Search

Background Exposing blood serum samples to ambient white light-emitting diode (WLED) light may accelerate bilirubin photoisomer production. We previously demonstrated the quantitative effect of bilirubin configurational isomers (BCI) on direct bilirubin (DB) value using the vanadate oxidation method. However, the effects of bilirubin structural photoisomers (BSI) remain unclear. Methods In Study 1, the relationship between WLED irradiation time and BSI production was examined. Serum samples from five neonates were irradiated with WLED light for 0, 10, 30, 60 and 180 min. Bilirubin isomer concentration and BSI production rates were calculated. In Study 2, we performed quantitative investigation of BSI effect on DB values: Differences in DB, BCI and BSI values before and after irradiation were calculated as ⊿DB, ⊿BCI and ⊿BSI, respectively. Assuming the coefficient of BCI affecting DB values was ‘ a’, relational expression was ⊿DB = a*⊿BSI + 0.19*⊿BCI. Serum samples from 15 neonates were irradiated with green LED light for 10 and 30 s. The respective bilirubin isomer levels were measured, and the coefficient was derived. Results In Study 1, the median BSI production rate was 0.022 mg/dL per min in specimens with an unconjugated bilirubin concentration of 10.88 mg/dL. In Study 2, assuming that ⊿DB-0.19*⊿BCI was Y and ⊿BSI was X, the relational expression was Y = 0.34 X-0.03 ( R2 = 0.87; p < .01) and a = 0.34. Conclusions Under ambient WLED light, serum sample generated 1.3 mg/dL BSIs in 1 h. Approximately 34% (0.44 mg/dL) of BSI concentrations was measured as DB when using the vanadate oxidation method according to the above equation.

Glucotoxicity, impaired insulin secretion, suppression of insulin gene expression, and apoptosis, in pancreatic β-cells caused by chronic hyperglycemia is a key component of the pathogenesis of type 2 diabetes. Recently, it has been reported that rare sugar d-allulose has antihyperglycemic and antihyperlipidemic effects in diabetic rats. However, the direct effects of rare sugars including d-allulose on pancreatic β-cell function are unclear. In this study, we investigated whether chronic exposure to ketohexoses causes glucotoxicity, suppression of insulin gene expression, and apoptosis, in INS-1 rat pancreatic insulinoma cells. d-Fructose, d-tagatose, l-allulose, and l-sorbose treatment for 1-week reduced insulin gene expression, whereas d-allulose, d-sorbose, l-fructose, and l-tagatose did not. All ketohexoses were transported into INS-1 cells, but were not metabolized. In addition, the ketohexoses did not induce apoptosis and did not affect glucose metabolism. These results suggest that long-term administration of d-allulose, d-sorbose, l-fructose, and l-tagatose does not affect pancreatic β-cell function.

Objective:Thrombospondin-1 (TSP-1) plays an important role in platelet activation and aggregation and aggravates thrombosis. Chronic stress can cause a variety of diseases, including coagulation disorders, increased thrombosis, atherosclerosis, and a series of cardiovascular and cerebrovascular diseases. However, it is still unknown how chronic stress regulates the expression of TSP-1 after glucocorticoid receptor activation.Approach and Results:rats chronic unpredictable mild stress model was applied and the changes of TSP-1 and microRNAs in plasma were examined. Effects of glucocorticoid receptor activation on human umbilical vein endothelial cells and platelets were observed. Glucocorticoid receptor (GR) activation upregulated the expression of TSP-1 and downregulated the expression of microRNA-1-3p accompanied with increase of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and argonaute-2 (AGO-2). Blockade of p38 MAPK phosphorylation resulted in decrease of phosphorylation level of AGO-2, increase of microRNA-1-3p expression, and decrease of TSP-1 expression. Transfection of AGO-2 Y393F point mutant plasmid, increased microRNA-1-3p expression and decreased TSP-1 expression, transfection of microRNA-1-3p mimic also decreased TSP-1 expression, while transfection of microRNA-1-3p inhibitor increased TSP-1 expression. Finally, GR activation led to an increase in the phosphorylation level of p38 MAPK in platelets and an increase in the level of TSP-1 in the supernatant.Conclusions:our study demonstrates that GR activation in HUVEC stimulates the phosphorylation of p38 MAPK, which in turn promotes the phosphorylation of AGO-2 and inhibits the maturation of microRNA-1-3p, leading to elevated expression of TSP-1, GR activation in platelets leads to the release of TSP-1.Abstract FigureGraphical AbstractHSS: Hydrocortisone sodium succinate

Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G0–G1in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo. Mol Cancer Ther; 11(3); 549–60. ©2012 AACR.

PDF file - 87K, Metformin structure.

Signal transduction of Angiotensin II (Ang II) induced autophagy and its role in Ang II-induced dysfunction of HUVECs are still unclear.HUVECs are stimulated with different doses of Ang II (10-9-10-5 mol/L) for different time (6-48 hours). Autophagy-related protein markers: LC3, Beclin-1 and SQSTM1/p62 are measured by western blot.Incubation with Ang II increases autophagic flux (Beclin-1, autophagosomes formation, and degradation of SQSTM1/p62, LC3-I). Increased autophagic levels are inhibited by pretreatment with Ang II type 1 receptor (AT1) blocker (Candesartan), NADPH Oxidase inhibitor (apocycin), mitochondrial KOur results demonstrate that Ang II stimulation increases autophagy levels via AT1 receptor, NADPH oxidase, mitochondrial K

Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.

It is quite rare that Cushing's disease shows acromegaly, and no pharmacotherapy has yet been discussed. A 21-year-old woman was diagnosed with Cushing's disease and underwent trans-sphenoidal surgery. Five years later, she was diagnosed with recurrent Cushing's disease and biochemical acromegaly because of elevated levels of serum growth hormone (GH), plasma insulin-like growth factor-1, plasma adrenocorticotropic hormone (ACTH), and the 24-hour urinary excretion of free cortisol. After treatment initiation with pasireotide-long-acting release (LAR), both the ACTH and GH declined. Our case is the first to show the efficacy of pasireotide-LAR in controlling both Cushing's disease and acromegaly.

Objective Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) influences hepatic cholesterol transportation. Accumulation of hepatic cholesterol leads to fatty liver disease, which is improved by glucagon-like peptide 1 (GLP-1) in diabetes. Therefore, we analyzed the molecular mechanism in the regulation of hepatic ABCA1 by GLP-1 analogue exendin-4. Methods Hepatic ABCA1 expression and transcription were checked by western blotting, real-time polymerase chain reaction (PCR), and luciferase assay in HepG2 cells. Chromatin immunoprecipitation (ChIP) and site-directed mutagenesis were employed to determine transcriptional regulation of the ABCA1 gene. Prolactin regulatory element-binding (PREB)-transgenic mice were generated to access the effect of exendin-4 on improving lipid accumulation caused by a high-fat diet (HFD). Results Exendin-4 stimulated hepatic ABCA1 expression and transcription via the Ca2+/calmodulin (CaM)-dependent protein kinase kinase/CaM-dependent protein kinase IV (CaMKK/CaMKIV) pathway, whereas GLP-1 receptor antagonist exendin9-39 cancelled this effect. Therefore, exendin-4 decreased hepatic lipid content. ChIP showed that PREB could directly bind to the ABCA1 promoter, which was enhanced by exendin-4. Moreover, PREB stimulated ABCA1 promoter activity, and mutation of PREB-binding site in ABCA1 promoter cancelled exendin-4-enhanced ABCA1 promoter activity. Silencing of PREB attenuated the effect of exendin-4 and induced hepatic cholesterol accumulation. Blockade of CaMKK by STO-609 or siRNA cancelled the upregulation of ABCA1 and PREB induced by exendin-4. In vivo, exendin-4 or overexpression of PREB increased hepatic ABCA1 expression and decreased hepatic lipid accumulation and high plasma cholesterol caused by a HFD. Conclusions Our data shows that exendin-4 stimulates hepatic ABCA1 expression and decreases lipid accumulation by the CaMKK/CaMKIV/PREB pathway, suggesting that ABCA1 and PREB might be the therapeutic targets in fatty liver disease., Graphical abstract Image 1, Highlights • The GLP-1R agonist exendin-4 suppressed lipid accumulation by upregulating ABCA1 expression in hepatocytes. • Exendin-4 regulated the expression and transcription of hepatic ABCA1 via the CaMKK/CaMKIV/PREB pathway. • Overexpression of PREB or exendin-4 protected mouse liver from fatty liver by upregulation of ABCA1.

Adiponectin (APN) is an adipokine that protects against diabetes and atherosclerosis. High-density lipoprotein (HDL) mediates reverse cholesterol transport, which also protects against atherosclerosis. In this process, the human homolog of the B class type I scavenger receptor (SR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. The level of circulating APN is positively correlated with the serum level of HDL-cholesterol. In this study, we investigated whether HDL stimulates the gene expression of APN through the Ca2+/calmodulin (CaM)-dependent protein kinase IV (CaMKIV) cascade. APN expression was examined using real-time PCR and western blot analysis in 3T3-L1 cells incubated with HDL. CaMKIV activity was assessed by the detection of activation loop phosphorylation (at Thr196 residue), and the effect of the constitutively active form, CaMKIVc, on APN promoter activity was investigated. Our results showed that HDL stimulated APN gene expression via hSR-BI/CLA-1. Furthermore, we explored the signaling pathways by which HDL stimulated APN expression in 3T3-L1 cells. The stimulation of APN gene expression by HDL appears to be mediated by CaMKK, as STO-609, a specific inhibitor of CaMKK2, prevents this effect. We revealed that CaMKIVc increased APN gene transcriptional activity, and the CaMKIV-dominant negative mutant blocked the effect of HDL on APN promoter activity. Finally, knockdown of hSR-BI/CLA-1 also canceled the effect of HDL on APN gene expression. These results suggest that HDL has an important role to improve the function of adipocytes by activating hSR-BI/CLA-1, and CaMKK/CaMKIV pathway is conceivable as one of the signaling pathways of this activation mechanism.

To assess the level of diabetes knowledge and its association with diabetes self-management practices during Ramadan fasting among patients with type 2 diabetes (T2D).A cross-sectional study was conducted involving a sample of Malaysian patients with T2D. Patients aged 18 years and above, and attending an outpatient diabetic unit of a government hospital were recruited between February and April 2021. A self-administered questionnaire was utilized to assess diabetes knowledge and diabetes self-management practices.A total of 306 participants completed the questionnaire. Most of them were females (54.2%) and above 55 years old (75.1%). Resultantly, knowledge of diabetes was considered average among 52% of the participants. Only 9.5% of them avoided the consumption of sweet foods during iftar. Practicing late suhoor (p = 0.012) and self-monitoring of blood glucose (SMBG) (p = 0.026) during Ramadan were significantly associated with a better diabetes knowledge score. Education level (p = 0.000), working status (p = 0.030), and monthly income (p = 0.000) were significantly associated with participants' knowledge level of diabetes. A higher proportion (72.2%) of the participants completed fasting for a month during Ramadan 2020. Meanwhile, hypoglycemia was the main reason (38.8%) for incomplete fasting.These findings reflect the need to improve patients' knowledge of diabetes and diabetes self-management practices, especially during Ramadan. Such objectives could be achieved by considering the associated factors identified in this study.

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

Background: Myelodysplastic syndromes (MDS) and idiopathic cytopenia of undetermined significance (ICUS) are heterogeneous hematological disorders characterized by hematopoietic dysplasia and/or chromosomal aberrancy. Objectives: This study aimed to evaluate the diagnostic value of flow cytometry standardized using the European LeukemiaNet (ELN) for MDS and ICUS by analyzing samples obtained from patients with cytopenia based on morphological examination, cytogenetic analysis, and flow cytometry. Methods: We retrospectively analyzed bone marrow samples aspirated from 253 consecutive patients (median age: 66 years [range: 1–92]) to identify the cause of cytopenia. Results: Sixty patients presented with MDS, and 16 with ICUS. MDS subtypes were distributed as follows: MDS with single-lineage dysplasia (n = 10); MDS with multi-lineage dysplasia (n = 10); MDS with ringed sideroblasts (n = 4); MDS with excess blasts-1 (n = 9); MDS with excess blasts-2 (n = 13), MDS unclassified (n = 5); 5q-syndrome (n = 6); and MDS/myeloproliferative neoplasms (n = 3). Four representative ELN indexes were used. Two or more ELN MDS indexes were in the abnormal range in 35 MDS cases (58.3%) and 4 ICUS cases (25.0%). Conclusions: Morphological examination remains the standard for MDS diagnosis. Considering the low incidence of genetically proven ICUS (20.2–27.5%), the low sensitivity of ELN MDS indexes for ICUS is considered a valuable alternative.

The patient was a 71-year-old woman with aquaporin-4-antibody positive neuromyelitis optica (NMO), with no history of diabetes. On admission, although she showed an extremely elevated plasma glucose level (1,080 mg/dL), her hemoglobin A1c level was low (7.1%), which indicated the rapid progression of diabetes. She also showed ketoacidosis and had a human leukocyte antigen haplotype, DRB1*09:01-DQB1*03:03 associated with Fulminant type 1 diabetes (FT1D). Based on these results, the patient was diagnosed with FT1D. We herein describe the first reported case of a patient with FT1D with NMO, which raises the possibility that T-cell-mediated autoimmunity is involved in the pathogenesis of both FT1D and NMO.

Chronic hyperglycemia causes pancreatic β-cell dysfunction, impaired insulin secretion and suppression of insulin gene expression, referred to as glucotoxicity. Insulin gene expression is regulated by several protein kinases and protein phosphatases. However, the molecular mechanisms of the suppressed insulin gene expression in glucotoxicity are not fully understood. In this study, we employed rat insulinoma INS-1 cells as a model of pancreatic glucotoxicity. In INS-1 cells, insulin gene expression is up-regulated by incubation with 11.2 mM glucose for 7 days and down-regulated by incubation with 22.4 mM glucose for the same period. To identify the protein kinases and protein phosphatases involved in the suppression of insulin gene expression, we analyzed gene expression in INS-1 cells cultured with 11.2 mM or 22.4 mM glucose for 7 days using microarray analysis and real-time PCR. The expression levels of nine protein kinases were affected by glucotoxic conditions. In particular, CPG16 expression level was increased in INS-1 cells under these conditions. Transfection of CPG16 decreased insulin promoter activity, whereas kinase-dead mutant of CPG16 did not affect this. These results suggest that CPG16 plays a role in the suppression of insulin gene expression in pancreatic β-cells under glucotoxic conditions.

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation and apoptosis and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or LY-294002. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on either the decreased insulin content or the ABCA1 suppression caused by TNF-α in INS-1 cells. We checked the influence of TNF-α of insulin secretion and glucose-stimulated insulin secretion in rat pancreatic islet and INS-1 cell. TNF-α suppressed the insulin secretion and glucose-stimulated insulin secretion in both rat pancreatic islet and INS-1 cell. In summary, TNF-α suppressed the expression of endogenous ABCA1 and suppress the insulin secretion in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

Background Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). Case presentation A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. Conclusions Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.

Chronic hyperglycemia causes pancreatic β-cell dysfunction, impaired insulin secretion and the suppression of insulin gene expression. This phenomenon is referred to as glucotoxicity, and is a critical component of the pathogenesis of type 2 diabetes. We previously reported that the expression of candidate plasticity gene 16 (CPG16) was higher in rat pancreatic INS-1 β-cells under glucotoxic conditions and CPG16 suppressed insulin promoter activity. However, the molecular mechanisms of the CPG16-mediated suppression of insulin gene expression are unclear. In this study, we found that CPG16 directly bound and phosphorylated jun dimerization protein 2 (JDP2), an AP-1 family transcription factor. CPG16 co-localized with JDP2 in the nucleus of INS-1 cells. JDP2 bound to the G1 element of the insulin promoter and up-regulated promoter activity. Finally, CPG16 suppressed the up-regulation of insulin promoter activity by JDP2 in a kinase activity-dependent manner. These results suggest that CPG16 suppresses insulin promoter activity by phosphorylating JDP2.

A 50-year-old man was referred to our department for overt Cushing's syndrome (CS). His plasma cortisol concentrations were 314 μg/L, and his urinary cortisol concentrations were 431 μg/day. The plasma adrenocorticotropic hormone (ACTH) concentration was below the detectable limit. Computed tomography revealed atrophy of both adrenal glands and the presence of a left pararenal tumor. 131I-6β-iodomethyl-norcholesterol scintigraphy showed an intense uptake by the left pararenal tumor. These findings suggested that the left pararenal tumor was ectopic cortisol-producing adrenocortical adenoma. This case serves as a reminder that 131I-6β-iodomethyl-norcholesterol scintigraphy is an effective method for diagnosing ACTH-independent CS in which no adrenal tumor has been found.

D-Allulose, a C-3 epimer of D-fructose, is a rare sugar and a non-caloric sweetener. D-Allulose is reported to have several health benefits, such as suppressing a rise in postprandial glucose levels and preventing fat accumulation in rodents and humans. Additionally, low HDL-cholesterol levels post-D-allulose feeding were observed in humans but it is unclear how D-allulose decreased HDL-cholesterol levels. It is necessary to research the mechanism of HDL-cholesterol reduction by D-allulose ingestion because low HDL-cholesterol levels are known to associate with increased atherosclerosis risk. We therefore investigated the mechanism by which D-allulose lowers HDL-cholesterol using rat's primary hepatocytes. Sprague Dawley rats were fed an AIN-93G based diet containing 3% D-allulose for 2 weeks. Thereafter, primary hepatocytes were isolated by perfusion of collagenase. We measured the ability of HDL-cholesterol uptake in hepatocytes and the protein levels of scavenger receptor class B type 1 (SR-B1) as a HDL-cholesterol receptor. D-Allulose enhanced hepatocyte uptake of HDL-cholesterol, with a concurrent increase in hepatic SR-B1 protein levels. The results suggest that D-allulose enhances HDL-cholesterol uptake into the liver by increasing SR-B1 expression. It is estimated that HDL-cholesterol levels decreased accordingly. Since SR-B1 overexpression would decrease HDL-cholesterol levels, reportedly preventing atherosclerosis development, D-allulose could be a useful sweetener for atherosclerosis prevention.

In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus.

Concentrations of 2-methoxyestradiol (2ME2), a principal metabolite of estradiol, are significantly lower in women with severe preeclampsia. Nitric oxide (NO) released by endothelial nitric oxide synthase (eNOS) plays an important role in regulating cardiovascular homeostasis. Importantly, high-density lipoprotein (HDL) stimulates eNOS activity via endothelial human scavenger receptor class B type I (hSR-BI/CLA-1). Here, we aimed to determine the effect of 2ME2 on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). hSR-BI/CLA-1 expression was measured by real-time PCR, western blotting and reporter gene assays; eNOS activity was assessed by the measurement of eNOS phosphorylation. Both the mRNA and protein concentrations of hSR-BI/CLA-1 were significantly increased by 2ME2 in HUVECs. 2ME2 also dose-dependently increased the transcriptional activity of the hSR-BI/CLA-1 promoter. The effect of 2ME2 treatment on the promoter activity of hSR-BI/CLA-1 was abrogated by treatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase, as was the increase in HDL-induced eNOS activation. Notably, constitutively active Akt increased the activity of the hSR-BI/CLA-1 promoter, whereas dominant-negative Akt abolished the effect of 2ME2 treatment on hSR-BI/CLA-1 promoter activity. The nuclear Sp1 protein concentration was significantly increased by exposure to 2ME2 and Sp1 overexpression increased the promoter activity of the hSR-BI/CLA gene. Furthermore, knockdown of Sp1 inhibited the effect of 2ME2 treatment on hSR-BI/CLA-1 protein expression. These results indicate that 2ME2 treatment increases HDL-dependent eNOS phosphorylation by upregulating endothelial hSR-BI/CLA-1 expression, suggesting that 2ME2 has a potential therapeutic value in the treatment of preeclampsia.

Background Recently, immune checkpoint inhibitors have widely been used for the management of advanced melanoma. However, high-grade immune-related adverse events can occur, particularly with combination immunotherapy. We report a case of a patient with melanoma who developed thyroid storm following treatment with ipilimumab and nivolumab. Case presentation An 85-year-old Japanese man with a history of malignant melanoma presented to our department with severe thyrotoxicosis and poor blood glucose control. He was already being treated for Hashimoto’s disease and type 2 diabetes mellitus before the treatment for the melanoma. During admission, laboratory investigations revealed the following thyroid functions: thyroid-stimulating hormone below sensitivity, free triiodothyronine 31.7 pg/ml, and thyroglobulin 48,000 IU/ml. Thyroid-stimulating hormone receptor antibody was negative, and a 99mTc-labeled thyroid scan revealed a markedly decreased uptake. He was treated with beta-blocker, orally administered potassium iodine, a relatively low dose of prednisolone, and insulin injection therapy to control his blood glucose, resulting in an improvement in thyroid function and his symptoms. Conclusion It might be important to be aware of the possibility of thyroid storm induced by immune checkpoint inhibitors.

We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin–angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p