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关键词： TNF   Parkinson's disease   Neurodegeneration   Neuroinflammation   alpha-Synuclein   PFF   CIITA  

摘要： Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, alpha-Synuclein (alpha-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and alpha-Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to alpha-Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust alpha-Syn-induced PD-like pathology in rats. We used a model combining rAAVmediated alpha-Syn overexpression in SNpc with striatal injection of alpha-Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-alpha-Syn. We observed up to 70 % loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological alpha-Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1 beta levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.

关键词： antioxidant   gastric ulcer   immunohistochemistry   inflammation   rhamnetin  

摘要： Rhamnetin is a naturally occurring flavonoid compound found in many wild plant species and indigenous fruits. Despite its numerous biological potentials, such as anti-inflammatory, antioxidant and antimicrobial effects, there is a lack of literature elucidating its gastroprotective action and anticipating molecular mechanism. Natural products can be a good alternative to overcome the side effects and relapses associated with anti-ulcer drugs. This study aims to elucidate rhamnetin's acute toxicity and gastroprotective effects using the indomethacin ulceration model. Animals were arbitrarily divided into five groups: a negative control group (A) and a positive control group (B), both treated with 1% carboxymethyl cellulose;a reference group (C) receiving 20 mg/kg omeprazole;and low-dose (D) and high-dose (E) rhamnetin groups receiving 30 and 60 mg/kg, respectively. After 1 h, rats in Groups B-E were subjected to indomethacin-induced ulceration. Toxicity evaluations indicated the safety of rhamnetin at doses of up to 400 mg/kg in rats, without any noticeable physiological alterations. Rhamnetin (30 and 60 mg/kg) administered orally 1 h before indomethacin-induced gastric ulcer ameliorated the stomach lesions and lowered the ulcer index area by 73.81% and 77.87%, respectively. Rhamnetin supplementation ameliorated histopathological alterations and restored gastric barriers, including gastric pH and mucin secretion. Moreover, rhamnetin-treated rats exhibited increased anti-apoptotic heat shock protein 70 and decreased Bax protein in stomach tissues. These findings were in line with lowered accumulated MDA, increased superoxide dismutase, catalase and prostaglandin E2 levels, reduced serum inflammatory mediators (TNF-alpha and interleukin-6) and elevated interleukin-10 cytokines. The outcomes indicate rhamnetin's cicatrising and gastroprotective effects against indomethacin-mediated ulceration, possibly due to its modulatory actions on oxidative stress, inflammation and

关键词： HLA-DRB1*12:109   new allele   next-generation sequencing (NGS)  

摘要： The new HLA-DRB1*12:109 allele differs from its most closely related allele DRB1*12:02:01:04 in exon 1.

关键词： Hydrogel   PASI score   Psoriasis   Topical delivery   Transferosomes  

摘要： Psoriasis is a multifactorial autoimmune disease characterized by excessive proliferation of keratinocytes. This excessive proliferation led to the formation of plaque with itching and silvery patches. The transferosome-loaded hydrogel was developed using a 1 % hyaluronic acid gel base and subjected to in vitro (pH, rheology, spread- ability, and in vitro release studies) and in vivo evaluation. The imiquimod-induced psoriatic mice model was developed for the determination of anti-psoriatic activity of the transferosome-loaded hydrogel formulation. The transferosomal hydrogel formulation was found to be homogenous with a pH of 5.4 +/- 0.4, which is acceptable for topical delivery. The transferosomal hydrogel exhibited pseudoplastic behavior that is acceptable for dermatological therapy with 9.8 g cm sec-1 spreadability. It was found that diacerein released 88.44 +/- 2.11 % and berberine HCl released 81.56 +/- 0.11 % over 24 h, showing a sustained release profile. In the psoriatic BALB/ c mice model, berberine HCl and diacerein-loaded transferosomes containing hydrogel formulation (BDTG transferosomal gel) reduced erythema and scaling. The skin histology depicted an alleviation of epidermal thickness and reduced acanthosis. ELISA assay confirmed that the hydrogel formulation reduced inflammation by minimizing TNF-alpha and IL-17A levels. Thus, co-delivery of diacerein and berberine HCl in lipid-based nanocarriers has effective therapeutic outcomes in psoriatic animals due to the improved skin penetration and prolonged local residence time. However, the future scope necessitates clinical studies of the developed formulation to prove its anti-psoriatic activity.

关键词： Biomimetic mineralization   Non-collagenous proteins   Monetite   Macrophages   Interleukin-27   Osteoimmunomodulation  

摘要： Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FC gamma RIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration.

关键词： Crohn's disease   tumor necrosis factor   infliximab   adalimumab   therapeutic dose escalation   proactive  

摘要： Background Antitumor necrosis factor (TNF) dose escalation is performed to improve therapeutic response and optimize outcomes in patients with Crohn's disease (CD). We aimed to describe the durability of anti-TNF therapy in patients with CD receiving escalated anti-TNF therapy, along with the overall durability of anti-TNF treatment between patients managed with a proactive versus reactive therapeutic drug monitoring (TDM) *** We undertook a retrospective multicentre cohort study. One center practiced proactive TDM with a weekly virtual TDM clinic, while the other practiced reactive TDM. Patients receiving escalated infliximab or adalimumab therapy for CD from January 2015 to April 2022 were included. Durability was defined as the time from biologic start to cessation for treatment *** About 239 patients (45% female, median age 39) meeting criteria for inclusion were identified. About 165 patients were included in the proactive TDM cohort and 74 in the reactive TDM cohort. Anti-TNF na & iuml;ve patients had significantly higher durability of therapy when compared with the anti-TNF exposed patients for both overall durability (P = .045) and durability postescalation (P = .017). The proactive TDM cohort had significantly higher durability when compared with the reactive cohort for both overall durability (P = .001) and durability postescalation (P = .002).Results About 239 patients (45% female, median age 39) meeting criteria for inclusion were identified. About 165 patients were included in the proactive TDM cohort and 74 in the reactive TDM cohort. Anti-TNF na & iuml;ve patients had significantly higher durability of therapy when compared with the anti-TNF exposed patients for both overall durability (P = .045) and durability postescalation (P = .017). The proactive TDM cohort had significantly higher durability when compared with the reactive cohort for both overall durability (P = .001) and durability postescalation (P = .002).Conclusions

关键词： CHB   HLA-DRB1   LGALSL   mendelian randomization study   prognosis biomarker  

摘要： Despite significant advances in chronic hepatitis B (CHB) treatment, some patients receiving entecavir (ETV) still experience poor clinical outcomes. Identifying host factors contributing to ETV anti-HBV failure in CHB patients with persistent HBV DNA positivity is crucial for developing targeted therapies. We conducted a comprehensive study using univariate and reverse Mendelian randomization (MR), incorporating sequencing data and publicly available genetic data, followed by gene set variation analysis (GSVA), gene set enrichment analysis (GSEA) and immune cell infiltration analysis to systematically explore causal associations between host factors and CHB. Univariate MR analyses revealed a significant inverse association between increased HLA-DRB1 levels and CHB risk (odds ratio [OR] 0.607, 95% confidence interval [CI] 0.478-0.771, p = 0.00004), while increased LGALSL levels were significantly associated with a heightened risk of poor CHB prognosis (OR 1.110, 95% CI: 1.017-1.212, p = 0.01885), as estimated using the inverse variance weighting (IVW) method. Analysis of immune cell infiltration showed significantly higher HLA and mast cell levels in the poor prognosis group. HLA-DRB1 showed a significant positive correlation with HLA, whereas LGALSL showed a significant negative correlation. Compared to patients with favorable prognoses, those with poor prognoses exhibited significantly higher serum LGALSL levels (ELISA), lower HLA-DRB1 expression in peripheral blood mononuclear cells (PBMCs) (qPCR), and significantly increased LGALSL expression in liver tissue (IHC). Therefore, LGALSL and HLA-DRB1 may serve as potential prognostic biomarkers for CHB patients receiving ETV, providing novel avenues for diagnosis and treatment.

关键词： Diabetes mellitus   Inflammation   Monocytes   Type 2   Wound healing  

摘要： The exact mechanisms underlying impaired wound healing in diabetes are not fully understood. In this study, we aimed to investigate the effect of classical and non-classical monocyte ratios along with TNF-alpha and TGF-(3 plasma levels on diabetic wound healing. Twenty-four patients with confirmed type 2 diabetes and twenty healthy controls were enrolled in this study. The peripheral blood mononuclear cells (PBMC) isolation was performed by FicollPaque density gradient centrifugation method. The frequency of different subsets of monocytes was characterized in diabetic patients and healthy controls using flow cytometry. TNF-alpha and TGF(3 plasma levels were measured by the enzyme-linked immunosorbent assay (ELISA) method. We found a significant difference in the frequency of classical and non-classical monocytes in healthy controls and diabetic patients. The plasma level of TNF-alpha was higher in diabetic patients than in healthy controls, and its level was associated with wound grade. Moreover, the plasma level of TGF-(3 was lower in diabetic patients rather than healthy controls. Also, our data showed a higher percentage of non-classical monocytes as wound grade increased. In conclusion, the wound healing process is affected by diabetes via changes in non-classical and classical monocyte percentages, which may be the result of TNF-alpha increase and TGF-(3 levels decreasing in diabetic patients' plasma.

关键词： HLA-C   NGS   novel HLA allele   Russian  

摘要： Five novel HLA-C alleles have been identified using full next-generation sequencing.

关键词： fibrosis   inflammation   lung   stromal cells   TNFSF  

摘要： Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis and tissue remodeling in the clinic. Thus, there is an unmet need to develop novel antifibrotic drugs capable of reversing disease. Our lab has identified two novel mediators of pulmonary fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Aside from their inflammatory roles, LIGHT and TL1A can directly activate structural cells involved in fibrosis, which express their receptors. Here, we show that LIGHT and TL1A receptors are both significantly elevated in patient pulmonary fibrosis biopsies as compared with healthy control lungs. Using gain-of-function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another. Furthermore, these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits transforming growth factor beta-driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic signatures, including additive and synergistic profibrotic activities, in addition to some redundant profibrotic functions. Importantly, using antagonistic reagents neutralizing both LIGHT and TL1A signaling concomitantly post-disease onset in a bleomycin mouse model of pulmonary fibrosis, we observe a significant decrease in collagen deposition and smooth muscle accumulation as opposed to respective monotherapies blocking each molecule in isolation. This work highlights a therapeutic need to concomitantly target LIGHT and TL1A for treatment of pulmonary fibrosis disorders in humans. The Editors have selected this article as a highlight of the issue.