课程文献中心 更多>>

关键词： Manganese   D-ribose- L-cysteine   Oxidative damage   ERK pathway   Brain  

摘要： Manganese (Mn), though an essential trace element, can become neurotoxic after excessive exposure. Established mechanisms of Mn neurotoxicity include oxidative stress, apoptotic signalling, and inflammatory responses. D-ribose-L-cysteine (RibCys), a cysteine derivative, is reported to mitigate oxidative damage. In this study, we investigated its effects on B-cell lymphoma 2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) apoptotic signaling, tumor necrosis factor-alpha (TNF-alpha) inflammatory response, and extracellular signal-regulated kinase (ERK) pathway across various brain regions. Adult male Wistar rats were treated with saline (control), Mn (25 mg/kg intraperitoneally for 2 weeks, 8 doses at 48-hour intervals), RibCys (200 mg/kg orally for 2 weeks), or both Mn and RibCys. Biochemical assays for oxidative stress and antioxidant activity, Golgi staining for dendritic morphology, and immunohistochemistry for key protein markers were performed. Results showed that RibCys reduced Mn-induced distortions in brain neurochemistry and dendritic morphology. Mn increased lipid peroxidation, myeloperoxidase, and nitric oxide levels while decreasing glutathione peroxidase and sulfhydryl content, and these effects were attenuated by RibCys. Mn also disrupted dendritic arborization, which improved with RibCys treatment. Furthermore, Mn exposure elevated Bax/Bcl-2, TNF-alpha, and ERK1/2 expression in selected brain regions. RibCys co-administration mitigated these molecular alterations. Our findings suggest that RibCys is a promising therapeutic agent against Mn-induced neurotoxicity with potential for broader application. A notable limitation of this study was the absence of direct measurements of reduced and oxidized glutathione, and cysteine. Future studies should include these key antioxidant markers, assess long-term outcomes of RibCys treatment, and incorporate female animal models to evaluate potential sex-specific responses to Mn toxicity and intervention.

关键词： Glatiramer acetate   Multiple sclerosis   Biomarker   Treatment response   HLA   Genetics  

摘要： Background Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment. Methods T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis. Findings Common GA-associated TRB expansions were exclusively detected in HLA-A*03:01 or in HLA-DRB1*15:01 backgrounds, within CD8+ effector-or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A*03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A*03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1*15:01. Interpretation HLA-A*03:01 carrying patients with MS specifically benefit from GA treatment and GA signi

摘要： Adolescent idiopathic scoliosis (AIS) is a common spinal deformity in adolescents that can affect posture and movement in mild cases and may lead to cardiopulmonary dysfunction in severe instances, often requiring prompt intervention. , For mild A...

关键词： Diet-induced dyslipidemia   CD1-restricted T cells   Mycolic acid   Mycobacterium tuberculosis   Transgenic mice  

摘要： Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-gamma production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN-gamma production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in Tcell functions.

关键词： gfap   il-6   oxidative stress   s100β   traumatic brain injury  

摘要： Background Traumatic brain injury (TBI) is a leading cause of neurological morbidity and mortality worldwide. Secondary injury mechanisms such as neuroinflammation and oxidative stress play a pivotal role in the progression of neuronal damage. Biomarkers, including S100β, glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and oxidative stress parameters, can reflect the severity and progression of TBI, and their evaluation may assist in clinical decision-making. Objective This study aims to evaluate the serum levels of S100β, GFAP, IL-6, and oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and catalase) in patients with TBI compared to healthy controls. Methods This case-control study was conducted at The University of Lahore from July to December 2024. A total of 96 participants were enrolled, including 48 TBI patients and 48 age- and sex-matched healthy controls. Blood samples were collected within 24 hours of injury in TBI patients. Serum concentrations of S100β, GFAP, and IL-6 were measured using ELISA (enzyme-linked immunosorbent assay), while MDA, SOD, and catalase levels were assessed using standard biochemical assays. Data were analyzed using IBM SPSS Statistics for Windows, Version 26 (Released 2019; IBM Corp., Armonk, New York). Independent sample t-tests were used for group comparisons, and Pearson's correlation was applied to examine biomarker relationships. Results TBI patients exhibited significantly higher serum levels of S100β (1.92 ± 0.46 vs. 0.61 ± 0.18 ng/mL), GFAP (3.45 ± 0.71 vs. 1.12 ± 0.33 ng/mL), IL-6 (82.6 ± 18.4 vs. 19.5 ± 7.6 pg/mL), and MDA (5.12 ± 1.03 vs. 2.23 ± 0.66 µmol/L) compared to controls (p < 0.001 for all). SOD and catalase activities were significantly reduced in TBI patients (p < 0.001). S100β and GFAP correlated positively with IL-6 and MDA and negatively with SOD and catalase. Conclusion TBI is associated with elevated neural injury, inflammation, and oxidative stress biomarkers. These