factors. Among the 31 patients who received a preventive chest tube, more patients in the high‐risk group defined by the model had postoperative pleural effusions compared to the low‐risk group (P = .012). Conclusion Our predictive model for sPOPE using four risk factors allows for reliable prediction and may be useful for selection of preventive chest tube in patients undergoing hepatectomy.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.

Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/ lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) α, Pparγ-1, Pparγ-coactivator-1α, and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolismrelated genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies. [ABSTRACT FROM AUTHOR]