Decoding cardiovascular risks: analyzing type 2 diabetes mellitus and ASCVD gene expression.

Background: ASCVD is the primary cause of mortality in individuals with T2DM. A potential link between ASCVD and T2DM has been suggested, prompting further investigation. Methods: We utilized linear and multivariate logistic regression, Wilcoxon test, and Spearman's correlation toanalyzethe interrelation between ASCVD and T2DM in NHANES data from 2001-2018.The Gene Expression Omnibus (GEO) database and Weighted Gene Co-expression Network Analysis (WGCNA) wereconducted to identify co-expression networks between ASCVD and T2DM. Hub genes were identified using LASSO regression analysis and further validated in two additional cohorts. Bioinformatics methods were employed for gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, along with the prediction of candidate small molecules. Results: Our analysis of the NHANES dataset indicated a significant impact of blood glucose on lipid levels within diabetic cohort, suggesting that abnormal lipid metabolism is a critical factor in ASCVD development. Cross-phenotyping analysis revealed two pivotal genes, ABCC5 and WDR7, associated with both T2DM and ASCVD. Enrichment analyses demonstrated the intertwining of lipid metabolism in both conditions, encompassing adipocytokine signaling pathway, fatty acid degradation and metabolism, and the regulation of adipocyte lipolysis. Immune infiltration analysis underscored the involvement of immune processes in both diseases. Notably, RITA, ON-01910, doxercalciferol, and topiramate emerged as potential therapeutic agents for both T2DM and ASCVD, indicating their possible clinical significance. Conclusion: Our findings pinpoint ABCC5 and WDR7 as new target genes between T2DM and ASCVD, with RITA, ON-01910, doxercalciferol, and topiramate highlighted as promising therapeutic agents.

CTRP13 Mitigates Endothelial Cell Ferroptosis via the AMPK/KLF4 Pathway: Implications for Atherosclerosis Protection.

BACKGROUND C1q/tumor necrosis factor-related protein 13 (CTRP13) preserves endothelial function and possesses anti-oxidation activity. However, its effects on ferroptosis of human umbilical vein endothelial cells (HUVECs) remain unclear. We investigated the effects of CTRP13 on HUVEC ferroptosis induced by oxidized low-density lipoprotein (ox-LDL) and explored the underlying mechanisms of CTRP13 against ferroptosis via the AMPK/KLF4 pathway. MATERIAL AND METHODS Cell Counting Kit-8 assay was used to evaluate cell viability. Lactate dehydrogenase activity and malondialdehyde content analysis were performed to evaluate the cell membrane integrity and lipid peroxidation. Mito-Tracker, JC-1, and 2',7'-dichlorofluorescein di-acetate were used to evaluate the biological activity of mitochondria, mitochondrial membrane potential, and reactive oxygen species (ROS) in endothelial cells. The ferroptosis indicator expressions, recombinant solute carrier family 7, member 11, glutathione peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 were examined using real-time reverse transcription-polymerase chain reaction and Western blot. Immunofluorescence staining detected GPX4 location in endothelial cells. RESULTS The results demonstrate that CTRP13 (450 ng/mL) prevented HUVEC ferroptosis by inhibiting ROS overproduction and mitochondrial dysfunction, and CTRP13 accelerated antioxidant enzyme expression levels, such as heme oxygenase 1, superoxide dismutase 1, and superoxide dismutase 2, compared with the ox-LDL (100 µg/mL) group for 48 h. Additionally, CTRP13 treatment increased p-AMPK/AMPK expression by 47.65% (P<0.05) while decreasing Krüppel-like factor 4 expression by 37.43% (P<0.05) in ox-LDL-induced HUVECs and elucidated the protective effect on endothelial dysfunction from ferroptosis. CONCLUSIONS These findings provide new insights for understanding the effects and mechanism of CTRP13 on preventing endothelial cell ferroptosis.

Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.

Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

Wafer-Scale 1T' MoTe2 for Fast Response Self-Powered Wide-Range Photodetectors.

The semimetal-based photodetector possesses the intrinsic advantage of high response speed, low power consumption, and wide-range photoresponse. Here, we report the synthesis and application of 1 inch wafer-scale polycrystalline few layer 1T'-MoTe2 on the SiO2/Si substrate by employing a modified chemical vapor deposition method of predeposition of precursors. A continuous film with seamlessly stitched micrometer scale grains has been realized, and the pure 1T' phase was confirmed by Raman spectroscopy. An asymmetric metal electrode photodetector device of Pd-MoTe2-Au was designed and fabricated by using shadow mask-assisted UHV deposition. By measuring the self-powered photocurrent under the illumination of Xe lamp, we show that the device is sensitive to a wide spectra range (λ = 320-1200 nm) while maintaining high performance of the ON/OFF ratio (∼103), responsivity (1.2 A/W), and specific detectivity (7.68 × 1012 Jones). Under 450, 648, and 850 nm pulsed laser illumination, the response time achieves tens of microsecond scale. The device shows polarized photoresponse as well. Our work may promote the potential application of a self-powered high-performance photodetector based on 1T'-MoTe2.

Identification of signalling downstream of the transcription factor forkhead box protein M1 that protects against endoplasmic reticulum stress in a diabetic foot ulcer model.

AIMS: Diabetic foot ulcer (DFU) has a significant impact on the quality of life of diabetic mellitus (DM) patients. Here, we aimed to explore the molecules with aberrant expression and their regulatory mechanisms in DFU. METHODS: The expression of gene and protein was examined using quantitative polymerase chain reaction (qPCR) and western blot. Pearson's correlation analysis was used to analyse interactions among FOXM1, GAS5 and SDF4. Immunofluorescence was used to detect PDI and GRP78 expression. Flow cytometry was used to assess cell apoptosis. Tube formation assay was used to determine angiogenic capacity. Fluorescence in situ hybridization (FISH) assay was employed to determine the cellular localization of GAS5 and SDF4 in human umbilical vein endothelial cells (HUVECs). The interactions among FOXM1, GAS5 and SDF4 were validated by chromatin immunoprecipitation (ChIP), luciferase, RNA pull-down and RNA immunoprecipitation (RIP) assays. RESULTS: FOXM1, GAS5 and SDF4 were decreased in the skin tissues of DFU patients. High glucose (HG) stimulation induced endoplasmic reticulum (ER) stress and cell apoptosis but suppressed angiogenesis in HUVECs, which were abolished by FOXM1 overexpression. FOXM1 promoted GAS5 transcriptional activity, resulting in increased GAS5 expression, and GAS5 knockdown reversed the effects of FOXM1 overexpression in HG-treated HUVECs. Moreover, GAS5 recruited TAF15 to promote SDF4 expression in HUVECs. GAS5 overexpression inhibited ER stress, cell apoptosis and induced angiogenesis in HG-treated HUVECs which could be reversed by silencing SDF4. CONCLUSION: Our results revealed that FOXM1 suppressed ER stress, cell apoptosis and promoted angiogenesis in HG-induced HUVECs via mediating GAS5/TAF15/SDF4 axis, providing a novel therapeutic molecule mechanism for DFU.

Droxidopa in the Management of Hepatorenal Syndrome.

PurposeHepatorenal syndrome (HRS) is renal dysfunction associated with the hemodynamic consequences of advanced liver disease and cirrhosis. HRS is associated with a high mortality, and there remain high failure rates with first-line therapy aimed at improving perfusion. We report the use of droxidopa, an oral norepinephrine precursor, to aid in the management of HRS-AKI refractory to first-line therapy. Summary: A 51-year-old Caucasian male with alcohol-related cirrhosis presented with 1-week history of pre-syncope and falls. He was found to have acute kidney injury meeting diagnostic criteria of HRS based on absence of identifiable contributing factors. After no response to volume expansion, medical management was initiated with midodrine and octreotide and eventually escalated to norepinephrine intravenous infusion. The patient's renal function and urine output improved initially on norepinephrine, but worsened when attempting to wean to a suitable outpatient regimen, becoming dependent upon norepinephrine. On day 13 of hospitalization, droxidopa was initiated at a dose of 100 mg three times daily and titrated to a dose of 400 mg three times daily. Norepinephrine infusion was weaned and discontinued on day 16 of hospitalization. The patient remained hemodynamically stable and was able to be discharged on droxidopa 400 mg three times daily, midodrine 20 mg three times day, and octreotide 200 mcg three times daily. Conclusion: Droxidopa, an oral norepinephrine precursor, presents a novel adjunctive agent for management of HRS refractory to first-line medical management.

Platelet reactivity testing in peripheral artery disease.

PURPOSE: Oral antiplatelet therapy is routinely used to prevent adverse cardiovascular events in patients with peripheral artery disease (PAD). Several laboratory tests are available to quantify the degree of platelet inhibition following antiplatelet therapy. This article aims to provide a review of the literature surrounding platelet functional testing in patients with PAD receiving oral P2Y12 inhibitors and to offer guidance to clinicians for the use and interpretation of these tests. SUMMARY: A literature search of PubMed and the Web of Science Core Collection database was conducted. All studies that performed platelet function testing and reported clinical outcomes in patients with PAD were included. Evaluation of the data suggests that, among the available testing strategies, the VerifyNow platelet reactivity unit (PRU) test is the most widely used. Despite numerous investigations attempting to define a laboratory threshold indicating suboptimal response to antiplatelet therapy, controversy exists about which PRU value best correlates with cardiovascular outcomes (ie, mortality, stent thrombosis, etc). In the PAD literature, the most commonly used PRU thresholds are 208 or higher and 235 or higher. Nonetheless, adjusting antiplatelet regimens based on suboptimal P2Y12 reactivity values has yet to be proven useful in reducing the incidence of adverse cardiovascular outcomes. This review examines platelet function testing in patients with PAD and discusses the interpretation and application of these tests when monitoring the safety and efficacy of P2Y12 inhibitors. CONCLUSION: Although platelet functional tests may be simple to use, clinical trials thus far have failed to show benefit from therapy adjustments based on test results. Clinicians should be cautioned against relying on this test result alone and should instead consider a combination of laboratory, clinical, and patient-specific factors when adjusting P2Y12 inhibitor therapy in clinical practice.

Elevated serum neurofilament light chain in children autism spectrum disorder: A case control study.

OBJECTIVE: We aimed to assess serum neurofilament light chain (sNfL) levels in autism spectrum disorder (ASD) and to investigate whether they are related to the severity of disease. METHODS: The cohorts consisted of 166 children aged 3-8 (83 children diagnosed with ASD and 83 children with typically-developing). sNfL were analyzed using Single Molecule Array (Simoa) technology. ASD symptom severity was assessed according to the Chinese version of the Childhood Autism Rating Scale (CARS) score. RESULTS: The mean age of those included ASD was 5.1 years (standard deviations [S.D.]: 1.7) and 78.3 % were boys. The mean (SD) sNfL concentrations were significantly (P < 0.001) higher in ASD than in TP children (10.2[5.0] pg/mL and 7.1[3.2]pg/mL). For each 1 pg/mL increase of sNfL, the risk of ASD would increase by 19 % (with the OR unadjusted of 1.19 [95 % CI 1.10-1.29], P < 0.001) and 11 % (with the OR adjusted of 1.11 [1.03-1.23], P < 0.001), respectively. sNfL concentrations in children with severe ASD were higher than in those children with mild-to-moderate ASD (12.4[5.1] pg/mL vs. 8.3[4.2]pg/mL; P < 0.001). Among ASD cases, each 1 pg/mL increase of sNfL is associated with 20 % higher unadjusted or 11 % higher adjusted odds, respectively, of severe (vs. mild-to-moderate) ASD. CONCLUSIONS: The data showed that sNfL was elevated in ASD and related to symptom severity, suggesting that sNfL may play a role in ASD progression.

Immunogenicity of High Dose Influenza Vaccine for Patients with Inflammatory Bowel Disease on Anti-TNF Monotherapy: A Randomized Clinical Trial.

BACKGROUND: Patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor alpha (TNF) agents may have lower immune response to the influenza vaccine. We aimed to evaluate the immunogenicity of the high dose (HD) vs standard dose (SD) influenza vaccine in patients with IBD on anti-TNF monotherapy. METHODS: We performed a randomized clinical trial at a single academic center evaluating the immunogenicity of the HD vs SD influenza vaccine in patients with IBD on anti-TNF monotherapy. Influenza antibody concentration was measured at immunization, at 2 to 4 weeks postimmunization, and at 6 months. RESULTS: Sixty-nine patients with IBD were recruited into the study, 40 on anti-TNF monotherapy, and 19 on vedolizumab, along with 20 healthy controls (HC). Patients with IBD receiving the HD influenza vaccine had significantly higher H3N2 postimmunization antibodies compared with those who received the SD influenza vaccine (160 [interquartile range 80 to 320] vs 80 [interquartile range 40 to 160]; P = 0.003). The H1N1 postimmunization levels were not significantly higher in the HD influenza vaccine (320 [interquartile range 150 to 320] vs 160 [interquartile range 80 to 320]; P = 0.18). Patients with IBD receiving the HD influenza vaccine and those on vedolizumab who received SD had equivalent antibody concentrations to HC (H1N1 P = 0.85; H3N2 P = 0.23; B/Victoria P = 0.20 and H1N1 P = 0.46; H3N2 P = 0.21; B/Victoria P = 1.00, respectively). CONCLUSIONS: Patients with IBD on anti-TNF monotherapy receiving the HD influenza vaccine had significantly higher postimmunization antibody levels compared with SD vaccine. Clinicaltrials.gov (#NCT02461758).

Immunosuppression Does Not Affect Antibody Concentrations to Measles, Mumps, and Rubella in Patients with Inflammatory Bowel Disease.

BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) recommends using the immunization record and not serologic testing to determine immunity against measles and rubella in the general population, due to potential false negatives. However, it is unknown whether the immune response is less durable among patients who are immunosuppressed. AIMS: The primary aim of this study was to evaluate sustained vaccine-induced measles, mumps, and rubella (MMR) antibody concentrations in immunosuppressed patients with inflammatory bowel disease (IBD). METHODS: We performed a cross-sectional study to compare antibody concentrations following the two-dose (MMR) vaccine among 46 patients with IBD and 20 healthy controls (HC). Three IBD groups stratified by the immunosuppressive regimen that preceded study entry for at least 3 months: (1) thiopurine monotherapy, (2) anti-TNF monotherapy, or (3) combination therapy (anti-TNF agent combined with an immunomodulator) were enrolled. RESULTS: All subjects had measurable antibody concentrations to the three vaccine viruses. Age and time since receipt of MMR series were similar in both groups. There were no difference in the antibody concentration of measles (IBD 667 mIU/ml vs HC 744 mIU/ml; p = 0.45), mumps (IBD 339 EU/ml vs HC 402 EU/ml; p = 0.62), or rubella (IBD 25 mIU/ml vs HC 62 mIU/ml; p = 0.11) among the groups. No differences in antibody concentrations were found among the IBD treatment groups. CONCLUSION: Immunosuppressed patients with IBD have sustained antibody concentrations comparable to healthy controls. Thus, gastroenterologist should follow the ACIP recommendations and use the immunization record when available to determine immunity to measles and rubella in patients with IBD. Clinical Trials Registry # NCT02434133.

Hydrogen breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in autism.

The aim of this study is to assess the prevalence of small intestinal bacterial overgrowth (SIBO) by hydrogen breath test in patients with autism spectrum disorders (ASD) with respect to a consistent control group. From 2011 to 2013, 310 children with ASD and 1240 sex- and age-matched typical children were enrolled in this study to undergo glucose breath test. The study participants were considered to exhibit SIBO when an increase in H2 of ≥20 ppm or CH4 of ≥10 ppm with respect to the fasting value was observed up to 60 min after the ingestion of glucose. Ninety-six children with autism suffered from SIBO, giving a prevalence rate of SIBO was 31.0% (95% CI 25.8-36.1%). In contrast, 9.3% of the typical children acknowledged SIBO. The difference between groups was statistically significant (P < 0.0001). The median Autism Treatment Evaluation Checklist (ATEC) score in the children with autism and with SIBO was significantly high when compared with the children without autism and without SIBO [98 (IQR, 45-120) vs. 63 (32-94), P < 0.001]. For the autism group, the 6-GI Severity Index (6-GSI) score was found to be strongly and significantly correlated with the total ATEC score (r = 0.639, P < 0.0001). SIBO was significantly associated with worse symptoms of autism, demonstrating that children with SIBO may significantly contribute to symptoms of autism.

Therapeutic efficacy of phentolamine in the management of severe hand, foot and mouth disease combined with pulmonary edema.

The aim of this study was to examine the effects of phentolamine on severe hand, foot and mouth disease (HFMD) combined with pulmonary edema (PE). From May 2008 to December 2012, 53 children with severe HFMD plus PE were enrolled in the treatment group, receiving phentolamine intravenously at a loading dose of 5 µg/kg/min. The control group comprised 52 children with the same disease who did not receive phentolamine infusion. Data concerning creatine kinase (CK), CK-MB, cardiac troponin I (cTnI), heart rate, systolic blood pressure (SBP) and the duration of ventilation dependence and hospitalization were collected. Adverse events were also recorded. It was found that the phentolamine-treated patients exhibited significantly lower CK, CK-MB and cTnI levels, heart rate and SBP than the controls (P<0.01 for all parameters). The average duration of ventilator dependence and hospitalization was significantly shorter (P<0.01) in the phentolamine group than in the control group. It was also found that the overall mortality rate was lower in the phentolamine group (5.8%) than in the control group (11.5%). No adverse events were observed in either group. Thus, these results offer preliminary evidence that phentolamine reduces mortality and relieves the symptoms of EV71-induced PE. Phentolamine is a potential therapeutic agent for this highly lethal disorder.