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Oral squamous cell carcinoma (OSCC) is a frequently occurring type of head and neck cancer with a high mortality and morbidity rate. Rhopaloic acid A (RA), a terpenoid derived from sponges, has demonstrated a promising anti-tumor activity, but its effectiveness for treating OSCC remains unknown. The aim of this study was to investigate whether RA inhibits the growth of OSCC. Cell viability was evaluated using CCK-8 assays in OSCC cells (Ca9-22, HSC-3 and SAS) and in normal cells (HGF-1) treated with RA. DAPI staining, AO staining, JC-1 staining and immunofluorescence were used to determine apoptosis, mitochondrial membrane potential and autophagy in RA-treated OSCC cells. Protein expression levels were determined by western blotting. Furthermore, the anti-tumor effect of RA was confirmed in vivo using a zebrafish oral cancer xenotransplantation model. OSCC cells had a significantly reduced viability after RA treatment, but normal cells were not affected. Treatment with RA caused chromatin condensation in OSCC cells, which increased their expression of autophagy- and apoptosis-related proteins. Furthermore, RA caused mitochondrial damage and increased autophagosome formation. Mitophagy was also induced by RA through the JNK/BNIP3/Nix/LC3B pathway. The JNK inhibitor SP600125 prevented both RA-mediated cell death and mitophagy of OSCC cells. A zebrafish xenograft model demonstrated that RA inhibits OSCC growth. In conclusion, RA showed a potent anticancer activity in in vitro and in in vivo oral cancer models by promoting mitochondrial damage-induced apoptosis and mitophagy, which suggests that RA may be useful as a novel and effective treatment for OSCC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/purpose: Diabetic macrovascular complications contribute to nonignorable causes of morbidity and mortality in patients with diabetes mellitus (DM). In this study, the trends of risk factors and macrovascular complications were examined in patients with DM in Taiwan.Methods: Health care information and International Classification of Diseases, Ninth Revision diagnostic codes were retrieved from the Taiwan Bureau of National Health Insurance claims files between 2005 and 2014. Using these data, the number of cases and annual prevalence of diabetic macrovascular complications in individuals with DM were stratified by age and sex.Results: The prevalence of DM with either stroke or cardiovascular disease (CVD) showed a decreasing trend in enrolled patients with DM (p for trend < 0.005), but that of DM with peripheral vascular diseases (PVDs) showed an increasing trend (p for trend < 0.001). Notably, the trend of changes in the prevalence of heart failure (HF) was similar to that of changes in the prevalence of stroke, although the decrease in prevalence was not statistically significant (p for trend = 0.053).Conclusion: From this nationwide study, we observed a decrease in the prevalence of diabetic macrovascular complications, such as stroke, CVD, and HF, but an increase in the prevalence of PVDs in the past decade in Taiwan. [ABSTRACT FROM AUTHOR]

Acute hyperglycemia is a common condition among patients with diabetes who are admitted to the emergency department (ED) for acute ischemic stroke (AIS). Previous findings regarding the association between hyperglycemia at admission and adverse outcomes among patients with diabetes and AIS have been inconsistent. When investigating this association, it is necessary to consider premorbid blood glucose control. The objective of the current study was to assess whether HbA1c-based adjusted glycemic variables were associated with unfavorable outcomes among patients admitted to the hospital for AIS. We retrospectively analyzed data from 309 patients who were hospitalized for AIS at a single medical center in Taiwan between January 1, 2013, and October 31, 2015. We found that 1) HbA1c-based adjusted glycemic variables, including the glycemic gap and stress hyperglycemia ratio, were associated with both AIS severity and neurological status at discharge; additionally, 2) HbA1c-based adjusted glycemic variables showed superior discriminative power compared with acute hyperglycemia regarding the development of severe AIS. We conclude that both the glycemic gap and stress hyperglycemia ratio might be useful in assessing the disease severity and prognosis of patients presenting with AIS. Further prospective long-term follow-up studies should be performed to validate these findings. [ABSTRACT FROM AUTHOR]

Oral cancer is one of the leading causes of cancer-related deaths worldwide. Chemotherapy is widely used in the treatment of oral cancer, but its clinical efficacy is limited by drug resistance. Hence, novel compounds capable of overcoming drug-resistance are urgently needed. Plumbagin (PG), a natural compound isolated from Plumbago zeylanica L, has been used to treat various cancers. In this study, we investigated the anticancer effects of PG on drug-resistant oral cancer (CR-SAS) cells, as well as the underlying mechanism. MTT assays were used to evaluate the effect of PG on the viability of CR-SAS cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined using flow cytometry. Protein expression levels were detected by western blotting. The results show that PG reduces the viability and causes the apoptosis of CR-SAS cells. PG is able to induce intracellular and mitochondrial ROS generation that leads to mitochondrial dysfunction. Furthermore, endoplasmic reticulum (ER) stress was triggered in PG-treated CR-SAS cells. The inhibition of ROS using N-acetylcysteine (NAC) abrogated the PG-induced ER stress and apoptosis, as well as the reduction in cell viability. Meanwhile, similar results were observed both in zebrafish and in murine models of drug-resistant oral cancer. Our results indicate that PG induces the apoptosis of CR-SAS cells via the ROS-mediated ER stress pathway and mitochondrial dysfunction. It will be interesting to develop the natural compound PG for the treatment of drug-resistant oral cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator with fat depot-specific expression. Its functional roles and epigenetic regulation in abdominal adipogenesis remain uncertain. We collected different fat depots from healthy, severely obese, and uraemic subjects to measure fat-depot specific gene expression and quantify regional adiposity via dual-energy X-ray absorptiometry (DXA). HOTAIR was overexpressed to evaluate its functional roles. Reduced representation bisulfite sequencing (RRBS), RNA-sequencing, real-time qPCR and RNA/chromatin immunoprecipitation were performed to analyse HOTAIR -mediated epigenetic regulation. A negative correlation between adipose tissue HOTAIR expression (arm or abdominal subcutaneous fat depots) and regional adiposity under the status of severe obesity or uraemia was observed. HOTAIR overexpression using human immortalized abdominal preadipocytes further revealed its anti-adipogenic effects. Integrative analysis of genome-wide DNA methylation by reduced representation bisulfite sequencing (RRBS) and gene expression was performed. Overall, the differentially methylated genes were functionally enriched for nervous system development, suggesting that HOTAIR may be epigenetically associated with cell lineage commitment. We specifically found that HOTAIR -mediated genes showed strong changes in both DNA methylation and gene expression during abdominal adipogenesis. We observed that two HOTAIR -repressed genes, SLITRK4 and PITPNC1, present an obesity-driven fat-depot specific expression pattern that is positively correlated with the central body fat distribution. Our study indicated that HOTAIR is a key regulator of abdominal adipogenesis via intricate DNA methylation and is likely to be associated with the transcriptional regulation of genes involved in nervous system development and lipid metabolism, such as SLITRK4 and PITPNC1. • HOTAIR was lowly expressed in abdominal and arm fats compared to the gluteal fat. • Fat-depot-specific HOTAIR expression could be altered in the obese or uraemic status. • HOTAIR overexpression suppressed abdominal adipogenesis and modulated methylome. • HOTAIR -suppressed genes were associated with neural development and lipid metabolism. [ABSTRACT FROM AUTHOR]

• The flavonoid 6-methoxyflavone (6-MeOF) prevents cell death and decreases pro-inflammatory mediators in LPS- -stimulated BV2 microglia cells. • 6-MeOF suppresses p38 MAPK/NF-κB signaling and the MyD88-dependent TLR pathway. • 6-MeOF activates the HO-1/NQO1 axis. • 6-MeOF inhibits LPS-induced NO generation and microglia activation in vivo. • 6-MeOF has potential anti-inflammatory and anti-oxidant effects against microglia-associated neuroinflammatory disorders. Microglia-related neuroinflammation is associated with a variety of neurodegenerative diseases. Flavonoids have demonstrated different pharmacological effects, such as antioxidation, neuroprotection and anti-inflammation However, the effect of flavonoid 6-methoxyflavone (6-MeOF) on microglia-mediated neuroinflammation remain unknown. The current study aim to study the antineuroinflammatory effects of 6-MeOF in lipopolysaccharide- (LPS-) induced microglia in vitro and in vivo. Pretreatment of BV2 microglia cells with 6-MeOF for 1 h then stimulated with LPS (100 ng/ml) for 24 h. The expression levels of pro-inflammatory factors, NO and reactive oxygen species (ROS) were performed by the enzyme-linked immunosorbent assay (ELISA), Griess assay and flow cytometry. Western blotting was used to assess MAPK, NF-κB signal transducer and antioxidant enzymes-related proteins. Analysis of ROS and microglial morphology was confirmed in the zebrafish and mice brain, respectively. Our results demonstrated that 6-MeOF dose-dependently prevent cell death and decreased the levels of pro-inflammatory mediators in LPS-stimulated BV2 microglia cells. Phosphorylated NF-κB/IκB and TLR4/MyD88/p38 MAPK/JNK proteins after exposure to 6-MeOF was suppressed in LPS-activated BV-2 microglial cells. 6-MeOF also presented antioxidant activity by reduction of NO, ROS, iNOS and COX-2 and the induction of the level of HO-1 and NQO1 expressions in LPS-activated BV2 microglial cells. Furthermore, we demonstrated that 6-MeOF inhibited LPS-induced NO generation in an experimental zebrafish model and prevent the LPS-induced microgliosis in the prefrontal cortex and substantia nigra of mice. These results explored that 6-MeOF possesses potential as anti-inflammatory and anti-oxidant agents against microglia-associated neuroinflammatory disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Microglia-related neuroinflammation is associated with a variety of neurodegenerative diseases. Flavonoids have demonstrated different pharmacological effects, such as antioxidation, neuroprotection and anti-inflammation However, the effect of flavonoid 6-methoxyflavone (6-MeOF) on microglia-mediated neuroinflammation remain unknown.Purpose: The current study aim to study the antineuroinflammatory effects of 6-MeOF in lipopolysaccharide- (LPS-) induced microglia in vitro and in vivo.Methods: Pretreatment of BV2 microglia cells with 6-MeOF for 1 h then stimulated with LPS (100 ng/ml) for 24 h. The expression levels of pro-inflammatory factors, NO and reactive oxygen species (ROS) were performed by the enzyme-linked immunosorbent assay (ELISA), Griess assay and flow cytometry. Western blotting was used to assess MAPK, NF-κB signal transducer and antioxidant enzymes-related proteins. Analysis of ROS and microglial morphology was confirmed in the zebrafish and mice brain, respectively.Results: Our results demonstrated that 6-MeOF dose-dependently prevent cell death and decreased the levels of pro-inflammatory mediators in LPS-stimulated BV2 microglia cells. Phosphorylated NF-κB/IκB and TLR4/MyD88/p38 MAPK/JNK proteins after exposure to 6-MeOF was suppressed in LPS-activated BV-2 microglial cells. 6-MeOF also presented antioxidant activity by reduction of NO, ROS, iNOS and COX-2 and the induction of the level of HO-1 and NQO1 expressions in LPS-activated BV2 microglial cells. Furthermore, we demonstrated that 6-MeOF inhibited LPS-induced NO generation in an experimental zebrafish model and prevent the LPS-induced microgliosis in the prefrontal cortex and substantia nigra of mice.Conclusion: These results explored that 6-MeOF possesses potential as anti-inflammatory and anti-oxidant agents against microglia-associated neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown.Purpose: This study investigated the underlying mechanisms of loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord.Methods: Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies.Results: Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1β, and IL-18 were enhanced on day 7 after CCI, and all were reduced after loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in loganin-treated rats. Moreover, loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome.Conclusion: Our findings suggest that loganin might be a suitable candidate for managing CCI-provoked neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.Purpose: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.Methods: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.Results: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.Conclusion: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC. [ABSTRACT FROM AUTHOR]

Abstract: Background/Purpose: Inward rectifying potassium channel 6.2 (Kir6.2 Δ C26 channel) is closely related to ATP-sensitive potassium channels. Whether sodium azide, barium ion, d-amphetamine or procaine acts directly on the Kir6.2 Δ C26 channel remains unclear. We studied the effects of these compounds on Kir6.2 Δ C26 channel expressed in Xenopus oocytes. Methods: The coding sequence of a truncated form of mouse Kir6.2 (GenBank accession number NP_034732.1), Kir6.21-364 (i.e. Kir6.2 Δ C26), was subcloned into the pET20b(+) vector. Plasmid containing the correct T7 promoter-Kir6.21-364 cDNA fragment [Kir6.2/pET20b(+)] was then subject to Not I digestion to generate the templates for in vitro run-off transcriptions. The channel was expressed in Xenopus laevis oocytes. Two-electrode voltage clamping was used to measure the effects of sodium azide, barium ion, d-amphetamine and procaine on Kir6.2 Δ C26 channel current. Results: Sodium azide activated and barium ion and d-amphetamine inhibited the Kir6.2 Δ C26 channel. Procaine did not have any significant effect on the Kir6.2 Δ C26 channel. Conclusion: Kir6.2 Δ C26 channel expressed in Xenopus oocytes can be used as a pharmacological tool for the study of inward rectifying potassium channels. [Copyright &y& Elsevier]

Abstract: Both slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines and inflammatory markers of both regimens in patients with type 2 diabetes mellitus. A prospective, randomized, double-blind study enrolled 55 patients with type 2 diabetes mellitus, which were randomly assigned to receive either metformin SR or RR (at a maximal dosage of 2000 mg/d for 12 weeks). Glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, adipocytokines, C-reactive protein, and insulin resistance and pancreatic beta-cell function were measured before and after treatment. Significant decreases (P < .001) in mean HbA1c and fasting plasma glucose levels were observed in each group. However, the mean changes in HbA1c from baseline to end point in the 2 groups were not significantly different. Changes in metabolic parameters were similar except that a decreased total cholesterol level was observed in the metformin RR group. Neither regimen treatment had any influence on insulin resistance, but metformin RR improved beta-cell function. Neither regimen had an effect on serum adipocytokines or inflammatory markers. Once-daily metformin SR was as safe and effective as metformin RR in type 2 diabetic patients. Neither dosage form affected serum adipocytokines and inflammatory markers. [Copyright &y& Elsevier]

Summary: Aims: Sulfonylurea with long half-life such as gliclazide has sustained stimulation on insulin secretion compared to repaglinide which has short half-life for only about 1h. In this hospital cohort, randomized, cross-over study, we used modified low dose graded glucose infusion test (M-LDGGI) to evaluate second phase insulin secretion after 4 months of treatment with either gliclazide or repaglinide. Methods: Sixteen fresh type 2 diabetes with age of 49.5±2.6 years old and BMI of 25.3±0.9kg/m2 were included. After titration and maintain dose stage, all cases were randomized to the repaglinide or gliclazide treatment for 4 months. At the end of each treatment period, an M-LDGGI was done. Results: The general linear model repeated measurement was used to evaluate the plasma glucose, insulin and insulin/glucose curve during M-LDGGI. Although the plasma insulin and insulin/glucose ratios were higher at 40min and 100–120min, they did not reach statistically significant. The area under curve of the plasma glucose, insulin and insulin/glucose ratio was also used to evaluate the secretory capacity of beta cell. Although the AUC of the ratio of plasma insulin/plasma glucose seems to be more evident than the curves, they are still not significantly different with each other. Conclusions: In conclusion, although non-significant, better second phase insulin secretion could be noted with treatment of repaglinide than gliclazide for 4 months. Further study with longer duration and larger study cohort are needed to solve this interesting and important question. [Copyright &y& Elsevier]

Abstract: The aim of this study is to evaluate the effect and safety of chromium-containing milk powder in patients with type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial was conducted in Taiwan. A total of 60 patients with type 2 diabetes mellitus, aged 30 to 75 years, and on a dose of gliclazide sulfonylurea agent (≤160 mg/d) for at least 3 months were enrolled. Their glycosylated hemoglobin ranged from 7.5% to 12%, fasting plasma glucose (FPG) from 140 to 250 mg/dL, and body mass index from 20 to 35 kg/m2. The subjects were divided into 2 groups, one group to receive chromium-containing milk powder (chromium 200 μg/20 g milk powder) and the other to receive placebo twice a day for 16 weeks. Frequently sampled intravenous glucose tolerance test (IVGTT) was performed before and after treatment. The chromium group demonstrated a lower FPG and fasting insulin (−38.1 ± 9.2 vs 63 ± 8. 5 mg/dL and −1.7 ± 0.2 vs 1.9 ± 0.3 μU/mL, respectively; P < .05), especially in male patients (−41 ± 9.2 vs 85 ± 11.7 mg/dL and −2.7 ± 0.2 vs 3.1 ± 0.3 μU/mL, respectively; P < .01), at the end of the study. Lower glycosylated hemoglobin was observed in chromium-treated male patients (−1.1 ± 0. 5 vs 0.7 ± 0. 2; P < .05). However, there were no significant changes in other metabolic parameters (lipid profiles including total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), except improvement of insulin resistance (homeostasis model assessment for insulin resistance and insulin sensitivity index from frequently sampled intravenous glucose tolerance test) observed in male patients (−2.1 ± 1.1 vs −0.41 ± 1.12 and 0.18 ± 0.11 vs −0.15 ± 0. 2, respectively; P < .05). There were no adverse events in both groups, except for mild complaints in the chromium group on constipation (5%) and flatulence (5%). Intake of milk powder containing 400 μg/d of chromium for 16 weeks in subjects with type 2 diabetes mellitus resulted in lowering of FPG, fasting insulin, and improvement of metabolic control in male patients. [Copyright &y& Elsevier]

Background: Syringin (Syr), a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, possesses various biological properties, including anticancer activities. However, the cytotoxicity effects of Syr on breast cancer have not yet been elucidated.Purpose: In this study, we evaluated the anticancer potential of Syr on breast carcinoma and the mechanism involved.Study Design/methods: Non-tumorigenic (M10), tumorigenic (MCF7) and metastatic (MDA-MB-231) breast cancer cell lines as well as xenograft model were treated with Syr. Proliferation and cell cycle distribution were evaluated using the MTT, the colony formation assay and flow cytometry. The expression levels of cytotoxicity-related proteins were detected by Western blot.Results: Here, we found that colony formation inhibition, cell cycle arrest in the G2/M phase, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3/9 activation were observed in MCF7 and MDA-MB-231 cells treated with Syr. Moreover, pretreatment with a pan-caspase inhibitor (Z-DEVD-FMK) inhibited Syr-induced apoptosis. In addition, treatment with Syr also increased the production of reactive oxygen species (ROS). However, the antioxidant N-acetyl-cysteine (NAC) reversed the ROS levels and rescued the apoptotic changes. Meanwhile, Syr inhibited the growth of breast cancer xenograft models and dramatically decreased tumor volume without any obvious body weight loss in vivo.Conclusion: Our findings suggest that Syr induces oxidative stress to suppress the proliferation of breast cancer and thus might be an effective therapeutic agent to treat breast cancer. [ABSTRACT FROM AUTHOR]