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关键词： Anxiety   Depression   Mitotherapy   Neuroinflammation   Restraint stress  

摘要： Neuroinflammation and oxidative stress are known to be implicated in the pathogenesis of depression. Exogenous mitochondrial transplantation has exhibited beneficial effects for treating neurological disorders. Hence, this research aimed to evaluate the impact of nasal administration of mitochondria on neuroinflammation and oxidative stress in mouse models displaying depressive- and anxiety-like behaviors caused by restraint stress (RS). Thirty male BALB/c mice were divided into control, RS, and RS + 340 mu g of mitochondrial. Mice were subjected to RS using an immobilization falcon tube (2 h/day) for 2 weeks except for the control group. We conducted two behavioral tests to evaluate anxiety-like behaviors: elevated plus maze (EPM) and open field test (OFT). Tail suspension test (TST) was implemented to assess depressive-like behavior. ATP and reactive oxygen species (ROS) levels were measured in the hippocampus. Besides, serum corticosterone (CORT) levels were evaluated using the ELISA method. The expression of NLRP3 inflammasome, caspase-1 (Cas-1), and IL-1 beta was tested by western blot. We found that mitotherapy increased the time spent in the center of OFT and open arms of the EPM, while it diminished immobility time in TST. Mitochondrial administration considerably attenuated ROS generation and CORT levels and restored ATP levels. Additionally, mitotherapy prevented RS-induced upregulation of IL-1 beta, cleaved Cas1/Pro Cas1 ratio, and NLRP3/1 in the hippocampus of mice. These findings suggested that the beneficial effects of intranasal mitochondria on depression and anxiety may be attributed to suppression of the ROS/NLRP3/IL-1 beta/caspase-1 signaling pathway.

关键词： Biomarkers   IL-6 inhibitors   Metabolomics   Methotrexate   Rheumatoid arthritis   Tumor necrosis factor   Treatment responsiveness  

摘要： Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease characterized by joint damage and systemic involvement. Despite advancements in understanding RA, early diagnosis and effective treatment remain challenging due to the complex pathogenesis and limited specificity of current biomarkers. Metabolomics, offers a promising approach for identifying new biomarkers to assess treatment responsiveness in RA. A systematic review was conducted to identify key metabolites and metabolic pathways that may reveal responsiveness to different drug therapy strategies (methotrexate, TNF, and IL-6 inhibitors) in RA treatment. The systematic search was conducted in PubMed and Google Scholar in accordance with PRISMA recommendations. The risk of bias and the quality of the final selected studies were assessed in duplicate using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool and using the QUADOMICS tool. Eighteen studies were eligible for data extraction. Metabolomic studies revealed distinct profiles for responders and non-responders to different RA treatments. For methotrexate therapy, key metabolites included for example: homocysteine, glycerol-3-phosphate, and diphosphoglyceric acid. TNF inhibitor response was associated mainly with changes in carbohydrate derivatives and amino acids. IL-6 inhibitor studies identified metabolites such as N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid as potential predictors of response. Across studies, metabolomic profiles demonstrated high sensitivity and specificity in distinguishing responders from non-responders. These studies collectively highlight alterations in TCA cycle metabolites, amino acids, nucleotide metabolism, and lipid profiles, among others. This review supports the identification of better treatment strategies choosing methotrexate, TNF, or IL-6 inhibitors as therapeutic interventions based on metabolomics profiling.

关键词： Interleukin-2   Cytokine   Protein engineering  

摘要： The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and antiinflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or promotion of CD8 T cell responses via the dimeric IL2RBG receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either Treg or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS and dTANGO, computational algorithm-based methods, to predict mutations within the IL2 structure to improve protein production yield in muteins with altered cellular selectivity, to generate combined muteins with elevated therapeutic potential. The design and testing process identified the V106R (murine) / V91R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N90R T131R aggregation-protecting mutations could improve protein yield of the V91R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y59K created a cation-cation repulsion with IL2RA, while Q30W enhanced CD8 T cell activity through potential it-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y45K (homolog to murine Y59K) coupled with E62K prevented IL2RA binding, however it required the aggregation-protecting mutations of N90R T131R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.

摘要： Atlantic cod (Gadus morhua) is well-known to show poor specific antibody responses after immunization, despite having high natural IgM levels. Unlike mammals and nearly all examined other vertebrates, cod lack the MHC II-CD4 axis required for T cell-dependent (TD) antibody responses. We evaluated the cod's antibody response to hapten carriers inducing T cell-independent (TI) and TD responses in mammals. Remarkably, cod generated strong hapten-specific IgM levels against hapten linked to the TI-2 antigens ficoll or dextran. Specific IgM levels plateaued 6-9 weeks after a single immunization and remained stable for six months. The serum half-life of IgM was 4 days, indicating continuous IgM production during this period. These findings reveal unique immune mechanisms in Atlantic cod, enhancing our understanding of vertebrate immunology and aiding the development of novel vaccination strategies in aquaculture.

关键词： HLA-A   new alleles   next-generation sequencing  

摘要： Genomic sequence of HLA-A*01:01:01:119, -A*23:01:01:34, -A*23:01:01:35, -A*29:02:01:40, -A*33:01:01:17 and -A*33:01:01:19 alleles.

关键词： l-DOPA-induced dyskinesia   neuroinflammation   NF-kappa B signalling pathway   TNF-alpha  

摘要： Levodopa-induced dyskinesia (LID) is a common and debilitating complication of long-term Parkinson's disease treatment. This review explores the roles of NF-kappa B and TNF-alpha signalling pathways in LID pathophysiology and potential therapeutic approaches targeting these mechanisms. Chronic levodopa treatment leads to aberrant neuroplasticity and neuroinflammation, involving activation of NF-kappa B and increased production of pro-inflammatory cytokines like TNF-alpha. NF-kappa B activation in glial cells contributes to sustained neuroinflammation and exacerbates dopaminergic neuron loss. TNF-alpha levels are elevated in brain regions affected by LID and correlate with dyskinesia severity. Several compounds are involved in mitigating LID by modulating these pathways. Agmatine reduces NF-kappa B activation and NMDA receptor expression while protecting dopaminergic neurons. Resveratrol and doxycycline demonstrate antidyskinetic effects by attenuating neuroinflammation and TNF-alpha production. The Rho-kinase (ROCK) inhibitor fasudil and cannabinoid receptor 2 (CB2) receptor agonists also show efficacy in reducing LID severity and neuroinflammation. Hydrogen gas inhalation decreases pro-inflammatory cytokine levels associated with LID. These findings highlight the complex interplay between NF-kappa B, TNF-alpha and other neurotransmitter systems in LID pathogenesis. Targeting neuroinflammation and glial activation through these pathways represents a promising strategy for developing novel LID treatments. Further research is needed to fully elucidate the mechanisms and optimize therapeutic approaches targeting NF-kappa B and TNF-alpha signalling in LID.

关键词： A*02:1173   A*03:01:128   A*03:489   A*23:141   new HLA allele   NGS  

摘要： Four novel HLA-A alleles HLA-A*02:1173, -A*03:01:128, -A*03:489, and -A*23:141 alleles were detected during routine next generation sequencing.

摘要： Atopic dermatitis (AD) is a chronic, inflammatory skin disease that can significantly affect quality of life. Presence, severity, and therapeutic response of AD are traditionally reported through clinical assessments including the Eczema Area and Severity Index or Investigator's Global Assessment. These clinical rating scales are visual assessments used in clinical trials to denotate AD severity. Alternatively, biomarkers open the potential to further enhance diagnosis of AD, assess disease status and severity, and potentially enable tailored treatment options for patients. Biomarkers can be classified according to their clinical use, clinical presentation, and underlying/endogenous molecular mechanisms. Specifically, interleukin (IL)-13, which has been shown to be a key biomarker in AD pathogenesis, can be used for prediction of AD development and to monitor clinical severity/response to treatment. Treatment with tralokinumab, a human monoclonal antibody that binds directly to-and subsequently blocks signaling of-IL-13, has been shown to reduce inflammation, re-balance the skin microbiome, and improve the skin barrier in patients with AD. In this review, key AD-related biomarkers, the role of IL-13 in driving AD pathogenesis, and the impact of IL-13 inhibition by tralokinumab on other AD-related biomarkers are discussed.

关键词： Necrotizing enterocolitis (NEC)   Proteomic analysis   TRAF6   CXCL8   IL-8 tandem mass spectrometry tags (TMT)  

摘要： Necrotizing enterocolitis (NEC) is a common gastrointestinal complication in premature infants, resulting in high morbidity and mortality, and its early detection is crucial for accurate treatment and outcome prediction. Extensive research has demonstrated a clear correlation between NEC and extremely low birth weight, degree of preterm, formula feeding, infection, hypoxic/ischemic damage, and intestinal dysbiosis. The development of noninvasive biomarkers of NEC from stool, urine, and serum has attracted a great deal of interest because to these clinical connections and the quest for a deeper knowledge of disease pathophysiology. Therefore, this study aims to identify protein expression patterns in NEC and discover innovative diagnostic biomarkers. In this study, we recruited five patients diagnosed with NEC and paired necrotic segments of intestinal tissue with adjacent normal segments of intestine to form experimental and control groups. Quantitative proteomics tandem mass tagging (TMT) labeling technique was used to detect and quantify the proteins, and the expression levels of the candidate biomarkers in the intestinal tissues were further determined by quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, Immunofluorescence methods and enzyme-linked immunosorbent assay (ELISA). A total of 6880 proteins were identified and quantified in patients with NEC. A significant disparity in protein expression was observed between necrotic and normal segments of intestinal tissue in NEC patients. A total of 55 proteins were found to be upregulated, and 40 proteins were found to be downregulated in NEC patients when using a p-value of < 0.05, and an absolute fold change of > 1.2 for analysis. GO function enrichment analysis showed the positive regulation of significant biological processes such as mitochondrial organization, vasoconstriction, rRNA catabolism, fluid shear stress response, and glycerol ether biosynthesis processes. Enrichment analysis als