Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis

xloma.fota13 shared this article with you from Inoreader Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis Via Latest Results for Inflammation Research Abstract Background As an inhibitor of GSDMD, Disulfiram (DSL) can significantly inhibit cell pyroptosis. Cell pyroptosis plays an important role in renal fibrosis. Methods HK-2 cells were induced by Lps and ATP to form a pyroptosis model, and the cells were treated by DSL. CCK-8 detected the cell activity. Immunofluorescence (IF) detected the GSDMD. ELISA detected the expression of inflammatory cytokines. Flow cytometry and Western blot detected cell apoptosis and pyroptosis. Collagen type I kit detected collagen secretion, and western blot detected fibrosis marker protein expression. Then, a rat model of unilateral ureteral obstruction (UUO) was established. HE staining detected the degree of renal tissue injury, and Masson staining detected the degree of fibrosis. What's more, the apoptosis level of tissue cells was detected by TUNEL. And the inflammatory factors in peripheral blood and renal tissue were detected by ELISA. Furthermore, the expression of GSDMD was detected by immunohistochemistry (IHC), and Western blot was used to detect the expression levels of apoptosis and pyroptosis-related proteins in tissues. Results It was found that DSL can inhibit the cell membrane perforation of GSDMD-N by inhibiting the cleavage of GSDMD, hence, it inhibited the occurrence of inflammation, cell pyroptosis, and the fibrosis of HK-2 cells. But if the cell has already undergone pyroptosis, DSL does not provide significant prevention. In vivo experiment, it further verified that pretreated DSL had inhibited renal fibrosis injury. Conclusion Disulfiram can inhibit inflammation and fibrosis in renal fibrosis rats by inhibiting GSDMD. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia

xloma.fota13 shared this article with you from Inoreader Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia Via Brain - Advance Access Abstract Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer's disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer's disease, and 51 healthy older control participa nts. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer's disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular co rtices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis

xloma.fota13 shared this article with you from Inoreader Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis Via Brain - Advance Access Abstract Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analyzed 546 patients with autoimmune neuro-inflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters altered across all autoimmune neuro-inflammatory CNS-diseases and differentiating them from other neurological conditions and inter-autoimmunity classifiers sub-differentiating variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist classification of neurological patients. Overall, we show that an integrated analysis of blood and CSF parameters improves differential diagnosis of neurological diseases, thereby facilitating early treatment decisions. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Photo-oxygenation by a biocompatible catalyst reduces amyloid-β levels in Alzheimer’s disease mice

xloma.fota13 shared this article with you from Inoreader Photo-oxygenation by a biocompatible catalyst reduces amyloid-β levels in Alzheimer's disease mice Via Brain - Advance Access Abstract Amyloid formation and the deposition of the amyloid-β peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-β antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-β peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-β via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-β from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-β peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-β strategy in Alzheimer's disease, which is compatible with immunotherapy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Phase 2 multicenter study of enzalutamide in metastatic castration resistant prostate cancer to identify mechanisms driving resistance

xloma.fota13 shared this article with you from Inoreader Phase 2 multicenter study of enzalutamide in metastatic castration resistant prostate cancer to identify mechanisms driving resistance Via Clinical Cancer Research Online First Articles Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. Results: 65 patients initiated treatment, of whom 22 (33.8%) had receiv ed prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression. Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors

xloma.fota13 shared this article with you from Inoreader Targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors Via Clinical Cancer Research Online First Articles Purpose: Exome and whole-genome sequencing of muscle-invasive bladder cancer (BC) has revealed important insights into the molecular landscape; however, there are few studies of non-muscle invasive BC with detailed risk factor information. Experimental Design: We examined the relationship between smoking and other BC risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in BC was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RRs) and 95%CIs, evaluating signatures and risk factors. Results:Non-silent KDM6A mutations were more common in females than males (OR=1.83,95%CI:1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared to former (p-value=0.024) and never smoking (RR=1.40, 95% CI: 1.09-1.80, p-value=0.008); former smoking was associated with greater APOBEC-Signature13 mutations (p-value=0.05); and never smoking was associated with greater APOBEC-Signature2 mutations (RR=1.54, 95% CI: 1.17-2.01, p-value=0.002). There was evidence that smoking duration (the component most strongly associated with BC risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (p-trend=0.005) and former smokers (p=0.0004), respectively. Conclusions: These data quantify the contribution of BC risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.< /p> View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Effect of An Online Physical Activity Promotion Program and Cardiovascular Symptoms Among Asian American Women at Midlife

xloma.fota13 shared this article with you from Inoreader Effect of An Online Physical Activity Promotion Program and Cardiovascular Symptoms Among Asian American Women at Midlife Via Computers Informatics Nursing - Current Issue Despite an increasing number of online programs to promote physical activity, they have rarely been evaluated for their effects on cardiovascular symptoms of racial/ethnic minority women at midlife. This study aimed to determine the preliminary efficacy of a newly developed online program for physical activity promotion on cardiovascular symptoms of Asian American midlife women. This study was a pilot repeated-measures randomized controlled trial (pretest/posttest) among 26 Asian American midlife women. The variables were measured using multiple instruments on background features, physical activity, and cardiovascula r symptoms at three points of time (baseline, after 1 month, and after 3 months). Linear mixed models were used to analyze the data. The prevalence and severity of cardiovascular symptoms did not show a statistically significant group-time interaction. However, the increase in lifestyle physical activity over time was significant only among the intervention group (Δ = 0.49, P = .016). The results supported the program's preliminary efficacy on lifestyle physical activity for Asian American women at midlife, but not on cardiovascular symptoms. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.