Search

Background: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). This study aimed to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Methods: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of various concentrations of glucose, pyruvate, or ATP-encapsulated liposomes. Results: In this study, human CRC cell lines treated with irinotecan in high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in normal glucose concentrations. Irinotecan induced apoptosis and necroptosis, both mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it did not affect necroptosis. In contrast, pyruvate attenuated the receptor-interacting protein kinase 1/3-dependent necroptosis via free radical scavenging without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated the irinotecan-induced G0/G1 shift, whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere size while pyruvate prevented the deformation of spheroid mass. Conclusions: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to a quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, contributing to tumor recurrence. Our findings challenged the traditional view of ATP as the main factor for irinotecan chemoresistance and provided novel insights of pyruvate acting as an antioxidant responsible for drug insensitivity, which may shed light on the development of new therapies against recalcitrant cancers.

Background: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). The aim of this study was to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Methods: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate or ATP-encapsulated liposomes. Cell apoptosis was measured by DNA fragmentation and caspase activities, and necroptosis was evaluated by immunoprecipitation of receptor-interacting protein kinase (RIP) 1/3 complex. Cell cycles were assessed by flow cytometric analysis.Results: Human CRC cell lines treated with irinotecan in the presence of high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in the presence of normal glucose. Irinotecan induced apoptosis and necroptosis, both of which were mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it had no effect on necroptosis. In contrast, pyruvate attenuated the RIP1/3-dependent necroptosis via free radical scavenging, without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere sizes while pyruvate prevented the deformation of spheroid mass. Conclusions: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, which might contribute to tumor recurrence.

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported "frequent dysmenorrhea" in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P 5 × 10

Key points Intestinal ischaemia causes epithelial death and crypt dysfunction, leading to barrier defects and gut bacteria-derived septic complications. Enteral glucose protects against ischaemic injury; however, the roles played by glucose metabolites such as pyruvate and ATP on epithelial death and crypt dysfunction remain elusive. A novel form of necrotic death that involves the assembly and phosphorylation of receptor interacting protein kinase 1/3 complex was found in ischaemic enterocytes. Pyruvate suppressed epithelial cell death in an ATP-independent manner and failed to maintain crypt function. Conversely, replenishment of ATP partly restored crypt proliferation but had no effect on epithelial necroptosis in ischaemic gut. Our data argue against the traditional view of ATP as the main cytoprotective factor by glucose metabolism, and indicate a novel anti-necroptotic role of glycolytic pyruvate under ischaemic stress. Abstract Mesenteric ischaemia/reperfusion induces epithelial death in both forms of apoptosis and necrosis, leading to villus denudation and gut barrier damage. It remains unclear whether programmed cell necrosis [i.e. receptor-interacting protein kinase (RIP)-dependent necroptosis] is involved in ischaemic injury. Previous studies have demonstrated that enteral glucose uptake by sodium-glucose transporter 1 ameliorated ischaemia/reperfusion-induced epithelial injury, partly via anti-apoptotic signalling and maintenance of crypt proliferation. Glucose metabolism is generally assumed to be cytoprotective; however, the roles played by glucose metabolites (e.g. pyruvate and ATP) on epithelial cell death and crypt dysfunction remain elusive. The present study aimed to investigate the cytoprotective effects exerted by distinct glycolytic metabolites in ischaemic gut. Wistar rats subjected to mesenteric ischaemia were enterally instilled glucose, pyruvate or liposomal ATP. The results showed that intestinal ischaemia caused RIP1-dependent epithelial necroptosis and villus destruction accompanied by a reduction in crypt proliferation. Enteral glucose uptake decreased epithelial cell death and increased crypt proliferation, and ameliorated mucosal histological damage. Instillation of cell-permeable pyruvate suppressed epithelial cell death in an ATP-independent manner and improved the villus morphology but failed to maintain crypt function. Conversely, the administration of liposomal ATP partly restored crypt proliferation but did not reduce epithelial necroptosis and histopathological injury. Lastly, glucose and pyruvate attenuated mucosal-to-serosal macromolecular flux and prevented enteric bacterial translocation upon blood reperfusion. In conclusion, glucose metabolites protect against ischaemic injury through distinct modes and sites, including inhibition of epithelial necroptosis by pyruvate and the promotion of crypt proliferation by ATP.

Background Prosthetic joint infections (PJIs) often require long-course antibiotic therapy. However, recent studies argue against the current practice and raise concerns such as the development of antibiotic resistance, side effects of medications and medical costs. Objectives To review and compare the outcomes of short-course and long-course antibiotics in PJIs. Methods We conducted a systemic review and meta-analysis using a predefined search term in PubMed and EMBASE databases. Studies that met the inclusion criteria from inception to June 2018 were included. The quality of the included studies was assessed. Results A total of 10 articles and 856 patients were analysed, comprising 9 observational studies and 1 randomized controlled trial. Our meta-analysis showed no significant difference between short-course and long-course antibiotics (relative risk = 0.87, 95% CI = 0.62–1.22). Additionally, the older the studied group was, the more short-course antibiotics were favoured. Conclusions When treating PJI patients following debridement, antibiotics and implant retention, an 8 week course of antibiotic therapy for total hip arthroplasty and a 75 day course for total knee arthroplasty may be a safe approach. For two-stage exchange, a shorter duration of antibiotic treatment during implant-free periods is also generally safe with the usage of antibiotic-loaded cement spacers.

Aims/Introduction Admission hyperglycemia is associated with poor outcome in patients with myocardial infarction. The present study evaluated the relationship between admission glucose level and other clinical variables in patients with ST‐elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Materials and Methods The 959 consecutive STEMI patients undergoing primary PCI were divided into five groups based on admission glucose levels of

This study investigates the effects of adding titanium dioxide (TiO2) particles to the negative electrode of a vanadium redox flow battery (VRFB) on the battery’s performance. Results show that TiO2 addition changes the wettability and electrical resistance of the electrode surface. The water contact angle on the electrode surface decreases with increased weight percentage of TiO2 particles in the electrode. The electrochemical performance of these electrodes with different loading amounts is studied by cyclic voltammetry and single-cell charge‐discharge measurements. Adding an adequate amount of TiO2 particles to the carbon electrode promotes the electrode specific capacitance and charge‐discharge efficiency of a single cell. An electrode with 20 wt% TiO2 loading at a scan rate of 0.04 V s −1 shows a high specific capacitance (Cs,t) of 156.2 F g −1 , which is 59.1% higher than that of pure carbon electrode (98.2 F g −1 ). Similarly, the energy storage efficiency (ηE = 72.5%) of a single TiO2/C cell with 20 wt% modified carbon felt is 30.4% higher than that of a cell with raw carbon felt (ηE = 55.6%). Thus, the TiO2/C electrode increases the cell energy storage efficiency. These results demonstrate the potential application of TiO2/C electrode in VRFBs.

Single-layered intestinal epithelia play key roles in the maintenance of gut homeostasis and barrier integrity. Various types of epithelial cell death, including apoptosis, necrosis, and necroptosis, have been detected in ischemic and hypoxic stress conditions, thus resulting in bacterial translocation and gut-derived septic complications. Cytoprotective strategies, such as enteral glucose uptake, rescue intestinal epithelium from cell death after ischemic and hypoxic injury. Although glucose metabolism and energy production are generally considered to be the key factors in cytoprotection, the precise modes and sites of action have not been clarified. Our recent studies have demonstrated that energy restoration promotes crypt hyperplasia but does not prevent epithelial cell death under ischemic stress. On the other hand, glycolytic pyruvate prevents epithelial cells from undergoing apoptosis and necroptosis by scavenging free radicals in an ATP-independent manner. Distinct gut protective mechanisms involving ATP, pyruvate, glucose metabolic enzymes, and sodium-dependent glucose transporter activation are discussed here. Overall, glucose-mediated cytoprotection may be a universal mechanism that has evolved in epithelial cells for the maintenance of intestinal homeostasis. Enteral glucose supplementation is beneficial as a perioperative supportive therapy for the protection of gut barrier integrity.

Background Current guidelines for treatment of osteomyelitis (OM) suggest antibiotics for 3–6 weeks. However, recent studies provided conflicting evidence about the benefits of the prolonged use of antibiotics. We conducted a systemic review and meta-analysis to assess the outcomes of short- and long-term antibiotics in patients with OM. Methods We used three queries to retrieve literature of vertebral OM, chronic OM, and diabetic foot OM from PubMed and Embase databases until December 2017. Each query comprised medical subject headings, title/abstract keywords, and exclusion terms. Two reviewers independently screened literature for three rounds and disagreements were resolved by a third reviewer. Quality of a cohort study and that of a randomized control trial (RCT) were assessed by Newcastle-Ottawa Quality Assessment Form and a modified Jadad scale, respectively. Results A total of 7,192 studies were retrieved (Figure 1). Eleven observation studies and five RCTs were included for analysis, including seven articles about vertebral OM, two chronic OM, five pediatric OM, and two diabetic foot OM. Of the 11 observational studies, only five were graded as good or fair quality. Thirteen studies demonstrated no significant difference in outcomes between short- and long-term of antibiotics, while three studies showed favorable outcomes in patients taking long-term antibiotics. The aggregate odds ratio (OR) of mortality was 0.46 (95% CI, 0.21, 1.02) for observational studies and 0.90 (95% CI, 0.58, 1.41) for RCTs, showing no significant benefits of long-term antibiotics in patients with OM (Figure 2). In patients with vertebral OM, outcomes were comparable between short- and long-term of antibiotics (OR 0.51, 95% CI, 0.26, 1.01). In seven studies where only intravenous (IV) antibiotics were used, there was no significant benefit of long-term antibiotics (OR 1.12, 95% CI, 0.68, 1.83). However, in the remaining nine studies where antibiotics were transitioned from IV to oral form, there was marginal benefit of long-term oral antibiotics (OR 0.44, 95% CI, 0.22, 0.91). Conclusion Both RCTs and observational studies demonstrated that long-term antibiotics use did not generate significantly better outcome as compared with short-term antibiotics in patients with all-cause or a specific type of OM. Disclosures All authors: No reported disclosures.

A 23-year-old non-diabetic woman presented to our emergency room with progressive headache. She was diagnosed with craniopharyngioma and received tumor resection. Her blood glucose level was within the normal limit before surgery, and she had no family history of diabetes. Three months after the surgery, acute hyperosmolar hyperglycemic state developed. After 4 months of follow-up, her diabetes persisted but improved with oral antidiabetic drugs. This is the third case report of diabetes developing several months after craniopharyngioma tumor resection. The possible mechanisms of cranipharyngioma or its surgery inducing diabetes mellitus are hypothalamic obesity or hypothalamic damage. The degree of hypothalamic damage before the operation is predictive of diabetes development, and blood glucose level monitoring is important for these patients.

Cancer cells may survive under oxygen and nutrient deprivation by metabolic reprogramming for high levels of anaerobic glycolysis, which contributes to tumor growth and drug resistance. Abnormally expressed glucose transporters (GLUTs) are colocalized with hypoxia (Hx) inducible factor (HIF)1α in peri-necrotic regions in human colorectal carcinoma. However, the underlying mechanisms of anti-necrotic resistance conferred by glucose metabolism in hypoxic cancer cells remain poorly understood. Our aim was to investigate signaling pathways of Hx-induced necroptosis and explore the role of glucose pyruvate metabolite in mechanisms of death resistance. Human colorectal carcinoma cells were Hx exposed with or without glucose, and cell necroptosis was examined by receptor-interacting protein (RIP)1/3 kinase immunoprecipitation and (32)P kinase assays. Our results showed increased RIP1/3 complex formation and phosphorylation in hypoxic, but not normoxic cells in glucose-free media. Blocking RIP1 signaling, by necrostatin-1 or gene silencing, decreased lactodehydrogenase (LDH) leakage and plasma membrane disintegration. Generation of mitochondrial superoxide was noted after hypoxic challenge; its reduction by antioxidants inhibited RIP signaling and cell necrosis. Supplementation of glucose diminished the RIP-dependent LDH leakage and morphological damage in hypoxic cells, whereas non-metabolizable sugar analogs did not. Hypoxic cells given glucose showed nuclear translocation of HIF1α associated with upregulation of GLUT-1 and GLUT-4 expression, as well as increase of intracellular ATP, pyruvate and lactate levels. The glucose-mediated death resistance was ablated by iodoacetate (an inhibitor to glyceraldehyde-3-phosphate dehydrogenase), but not by UK5099 (an inhibitor to mitochondrial pyruvate carrier), suggesting that glycolytic pathway was involved in anti-necrotic mechanism. Lastly, replacing glucose with cell-permeable pyruvate derivative also led to decrease of Hx-induced necroptosis by suppression of mitochondrial superoxide in an energy-independent manner. In conclusion, glycolytic metabolism confers resistance to RIP-dependent necroptosis in hypoxic cancer cells partly through pyruvate scavenging of mitochondrial free radicals.