Empagliflozin attenuates epithelial-to-mesenchymal transition through senescence in peritoneal dialysis.

Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.

Enhanced Electrochemical Stability and Extended Cycle Life in Sulfide-Based All-Solid-State Batteries: The Role of Li10 SnP2 S12 Coating on Ni-Rich NCM Cathode.

Recently, sulfide-based all-solid-state batteries (ASSBs) have attracted great attention because of their excellent safety and high energy density. However, by-products formed from side-reactions between the oxide-based cathodes and sulfide-based solid electrolytes (SEs) increase the interfacial resistance and degrade the cell performance. Suppression of this interfacial resistance is thus critical. In this study, the extraordinarily high stability of the cathode/SE interface is discovered when a Li10 SnP2 S12 (LSnPS) is applied to a cathode buffer layer. The electrochemical properties of the cathode interface at high potential are improved by synthesizing a core-shell structure cathode using LSnPS. The synthesized LSnPS is uniformly coated on a Li2 ZrO3 -coated LiNi0.8 Co0.1 Mn0.1 O2 (LZO-NCM) surface using the cost-efficient mechano-fusion method. The ASSB with LSnPS-coated LZO-NCM as the cathode and Li6 PS5 Cl (argyrodite, LPSCl) as the SE exhibited a capacity of 192 mAh g-1 and excellent cycle retention of ≈75% after 500 charge/discharge cycles. In addition, the degradation mechanism at the cathode/SE interface is investigated. The results indicated that LSnPS stabilizes the interface between NCM and argyrodite, thereby inhibiting the decomposition of the SE. This technology is expected to contribute to the commercialization of cathode materials for sulfide-based ASSBs due to its enhanced cycle performance, low-cost material application, and eco-friendly process.

Catheter salvage using revision for a peritoneal dialysis catheter with intractable exit site and/or tunnel infections.

BACKGROUND: In case of intractable exit site and/or tunnel infections, peritoneal dialysis (PD) catheter removal and re-insertion are recommended. Previous studies have reported the possibility of catheter salvage before removal, but they were either case-series or had a small sample size. METHODS: We identified all incident patients with PD who underwent revision at a tertiary medical center. In intractable exit site and/or tunnel infections, we tried catheter revision using a method with cuff shaving, using an original catheter, and creating a new tunnel. Revision success was defined as complete remission over more than 1 month after revision. We evaluated the infection-free and catheter survival rates. RESULTS: In total, 52 patients with PD underwent revision. The median age at the time of revision in the patients undergoing PD was 51 (21) years. There were 43 (82.7%) cases of revision success. Infection-free survival rates at 6 and 12 months were 57.0% and 35.1%, respectively. Catheter survival rates at 12 and 36 months were 72.5% and 56.2%, respectively. CONCLUSION: The present study demonstrated that catheter revision can be a useful bridging method for original catheter salvage before catheter removal in intractable exit site and/or tunnel infections.

Prehospital National Early Warning Score as a predictor of massive transfusion in adult trauma patients.

BACKGROUND: Previous studies have shown that an elevated prehospital National Early Warning Score (preNEWS) is associated with increased levels of adverse outcomes in patients with trauma. However, whether preNEWS is a predictor of massive transfusion (MT) in patients with trauma is currently unknown. This study investigated the accuracy of preNEWS in predicting MT and hospital mortality among trauma patients. METHODS: We analyzed adult trauma patients who were treated and transported by emergency medical services (EMS) between January 2018 and December 2019. The main exposure was the preNEWS calculated for the scene. The primary outcome was the predictive ability for MT, and the secondary outcome was 24 h mortality. We compared the prognostic performance of preNEWS with the shock index, modified shock index, and reverse shock index, and reverse shock index multiplied by Glasgow Coma Scale in the prehospital setting. RESULTS: In total, 41,852 patients were included, and 1456 (3.5%) received MT. preNEWS showed the highest area under the receiver operating characteristic (AUROC) curve for predicting MT (0.8504; 95% confidence interval [CI], 0.840-0.860) and 24 h mortality (AUROC 0.873; 95% CI, 0.863-0.883). The sensitivity of preNEWS for MT was 0.755, and the specificity of preNEWS for MT was 0.793. All indicies had a high negative predictive value and low positive predictive value. CONCLUSION: preNEWS is a useful, rapid predictor for MT and 24 h mortality. Calculation of preNEWS would be helpful for making the decision at the scene such as transfer straightforward to trauma center and advanced treatment.

An unusual complication of prolonged tunneled cuffed hemodialysis catheter.

A 57-year-old male patient visited our center owing to abnormal tunneled cuffed hemodialysis catheter (TC-HDC). He had been undergoing hemodialysis for 44 months. Hemodialysis was performed using a TC-HDC, which became dilatated between the hub and exit site 19 months after the initiation of hemodialysis. The first TC-HDC was exchanged using over the guidewire method. The second TC-HDC was maintained for 25 months after catheter exchange. However, the second TC-HDC was repeatedly dilatated 25 months later from the first catheter exchange. We re-exchanged the dilatated TC-HDC to the new TC-HDC using over the guidewire method. Our case presented general dilatation of both lumens without leakage. The portion of catheter dilatation was limited between the hub and exit site. The embedded segment of the catheter was preserved owing to encasement of the adjacent tissue. Our case showed that clinicians should inspect both exposed and embedded segments to prevent further catheter injury and exchange the catheter before the development of complications.

Association between the appendicular lean mass index or handgrip strength and bone mineral density in patients undergoing peritoneal dialysis.

Background: Few studies have investigated the association between muscle mass and bone mineral density (BMD) in patients undergoing peritoneal dialysis (PD). We aimed to investigate the association between muscle mass or strength and BMD in patients undergoing PD. Methods: The data of all prevalent PD cases at a tertiary medical center between September 2017 and November 2020 were collected. Among all patients, 199 patients undergoing PD were finally analyzed. Baseline measurements including handgrip strength (HGS), appendicular lean mass (ALM) index, and BMD were obtained during a peritoneal membrane equilibration test. Patients with a T-score of ≤ -2.5 were categorized into the low BMD group. Results: The number of male patients was 113 (56.8%). Significant differences were observed in various indices, such as BMD, body composition parameters, and laboratory findings, between male and female patients. There was a stronger association between BMD and ALM index than between BMD and HGS in male patients (r = 0.432 and P < 0.001). The association between BMD and HGS was more definitive in female patients than in male patients (r = 0.357 and P = 0.001). Univariate and mutivariate linear regression and AUROC analyses showed similar trends those obtained in correlation analyses. Conclusion: The present study demonstrated that BMD is associated with the ALM index in male patients and with HGS in female patients undergoing PD.

OCULAR MANIFESTATIONS OF ASP38ALA AND THR59LYS FAMILIAL TRANSTHYRETIN AMYLOIDOSIS.

PURPOSE: To describe the ophthalmic manifestations of familial transthyretin amyloidosis (FTA) mutations, including Asp38Ala and Thr59Lys, which have not been previously reported to have ocular involvement. METHODS: This is an observational case series of prospectively collected data of 16 patients with FTA who were taking tafamidis for mild peripheral neuropathy and underwent a comprehensive ophthalmic examination at a single tertiary center, between January 2013 and March 2020. The ocular involvement of each FTA mutation type and the specific manifestations were the main outcome measures. RESULTS: Six of 16 patients with FTA manifested ocular involvement. Ocular involvement was noted in two of three patients with Glu89Lys mutations having retinal deposits, retinal hemorrhages, and corneal opacity. Three of nine patients with Asp38Ala mutations and one of two patients with Thr59Lys mutations showed ocular involvement that had not been previously described. The ophthalmic findings included glaucoma, anterior lens capsule opacity, vitreous opacity, and retinal deposits. The decrease in vascular flow due to perivascular cuffing of the amyloid deposits was detected by optical coherence tomography angiography. CONCLUSION: The current study newly described that two transthyretin mutation types of FTA, Asp38Ala and Thr59Lys, may manifest with ocular findings such as anterior lens capsule opacity and retinal deposits.

Peritoneal dialysis catheter salvage performed by nephrologists in tunnel exposure management.

BACKGROUND: Tunnel exposure, a non-infectious complication, is a rare finding in peritoneal dialysis (PD) patients, which has been described in some case reports. Our study aimed to present catheter salvage therapy using a revision procedure of tunnel exposure by nephrologists. METHODS: Our retrospective study was conducted between July 1998 and October 2021. We identified all PD patients with tunnel exposure from a database of a tertiary medical center. Tunnel exposure was diagnosed following gross inspection by clinicians during outpatient consultations. We attempted revision with partial external cuff shaving and creating a new tunnel without catheter change. RESULTS: Fourteen cases in 12 patients were diagnosed as tunnel exposure. The median age at presentation of tunnel exposure was 51 years. Eleven patients underwent revision, and the PD catheter was removed in one patient. The patients who underwent revision were followed up for 6 months. The catheter salvage rate was 72.7%. CONCLUSIONS: The present study demonstrated that catheter revision performed by nephrologists could be a valuable alternative for original catheter salvage before considering catheter removal in tunnel exposure management.

Hemodialysis catheter malpositioned into the mediastinum: Lessons from two cases.

Hemodialysis catheter (HDC) using a tunneled cuffed catheter (TCC) is a viable option for acute hemodialysis. Vessel injury during catheter insertion can lead to malpositioning of the HDC into the mediastinum. We herewith present two malpositioned HDCs in various clinical settings. For the first case, the HDC was inserted without fluoroscopic guidance, but in the second case, the HDC was inserted under fluoroscopic guidance. Our first case involved HDC insertion via the right internal jugular vein (IJV), and the second case involved HDC insertion via the left IJV. We clinically suspected HDC malposition because of poor aspiration, despite good infusion via the two lumens. Chest radiography, computed tomography, and venography showed various abnormal positions of the HDC. Our case report provides additional information about malpositioned or malfunctioning HDCs in various clinical settings.

Alteration of unfolded protein responses and autophagy signaling represented the molecular basis underlying saccharin toxicity to Drosophila (Diptera: Drosophilidae).

The purpose of this study was to develop a new control method for Drosophila using saccharin sodium dihydrate (saccharin), an artificial sweetener that is safe for humans and the environment, and to elucidate its mode of action. In this study, we confirmed that saccharin can dose-dependently inhibit the development of or kill vinegar flies (VFs) and spotted wing Drosophila (SWDs). In addition, we found that low concentrations of saccharin induced a similar effect as starvation in Drosophila, whereas high concentrations of saccharin induced changes in the unfolded protein response (UPR) and autophagy signaling that were unlike starvation and inhibited development or killed the VF and the SWD by performing real-time quantitative polymerase chain reaction analyses. Spinosad is a widely used plant protection agent for SWD control. When saccharin was cotreated with 0.25-1.0 ppm spinosad, an additive insecticidal activity was observed only at high concentrations of saccharin. However, when saccharin was cotreated with 2.0 ppm spinosad, an additive insecticidal activity was observed at low concentrations of saccharin. Taken together, alteration of UPR and autophagy signaling represented the molecular basis underlying saccharin toxicity to Drosophila and concurrent spraying of an insecticide with saccharin could enhance the insecticidal activities.

Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.

BACKGROUND: Nanoparticles have been utilized in brain research and therapeutics, including imaging, diagnosis, and drug delivery, owing to their versatile properties compared to bulk materials. However, exposure to nanoparticles leads to their accumulation in the brain, but drug development to counteract this nanotoxicity remains challenging. To date, concerns have risen about the potential toxicity to the brain associated with nanoparticles exposure via penetration of the brain blood barrier to address this issue. METHODS: Here the effect of silica-coated-magnetic nanoparticles containing the rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO2(RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO2(RITC) using transmission electron microscopy, and glucose uptake efficiency, were analyzed in BV2 murine microglial cells. Each omics data was collected via RNA-sequencing-based transcriptome analysis, liquid chromatography-tandem mass spectrometry-based proteome analysis, and gas chromatography- tandem mass spectrometry-based metabolome analysis. The three omics datasets were integrated and generated as a single network using a machine learning algorithm. Nineteen compounds were screened and predicted their effects on nanotoxicity within the triple-omics network. RESULTS: Intracellular reactive oxygen species production, an inflammatory response, and morphological activation of cells were greater, but glucose uptake was lower in MNPs@SiO2(RITC)-treated BV2 microglia and primary rat microglia in a dose-dependent manner. Expression of 121 genes (from 41,214 identified genes), and levels of 45 proteins (from 5918 identified proteins) and 17 metabolites (from 47 identified metabolites) related to the above phenomena changed in MNPs@SiO2(RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO2(RITC) and ten other nanoparticles in vitro and in the murine brain, protecting mostly the hippocampus and thalamus. CONCLUSIONS: Combination of glutathione and citrate can be one of the candidates for nanotoxicity alleviating drug against MNPs@SiO2(RITC) induced detrimental effect, including elevation of intracellular reactive oxygen species level, activation of microglia, and reduction in glucose uptake efficiency. In addition, our findings indicate that an integrated triple omics approach provides useful and sensitive toxicological assessment for nanoparticles and screening of drug for nanotoxicity.

Myopic foveal detachment associated with pachychoroid characteristics.

PURPOSE: To describe myopic nontractional foveal detachment associated with pachychoroid diseases. METHODS: This retrospective study included 15 myopic eyes which had nontractional serous foveal detachment. The eyes were divided into myopic central serous chorioretinopathy (CSC) group (n = 8) and a myopic pachychoroid neovascularization (PNV) group (n = 7) according to the presence of type 1 choroidal neovascularization on multimodal imaging. The findings of multimodal imaging and treatment response were described. RESULTS: In myopic CSC group, pachychoroid features such as pachyvessels, choroidal vascular hyperpermeability and punctate hyperfluorescent spots were noted in 8 eyes (100%), 8 eyes (100%), 5 eyes (62.5%) respectively. The above features were noted in 7 eyes (100%), 5 eyes (83.3%), 5 eyes (83.3%), respectively, in the myopic PNV group. Five of 8 eyes in myopic CSC and all 7 eyes received treatment including anti-vascular endothelial growth factor injection and/or photodynamic therapy. However, only five eyes had a complete response. CONCLUSIONS: The pachychoroid phenotype may coexist with high myopia and lead to myopic nontractional serous foveal detachment. Our series suggest that the response to treatment for these conditions would be limited.

Renal infarction associated with low dose intravenous immunoglobulin in a kidney transplant recipient with sepsis: a case report and literature review.

BACKGROUND: The use of human intravenous immunoglobulin gamma (IVIG) is associated with thromboembolic events as a complication. There are few reported cases of renal infarction during IVIG use in the general population, but transplant kidney may be more susceptible to thromboembolic events following IVIG use. CASE PRESENTATION: A 41-year-old woman visited with fever and pain at the transplant kidney. Six years ago, she underwent kidney transplantation from a deceased donor. Laboratory and radiologic findings were compatible to septic condition, secondary to acute pyelonephritis. We started antibiotics, inotropics, and IVIG. The patient abruptly developed gross hematuria and urine output decreased to 100 cc/day during IVIG administration. Renal doppler and pathologic findings revealed renal infarction. Oliguria and azotemia persisted and she is undergoing maintenance hemodialysis. CONCLUSION: Our case shows that infarction of transplant kidney can be caused by IVIG use in a patient with severe infection. Thus, when using IVIG for kidney transplant patients with high risk of thromboembolic events, we may be careful to prevent the thromboembolic events.

Hemolytic uremic syndrome caused by sea anemone sting: a case report.

BACKGROUND: Some sea anemone toxins cause renal injuries resembling hemolytic uremic syndrome (HUS). To date, only a few cases of HUS caused by sea anemone stings have been reported. In this case report, we have described an HUS case caused by a sea anemone sting. CASE PRESENTATION: In November 2019, a 37-year-old man with no underlying disease was admitted to our hospital. He presented with intense pain, a rash on, and swelling in his right thigh. Two days prior, he had been stung by a sea anemone while scuba diving in Cebu, Philippines. His blood tests revealed renal dysfunction, and his platelet count was normal. However, on day three, the platelet count decreased rapidly. His blood haptoglobin level decreased, and schistocytes were identified on the peripheral blood smear. We suspected thrombotic microangiopathy and started the conventional treatment, comprising hemodialysis, blood transfusion, and antibiotic administration. ADAMTS-13 and genetic test results associated with atypical HUS were normal. Therefore, the patient was diagnosed with HUS caused by a sea anemone toxin. CONCLUSIONS: HUS caused by a sea anemone toxin is rare, but it is a serious medical disease. Clinicians should consider HUS in patients with such clinical presentations, and they should make prompt treatment-related decisions.

Effects of TGF-ß1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells.

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-ß) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-ß with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-ß treatment, but these changes were attenuated by cotreatment with GW788388. TGF-ß-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-ß and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-ß receptor type 1 inhibitor, effectively attenuated TGF-ß-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

Gastric antral vascular ectasia in a patient with lupus undergoing hemodialysis: a case report.

BACKGROUND: Gastric antral vascular ectasia (GAVE), associated with autoimmune diseases, such as systemic lupus erythematosus, and hepatic or renal disorders, is a rare cause of gastrointestinal bleeding. We report the case of a patient with lupus erythematosus undergoing hemodialysis with an uncorrectable anemia caused by GAVE. CASE PRESENTATION: A 76-year-old Korean woman with lupus undergoing hemodialysis frequently complained of symptoms or signs associated with anemia, such as dizziness, dyspnea, hypotension, melena, and hematemesis. Gastrointerstinal endoscopy revealed multiple erythematous and hyperemic mucosal lesions at the distal antrum without active bleeding, a finding compatible with GAVE. Although she frequently complained of symptoms or signs associated with anemia and had frequent gastrointestinal endoscopies with or without pre-emptive argon plasma coagulation, her clinical status is relatively stable, and she is undergoing maintenance hemodialysis without anticoagulants. CONCLUSION: This clinical case suggests that GAVE should be considered as a cause of the anemia resistant to erythropoiesis-stimulating agents and iron supplementation in patients with chronic kidney disease and lupus.

Association between Chronic Kidney Disease or Acute Kidney Injury and Clinical Outcomes in COVID-19 Patients.

BACKGROUND: A population-based study would be useful to identify the association between chronic kidney disease (CKD) or acute kidney injury (AKI) and prognosis of coronavirus disease 2019 (COVID-19) patients. METHODS: This retrospective study utilized the claim data from Korea. Patients who underwent COVID-19 testing and were confirmed to be positive were included and divided into the following three groups based on the presence of CKD or requirement of maintenance dialysis: Non-CKD (participants without CKD), non-dialysis CKD (ND-CKD), and dialysis-dependent CKD (DD-CKD) patients. We collected data on the development of severe clinical outcomes and death during follow-up. Severe clinical outcomes were defined as the use of inotropics, conventional oxygen therapy, high-flow nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation and the development of AKI, cardiac arrest, myocardial infarction, or acute heart failure after the diagnosis of COVID-19. AKI was defined as the initiation of renal replacement therapy after the diagnosis of COVID-19 in patients not requiring maintenance dialysis. Death was evaluated according to survival at the end of follow-up. RESULTS: Altogether, 7,341 patients were included. The median duration of data collection was 19 (interquartile range, 11-28) days. On multivariate analyses, odds ratio (OR) for severe clinical outcomes in the ND-CKD group was 0.88 (95% confidence interval [CI], 0.64-1.20; P = 0.422) compared to the Non-CKD group. The DD-CKD group had ORs of 7.32 (95% CI, 2.14-33.90; P = 0.004) and 8.32 (95% CI, 2.37-39.21; P = 0.002) compared to the Non-CKD and ND-CKD groups, respectively. Hazard ratio (HR) for death in the ND-CKD group was 0.79 (95% CI, 0.49-1.26; P = 0.318) compared to the Non-CKD group. The DD-CKD group had HRs of 2.96 (95% CI, 1.09-8.06; P = 0.033) and 3.77 (95% CI, 1.29-11.06; P = 0.016) compared to the Non-CKD and ND-CKD groups, respectively. DD-CKD alone was associated with severe clinical outcomes and higher mortality. There was no significant difference in frequency of severe clinical outcomes or mortality rates between the Non-CKD and ND-CKD groups. In patients not requiring maintenance dialysis, AKI was associated with old age, male sex, and high Charlson's comorbidity index score but not with the presence of CKD. HRs for patients with AKI were 11.26 (95% CI, 7.26-17.45; P < 0.001) compared to those for patients without AKI in the multivariate analysis. AKI was associated with severe clinical outcomes and patient survival, rather than underlying CKD. CONCLUSION: CKD requiring dialysis is associated with severe clinical outcomes and mortality in patients with COVID-19; however, the development of AKI is more strongly associated with severe clinical outcomes and mortality.

Glutamate Dehydrogenase as a Neuroprotective Target Against Neurodegeneration.

Regulation of glutamate metabolism via glutamate dehydrogenase (GDH) might be the promising therapeutic approach for treating neurodegenerative disorders. In the central nervous system, glutamate functions both as a major excitatory neurotransmitter and as a key intermediate metabolite for neurons. GDH converts glutamate to α-ketoglutarate, which serves as a TCA cycle intermediate. Dysregulated GDH activity in the central nervous system is highly correlated with neurological disorders. Indeed, studies conducted with mutant mice and allosteric drugs have shown that deficient or overexpressed GDH activity in the brain can regulate whole body energy metabolism and affect early onset of Parkinson's disease, Alzheimer's disease, temporal lobe epilepsy, and spinocerebellar atrophy. Moreover, in strokes with excitotoxicity as the main pathophysiology, mice that overexpressed GDH exhibited smaller ischemic lesion than mice with normal GDH expression. In additions, GDH activators improve lesions in vivo by increasing α-ketoglutarate levels. In neurons exposed to an insult in vitro, enhanced GDH activity increases ATP levels. Thus, in an energy crisis, neuronal mitochondrial activity is improved and excitotoxic risk is reduced. Consequently, modulating GDH activity in energy-depleted conditions could be a sound strategy for maintaining the mitochondrial factory in neurons, and thus, protect against metabolic failure.

Developing molecular diagnostics for detection of red imported fire ants using two genes, Sinv11108 and Sinv11977.

Aggressive red imported fire ants (RIFAs) are expanding their habitat due to active international trade and global warming. To prevent infestation and settlement, RIFAs must be removed during the quarantine process. Because RIFAs are social insects and have different morphological characteristics depending on their castes, non-ant taxonomists have difficulty confirming RIFAs based on their morphological characteristics alone. The disadvantages of previously reported RIFA molecular diagnostics are that they require additional steps, such as restriction enzyme digestion followed by agarose gel electrophoresis separation or DNA sequence verification for polymerase chain reaction (PCR)-amplified products. To overcome these drawbacks, two RIFA-specific genes were selected and used to develop diverse PCR-based RIFA molecular diagnostic techniques. We found that RIFAs could be confirmed by conventional PCR targeting of two RIFA-specific genes followed by agarose electrophoresis separation. In addition, TaqMan probe real-time PCR methods had the advantage of confirming RIFAs immediately after the reactions were completed by observing fluorescence indexes. Finally, multiplex PCRs enhanced RIFA specificity and sensitivity. The new molecular diagnostic methods developed in this study had the advantages of reducing false positive and negative results together with high specificity and sensitivity for RIFAs.

An investigation of the molecular and biochemical basis underlying chlorantraniliprole-resistant Drosophila strains and their cross-resistance to other insecticides.

Chlorantraniliprole is an anthranilic diamide insecticide that binds to the insect ryanodine receptor (RyR) and induces an uncontrolled release of Ca2+ , resulting in paralysis and ultimately death of the target insects. Recently, it was reported that chlorantraniliprole-resistant diamondback moths, Plutella xylostella Linnaeus, have mutations in their RyR. In this study, we developed two different chlorantraniliprole-resistant Drosophila melanogaster strain. The resistance ratio (RR) of the low-concentration chlorantraniliprole-treated resistant (Low-Res) strain was 2.3, while that of the high-concentration chlorantraniliprole-treated resistant (High-Res) strain was 21.3. The LC 50 of the untreated control (Con) strain was 23.8~25.9 ppm, which was significantly higher than that reported for the susceptible diamondback moth (0.03~0.51 ppm). The high LC 50 of the Con may be because the helix S2 amino acid sequence of D. melanogaster RyR ( DmRyR) is identical to the I4790M mutation of the chlorantraniliprole-resistant diamondback moths, resulting in a lower binding affinity of DmRyR for chlorantraniliprole. Among the tested detoxification enzymes, the activity of esterase was significantly increased in the two Res strains, but glutathione S-transferases and acetylcholinesterase were significantly decreased in the two Res strains. The cross-resistance of the High-Res strain to other insecticides with different modes of actions (MoAs) revealed that the RRs of the neuronal acetylcholine receptor allosteric and competitive modulators were significantly increased, while those of the Na 2+ channel modulators were significantly reduced. Our studies showed that RRs against the same insecticide vary with the treatment concentration, and that RRs against other insecticides with different MoAs can be altered.