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The new type 2 diabetes drug, dapagliflozin, reduces blood glucose levels and body weight by inhibiting sodium glucose transporter 2 (SGLT2) in proximal tubular cells. SGLT2 inhibitors might modulate glucose influx into renal tubular cells, thereby regulating the metabolic conditions that cause endoplasmic reticulum (ER) stress in the cells. In this study, we examined the effect of dapagliflozin on ER stress in the HK-2 proximal tubular cell line and in the kidney of db/db mice to characterise its function in diabetic nephropathy (DN). We found that dapagliflozin regulated ER stress-mediated apoptosis in vitro and in vivo . Only the elf2α-ATF4-CHOP pathway was regulated under these conditions. Notably, the drug rescued C2 ceramide-induced ER stress-mediated apoptosis and ER stress-mediated apoptosis, which might occur in DN, in db/db mice. Our study shows a novel role for dapagliflozin as an inhibitor of ER stress and suggests that dapagliflozin might be useful for the prevention of DN.

Context:Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism, and the genetic aberrations responsible remain unknown.Objective:To identify somatic genetic abnormalities in TSHomas.Design and Setting:A single-nucleotide polymorphism (SNP) array analysis was performed on 8 TSHomas. Four tumors with no allelic losses or limited loss of heterozygosity were selected, and whole-exome sequencing was performed, including their corresponding blood samples. Somatic variants were confirmed by Sanger sequencing. A set of 8 tumors was also assessed to validate candidate genes.Patients:Twelve patients with sporadic TSHomas were examined.Results:The overall performance of whole-exome sequencing was good, with an average coverage of each base in the targeted region of 97.6%. Six DNA variants were confirmed as candidate driver mutations, with an average of 1.5 somatic mutations per tumor. No mutations were recurrent. Two of these mutations were found in genes with an established role in malignant tumorigenesis (SMOX and SYTL3), and 4 had unknown roles (ZSCAN23, ASTN2, R3HDM2, and CWH43). Similarly, an SNP array analysis revealed frequent chromosomal regions of copy number gains, including recurrent gains at loci harboring 4 of these 6 genes.Conclusions:Several candidate somatic mutations and changes in copy numbers for TSHomas were identified. The results showed no recurrence of mutations in the tumors studied but a low number of mutations, thereby highlighting their benign nature. Further studies on a larger cohort of TSHomas, along with the use of epigenetic and transcriptomic approaches, may reveal the underlying genetic lesions.TSHomas were studied using SNP array and whole-exome sequencing, and a low mutation frequency was found. Several nonrecurrent candidate somatic mutations as well as copy number changes were identified.

Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose by the kidneys. Dapagliflozin is metabolized and inactivated by UGT1A9. Empagliflozin is metabolized and inactivated by UGT1A9 and by other related isoforms UGT2B7, UGT1A3, and UGT1A8. Tofogliflozin is metabolized and inactivated by five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, and CYP4F3. Dapagliflozin treatment of HCT116 cells, which express SGLT2 but not UGT1A9, results in the loss of cell adhesion, whereas HepG2 cells, which express both SGLT2 and UGT1A9, are resistant to the adhesion-related effects of dapagliflozin. PANC-1 and H1792 cells, which do not express either SGLT2 or UGT1A9, are also resistant to adhesion related effects of dapagliflozin. On the other hand, either empagliflozin or tofogliflozin treatment of HCT116, HepG2, PANC-1, and H1792 cells are resistant to the adhesion-related effects as observed in dapagliflozin treated HCT116 cells. Knockdown of UGT1A9 by shRNA in HepG2 cells increased dapagliflozin sensitivity, whereas the overexpression of UGT1A9 in HCT116 cells protected against dapagliflozin-dependent loos of cell adhesion. Dapagliflozin treatment had no effect on cellular interactions with fibronectin, vitronectin, or laminin, but it induced a loss of interaction with collagen I and IV. In parallel, dapagliflozin treatment reduced protein levels of the full-length discoidin domain receptor I (DDR1), concomitant with appearance of DDR1 cleavage products and ectodomain shedding of DDR1. In line with these observations, unmetabolized dapagliflozin increased ADAM10 activity. Dapagliflozin treatment also significantly reduced Y792 tyrosine phosphorylation of DDR1 leading to decrement of DDR1 function and detachment of cancer cells. Concomitant with these lines of results, we experienced that CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus treated by dapagliflozin in addition to chemotherapy was decreased (case 1). CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus was treated by dapagliflozin alone after radiation therapy was decreased but started to rise after cessation of dapagliflozin (case 2). CA19-9 in two of patients with pancreatic cancer and type 2 diabetes mellitus was resistant to the combination therapy of dapagliflozin and chemotherapy (case 3 and 4 respectively). PIVKAII in patients with liver cancer and type 2 diabetes mellitus, and CYFRA in patients with squamous lung cancer and type 2 diabetes mellitus was also resistant the combination therapy of dapagliflozin and chemotherapy (case 5 and 6 respectively). Taken together, these data suggest a potential role for dapagliflozin anticancer therapy against colon cancer cells that express SGLT2, but not UGT1A9.

Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

[This corrects the article DOI: 10.3389/fncel.2018.00490.].

Efficacy endpoint selection in adult primary central nervous system (CNS) tumor trials remains challenging because conventional solid tumor frameworks do not adequately capture the anatomical, radiographic, and biological complexity of brain tumors. In particular, postoperative irregular residual lesions, non-enhancing tumor components, and treatment-related imaging changes complicate the interpretation of objective response and progression. This narrative review examines the current landscape of endpoint selection in adult primary CNS tumor trials and discusses strategies for standardization in the Response Assessment in Neuro-Oncology (RANO) 2.0 era from integrated regulatory science and clinical perspectives. This study was conducted as a narrative review intended to provide a regulatory science-oriented synthesis of efficacy endpoint evaluation in adult primary CNS tumor trials. The literature search primarily utilized PubMed and ClinicalTrials.gov, supplemented by major consensus guidelines, pivotal clinical trials, and regulatory documents from the major regulatory authorities, including those in the United States, Europe, and Japan, published over the past two decades. Search terms included combinations of keywords such as \"brain tumor,\" \"glioblastoma,\" \"meningioma,\" \"Phase I,\" \"Phase II,\" \"efficacy endpoint,\" and \"RANO\". In addition to the literature synthesis, this review incorporates findings from our previously published empirical analyses regarding endpoint selection in Phase II glioblastoma trials, Phase II meningioma trials, and Phase I brain tumor trials. Response Evaluation Criteria in Solid Tumors-based response assessment remains fundamentally limited in neuro-oncology. Across recent early-phase trials, substantial heterogeneity persists in endpoint selection and in the operational definitions of objective response rate, progression-free survival, and progression. RANO 2.0 is intended to provide a more unified and implementation-oriented framework by refining baseline definition, progression confirmation, non-enhancing lesion interpretation, and the role of minor response, while improving compatibility with contemporary molecular classification and immunotherapy-era trial design. However, important implementation challenges remain, including potential reproducibility concerns in complex imaging assessments, operational complexity, imaging standardization, and the need for independent central review. Standardization of endpoint strategies in adult primary CNS tumor trials should move beyond simple adoption of conventional solid tumor metrics toward a disease-specific, harmonized framework integrating imaging, clinical context, tumor biology, and regulatory interpretability. This review provides a regulatory science-oriented synthesis linking response assessment criteria, early-phase adult primary CNS tumor trial endpoint trends, empirical analyses, and emerging endpoint frameworks. RANO 2.0 represents an important step toward this goal, but it should be regarded as an evolving framework that requires continued validation, international collaboration, and implementation-focused refinement.

Enough is enough Appetite is regulated — at least in part — in the hypothalamus, the brain region that links the nervous and endocrine systems. A screen for appetite-regulating molecules has now identified a fragment of the protein nucleobindin 2, dubbed nesfatin-1, as a satiety molecule produced in the hypothalamus. When nesfatin-1 is injected into the brain, rats eat less and lose weight. When nesfatin-1 is blocked, animals eat more. Nesfatin-1 is therefore a possible target for antiobesity drugs. A secreted protein, nesfatin-1, is expressed in the hypothalamus and induces the feeling of being full. In rats, its injection into the brain decreases food intake, but blocking its action stimulates appetite. The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour 1 , 2 , 3 . Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of α-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

Background/Objectives: In glioblastoma trials, efficacy evaluation often deviates from the standard Response Evaluation Criteria in Solid Tumors (RECIST), an objective response rate (ORR) method, because of the unique nature of brain tumors. In phase II trials from the fiscal years (FYs) 2017–2019, primary endpoints (PEs) were overall survival (OS) at 29%, ORR at 20%, progression-free survival (PFS) at 17%, and OS rate at 10%. Clinical trial methodologies have likely evolved in recent years. This study analyzed trends in efficacy endpoint settings for phase II trials from FY2020 to FY2022 compared with FY2017–2019. Methods: Using Clarivate’s Cortellis™ Clinical Trial Intelligence database, 116 phase II glioblastoma trials initiated between April 2020 and March 2023 were identified. After exclusions, 88 trials were analyzed. Trial characteristics, PEs, secondary endpoints (SEs), and designs were summarized and compared to prior data. Results: Of 101 PEs in the 88 trials, approximately half targeted newly diagnosed patients, and most tested pharmaceutical products. The most common PEs were FS (22%), OS (20%), and PFS rate (17%), while among 299 SEs, OS (15%), PFS (15%), and quality of life (14%) were most frequent. Time-to-event outcomes were employed in 74 (73%) trials, whereas ORR was used as a PE in only 7 trials (8%). ORR as a PE was significantly lower than in FY2017–2019 (p = 0.022). Conclusions: Recent glioblastoma trials show increased diversity in efficacy endpoints with less reliance on ORR compared to earlier periods, reflecting evolving strategies to address the unique challenges of glioblastoma treatment and evaluation.

BackgroundPatients with morbid obesity are complicated with metabolic diseases and have a high incidence of non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH).MethodsWe report on a follow-up study of a cohort included 102 obese patients (55 males and 47 females, mean age 42.9 ± 10.6 years) undergoing bariatric surgery for the management of morbid obesity. Abdominal computed tomography was performed before and 1 year after surgery. Anthropometric and biochemical measurements were performed at 1, 3, and 5 years after surgery.ResultsThe mean body mass index (BMI) of the NAFLD patients improved from 42.5 ± 8.3 kg/m2 to 28.5 ± 6.9, and 29.1 ± 5.7, 29.7 ± 5.5 kg/m2 at 1, 3, and 5 years, respectively. The liver fat accumulation and visceral fat areas were significantly improved at 1 year after surgery. The decrease in the BMI, waist-hip ratio, body fat percentage, and basal metabolic rate remained decreased for at least 5 years after surgery. Blood test findings including AST, ALT, γ-GTP, uric acid, albumin, CRP, HDL cholesterol, LDL cholesterol, triglycerides, and homeostasis model assessment insulin resistance (HOMA-IR) were also still improved at least 5 years after surgery.ConclusionBariatric surgery is useful for ensuring the long-term treatment of NAFLD/NASH in morbidly obese Japanese patients. Bariatric surgery is a therapeutic option for patients resistant to conventional treatment.