The local microenvironment drives activation of neutrophils in human brain tumors.

Neutrophils are abundant immune cells in the circulation and frequently infiltrate tumors in substantial numbers. However, their precise functions in different cancer types remain incompletely understood, including in the brain microenvironment. We therefore investigated neutrophils in tumor tissue of glioma and brain metastasis patients, with matched peripheral blood, and herein describe the first in-depth analysis of neutrophil phenotypes and functions in these tissues. Orthogonal profiling strategies in humans and mice revealed that brain tumor-associated neutrophils (TANs) differ significantly from blood neutrophils and have a prolonged lifespan and immune-suppressive and pro-angiogenic capacity. TANs exhibit a distinct inflammatory signature, driven by a combination of soluble inflammatory mediators including tumor necrosis factor alpha (TNF-ɑ) and Ceruloplasmin, which is more pronounced in TANs from brain metastasis versus glioma. Myeloid cells, including tumor-associated macrophages, emerge at the core of this network of pro-inflammatory mediators, supporting the concept of a critical myeloid niche regulating overall immune suppression in human brain tumors.

Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.

TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.

Epitranscriptomics m6A analyses reveal distinct m6A marks under tumor necrosis factor α (TNF-α)-induced apoptotic conditions in HeLa cells.

Tumor necrosis factor-α (TNF-α) is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-α-modulated epitranscriptomic m6A marks is unknown. We employed a genomewide approach to examine the extent of m6A RNA modifications under TNF-α-modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m6A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m6A RNA modification patterns were quite different under cisplatin- and TNF-α-mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF-α treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF-α treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF-α-mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway-specific m6A methylation marks exist in cells and TNF-α-METTL3-TP53INP1 axis modulates TNF-α-mediated apoptosis in HeLa cells.

HBV reactivation in HBsAg-/HBcAb+ rheumatoid arthritis patients receiving biologic/targeted synthetic DMARDs.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population. METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed. RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation. CONCLUSION: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy.

Cytokines Expression Compared to the Determinants of Cellular Apoptosis Prominently Attributes to the Deleterious Effects of 'A' Determinant Surface Gene Mutations in HBV Transfected Hepatoma Cell Line.

BACKGROUND: Previous studies have explored the role of AKT protein in anti-apoptotic/proliferative activities. However, there has been a lack of information regarding the role of Akt in association with cytokines expression in HBV-related (wild type HBV and HBV with mutations of 'a' determinant region) studies either in the case of HBV infection or in transfected hepatoma cells. The present study tries to determine the role of Akt and cytokines expression in the presence of small surface gene mutants in the hepatoma cell line. METHODS: Mutations of 'a' determinant region, viz. sA128V and sG145R, were created in wild-type pHBV1.3 by site-directed mutagenesis and transfected in hepatoma cell line. Secretory levels of HBsAg in the wild type as well as in both the mutants were analyzed by ELISA. Apoptotic analysis of transfected cells was studied by flow cytometry. Expression analysis of Akt and cytokines (TNF-alpha, IL-6, and IFN-gamma) was done by qPCR. RESULTS: The presence of significantly more alive cells in sG145R than sA128V transfected cells may be due to the up-regulation of the Akt gene expression. Cytokines expression was nearly similar between sA128V and wild-type pHBV1.3 transfected cells. Presence of sG145R showed dramatically high cytokines expression than sA128V and wild-type pHBV1.3. CONCLUSION: Cytokines expression predominantly contributes to the detrimental effects associated with the 'a' determinant region mutations particularly sG145R mutant. It may also be inferred that mechanisms associated with cellular apoptosis apparently do not play any major role to assign the 'a' determinant small surface gene mutation(s) for their pathological outcome.

Fenamates and ibuprofen as foundational components in the synthesis of innovative, targeted COX-2 anti-inflammatory drugs, undergoing thorough biopharmacological assessments and in-silico computational studies.

Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 µM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.

Exploring putative drug properties associated with TNF-alpha inhibition and identification of potential targets in cardiovascular disease using machine learning-assisted QSAR modeling and virtual reverse pharmacology approach.

Cardiovascular disease is a chronic inflammatory disease with high mortality rates. TNF-alpha is pro-inflammatory and associated with the disease, but current medications have adverse effects. Therefore, efficient inhibitors are urgently needed as alternatives. This study represents a structural-activity relationship investigation of TNF-alpha, curated from the ChEMBL database. Exploratory data analysis was performed to visualize the physicochemical properties of different bioactivity groups. The extracted molecules were subjected to PubChem and SubStructure fingerprints, and a QSAR-based Random Forest (QSAR-RF) model was generated using the WEKA tool. The QSAR random Forest model was built based on the SubStructure fingerprint with a correlation coefficient of 0.992 and 0.716 as the respective tenfold cross-validation scores. The variance important plot (VIP) method was used to extract the important features for TNF-alpha inhibition. The Substructure-based QSAR-RF (SS-QSAR-RF) model was validated using molecules from PubChem and ZINC databases. The generated model also predicts the pIC50 value of the molecules selected from the docking study followed by molecular dynamic simulation with the time step of 100 ns. Through virtual reverse pharmacology, we determined the main drug targets from the top four hit compounds obtained via molecular docking study. Our analysis included an integrated bioinformatics approach to pinpoint crucial targets like EGRF, HSP900A1, STAT3, PSEN1, AKT1, and MDM2. Further, GO and KEGG pathways analysis identified relevant cardiovascular disease-related pathways for the hub gene involved. However, this study provides valuable insights, it is important to note that it lacks experimental application. Future research may benefit from conducting in-vitro and in-vivo studies.

Paradoxical and bimodal immune-mediated dermatological side effects of TNF-α inhibitors: A comprehensive review.

INTRODUCTION: Due to the increasing prevalence of immune-mediated diseases such as psoriasis, lichen planus, rheumatoid arthritis and inflammatory bowel disease, dermatologists have turned to new biologic drugs known as DMARDs (disease-modifying anti-rheumatic drugs) in recent years. AREAS COVERED: In this study, we evaluate the immune-mediated dermatological side effects of DMARDS by reviewing and analyzing previous peer-reviewed research on the effects of TNF-α inhibitors in the treatment of skin diseases, as well as adverse effects of these drugs and some of the main causes of these effects. EXPERT OPINION: DMARDs are very effective in improving control of the above diseases. TNF-α inhibitors are an important group of DMARDs that are widely used. The paradoxical adverse events (PAEs) associated with the use of TNF-α inhibitors are divided into three categories: true paradoxical, borderline paradoxical, and non-paradoxical. True PAEs include conditions for which TNF-α inhibitors are approved for treatment. Borderline PAEs are considered to occur with this class of drugs for which there is no definite approval but for which there is sufficient evidence. Although these events are rare, early recognition of the accused drug and appropriate decision-making may prevent progression of complications and irreversible side effects.

Systemic Inflammation but not Oxidative Stress Is Associated with Physical Performance in Moderate Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) patients manifest muscle dysfunction and impaired muscle oxidative capacity, which result in reduced exercise capacity and poor health status. The aim of this study was to compare the physical performance, systemic inflammation, and oxidative stress of patients with moderate COPD, and to associate physical performance with inflammatory and oxidative stress plasma markers. Twenty CONTROL (n = 10) and moderate COPD (n = 10) patients participated in this study. Systematic inflammation and oxidative stress plasma markers, maximal aerobic capacity (VO2peak), and maximal isometric strength (MVIC) of the knee extensor (KE) muscles were measured. VO2peak was 31.3% greater in CONTROL compared to COPD (P = 0.006). The MVIC strength of the KE was 43.9% greater in CONTROL compared to COPD (P = 0.002). Tumor necrosis factor-alpha (TNF-α) was 79.6% greater in COPD compared to CONTROL (P < 0.001). Glutathione peroxidase activity (GPx) activity was 27.5% lesser in COPD compared to CONTROL (P = 0.05). TNF-α concentration was correlated with KE MVC strength (R = -0.48; P = 0.045) and VO2peak (R = -0.58; P = 0.01). Meanwhile, malondialdehyde (MDA) and GPx activity were not associated with KE strength or VO2peak (P = 0.74 and P = 0.14, respectively). COPD patients showed lesser muscle strength and aerobic capacity than healthy control individuals. Furthermore, patients with COPD showed greater systemic inflammation and lesser antioxidant capacity than healthy counterparts. A moderate association was evident between levels of systemic inflammation and physical performance variables.

Leishmaniasis in otorhinolaryngology: an emerging disease and its relationship with anti-tumor necrosis factor-alpha drugs.

PURPOSE: To investigate the clinical manifestations, management and outcomes of Leishmania lesions in the ear-nose-throat (ENT) region, and its relationship with tumor necrosis factor (TNF)-α blocking drugs. METHODS: Single-center retrospective observational study. Patients diagnosed with cutaneous and mucosal leishmaniasis in the otorhinolaryngologic area at a tertiary referral center over a period of 8 years. RESULTS: Three cases of Leishmania lesions in the ear and two in the nose were encountered at our institution. All patients were under treatment with TNF-α blocking drugs. Diagnosis was challenging, and it was important to have a clinical suspicion in order to use accurate detection techniques. All patients received systemic treatment and achieved a complete resolution of the lesions. CONCLUSIONS: With the increasing use of biologic treatments like TNF-α blockers, this type of infection will be increasingly frequent in endemic areas and also worldwide. It is important to include leishmaniasis in the differential diagnosis of inflammatory/infectious lesions in the ENT region.

Inflammatory Biomarkers and Gait Impairment in Older Adults: A Systematic Review.

Peripheral inflammation and gait speed alterations are common in several neurological disorders and in the aging process, but the association between the two is not well established. The aim of this systematic literary review is to determine whether proinflammatory markers are a positive predictor for gait impairments and their complications, such as falls in older adults, and may represent a risk factor for slow gait speed and its complications. The systematic review was performed in line with the Preferred Report Items for Systematic Review and Meta-Analyses (PRISMA). A protocol for literature searches was structured a priori and designed according to the International Perspective Register of Systemic Review (PROSPERO: CRD42023451108). Peer-reviewed original articles were identified by searching seven electronic databases: Excerpta Medica Database (EMBASE), SciVerse (ScienceDirect), Scopus, PubMed, Medline, Web of Science, and the Cochrane Library. The search strategy was formulated based on a combination of controlled descriptors and/or keywords related to the topic and a manual search was conducted of the reference lists from the initially selected studies to identify other eligible studies. The studies were thoroughly screened using the following inclusion criteria: older adults, spatiotemporal gait characteristics, and proinflammatory markers. A meta-analysis was not performed due to the heterogeneity of the studies, and the results were narratively synthesized. Due to the clinical and methodological heterogeneity, the studies were combined in a narrative synthesis, grouped by the type of biomarkers evaluated. A standardized data extraction form was used to collect the following methodological outcome variables from each of the included studies: author, year, population, age, sample size, spatiotemporal gait parameters such as gait velocity, and proinflammatory markers such as TNF-α, high sensitivity C-reactive (CRP) proteins, and IL-6. We included 21 out of 51 studies in our review, which examined the association between inflammatory biomarkers and gait impairment. This review highlights the role of TNF-α, CRP, and IL-6 in gait impairment. Biomarkers play an important role in the decision-making process, and IL-6 can be an effective biomarker in establishing the diagnosis of slow gait speed. Further longitudinal research is needed to establish the use of molecular biomarkers in monitoring gait impairment.

On Connective Tissue Mast Cells as Protectors of Life, Reproduction, and Progeny.

The connective tissue mast cell (MC), a sentinel tissue-residing secretory immune cell, has been preserved in all vertebrate classes since approximately 500 million years. No physiological role of the MC has yet been established. Considering the power of natural selection of cells during evolution, it is likely that the MCs exert essential yet unidentified life-promoting actions. All vertebrates feature a circulatory system, and the MCs interact readily with the vasculature. It is notable that embryonic MC progenitors are generated from endothelial cells. The MC hosts many surface receptors, enabling its activation via a vast variety of potentially harmful exogenous and endogenous molecules and via reproductive hormones in the female sex organs. Activated MCs release a unique composition of preformed and newly synthesized bioactive molecules, like heparin, histamine, serotonin, proteolytic enzymes, cytokines, chemokines, and growth factors. MCs play important roles in immune responses, tissue remodeling, cell proliferation, angiogenesis, inflammation, wound healing, tissue homeostasis, health, and reproduction. As recently suggested, MCs enable perpetuation of the vertebrates because of key effects-spanning generations-in ovulation and pregnancy, as in life-preserving activities in inflammation and wound healing from birth till reproductive age, thus creating a permanent life-sustaining loop. Here, we present recent advances that further indicate that the MC is a specific life-supporting and progeny-safeguarding cell.

Looking back on 51 years of the Carol Nachman Prize in Rheumatology-significance for the field of spondyloarthritis research.

The city and casino of Wiesbaden, capital of the German state Hessen, have endowed the Carol Nachman Prize to promote research work in the field of rheumatology since 1972. The prize, endowed with 37,500 €, is the second highest medical award in Germany and serves to promote clinical, therapeutic, and experimental research work in the field of rheumatology. In June 2022, the 50-year anniversary was celebrated. In the symposium preceding the award ceremony, an overview was given on the significance of spondyloarthritis for the work of the awardees in the past 30 years. This overview has now been put together to inform the interested community of the work performed, including the opinion of the awardees regarding what they consider to be their most important contribution.

Loeffler's Endocarditis- A cause of endomyocardial fibrosis in a patient of juvenile idiopathic arthritis: A Case Report.

Endomyocardial fibrosis secondary to hyper-eosinophilic syndrome also known as Loeffler's Endocarditis is a rare cause of restrictive cardiomyopathy. If left untreated, it carries a very high morbidity and mortality rate. The case of a 20 years old girl, a known case of polyarticular juvenile idiopathic arthritis since the age of 13 years was reported at Federal Government Polyclinic Hospital, Islamabad on 14th May 2022. She presented with an acute history of shortness of breath and cough for two weeks. Her initial echocardiogram showed suspicion of Loeffler's Endocarditis, which is attributed to be an adverse effect of etanercept- a tumour necrosis factor (TNF) inhibitor, which she had been prescribed for her arthritis. The patient is currently being managed with high doses of steroids, therapeutic anticoagulation with rivaroxaban, carvedilol for tachycardia and mycophenolate mofetil as an immunosuppressant.

Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8.

Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype. Irf8 is also a known risk gene for multiple sclerosis and lupus, and it has recently been shown to be downregulated in schizophrenia. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. Here, we show by RNAseq from Irf8 -/- male and female mouse brains that several genes involved in regulation of neural activity are dysregulated. We then show that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to lethal seizures in male and female Irf8 -/- mice. Finally, we identify that TNF-α is elevated specifically in microglia in the CNS, and genetic or acute pharmacological blockade of TNF-α in the Irf8 -/- CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. Our data further suggest that neuronal function is impacted by loss of IRF8, a factor involved in neuropsychiatric and neurodegenerative diseases.SIGNIFICANCE STATEMENT Here, we identify a previously unknown and key role for interferon regulator factor 8 (IRF8) in regulating neural excitability and seizures. We further determine that these effects on neural circuits are through elevated TNF-α in the CNS. As IRF8 has most widely been studied in the context of regulating the development and inflammatory signaling in microglia and other immune cells, we have uncovered a novel function. Further, IRF8 is a risk gene for multiple sclerosis and lupus, IRF8 is dysregulated in schizophrenia, and elevated TNF-α has been identified in a multitude of neurologic conditions. Thus, elucidating these IRF8 and TNF-α-dependent effects on brain circuit function has profound implications for understanding underlying, therapeutically relevant mechanisms of disease.

MEG3 alleviates ankylosing spondylitis by suppressing osteogenic differentiation of mesenchymal stem cells through regulating microRNA-125a-5p-mediated TNFAIP3.

Osteoblasts are important regulators of bone formation, but their roles in ankylosing spondylitis (AS) remain unclear. This study aims to explore the role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) MEG3 in AS. Serum from AS patients as well as AS mesenchymal stem cells (ASMSCs) and healthy donors mesenchymal stem cells (HDMSCs) was collected. Accordingly, poorly expressed MEG3 and TNF alpha induced protein 3 (TNFAIP3) as well as overexpressed microRNA-125a-5p (miR-125a-5p) were noted in the serum of AS patients and in ASMSCs during the osteogenic induction process. Meanwhile, the interaction among MEG3, miR-125a-5p, and TNFAIP3 was determined and their effect on osteoblast activity was examined in vitro and in vivo. Overexpression of MEG3 and TNFAIP3 or inhibition of miR-125a-5p was found to inactivate the Wnt/ß-catenin pathway, thus suppressing osteogenic differentiation of MSCs. MEG3 competitively bound to miR-125a-5p to increase TNFAIP3 expression, thereby inactivating the Wnt/ß-catenin pathway and repressing the osteogenic differentiation of MSCs. In proteoglycan (PG)-induced AS mouse models, MEG3 also reduced osteogenic activity of MSCs to inhibit AS progression through the miR-125a-5p/TNFAIP3/Wnt/ß-catenin axis. Therefore, up-regulation of MEG3 or depletion of miR-125a-5p holds potential of alleviating AS, which sheds light on a new therapeutic strategy for AS treatment.

The predictors of paradoxical reactions, especially psoriasis, to biologic therapy-findings from the TReasure database: a 5-year follow-up study.

OBJECTIVES: The objectives of this study were to assess the clinical characteristics, predictive factors, and practical algorithms of paradoxical reactions (PRs), specifically paradoxical psoriasis (PP). METHODS: The TReasure database is a web-based prospective observational cohort comprised of patients with RA and SpA from 17 centres around Turkey since 2017. A cohort study and a case-control study nestled within the cohort were identified. RESULTS: In total, 2867 RA and 5316 SpA patients were evaluated. The first biologic agent was found to have caused PRs in 60% of the 136 patients (1.66%) who developed the PRs. The median time interval between the PRs and biological onset was 12 months (range 1-132 months, mean 21 months). The most common types of PP, constituting 92.6% of PRs, were pustular (60.3%) and palmoplantar (30.9%). Adalimumab (30.9%), infliximab (19%) and etanercept (17.4%) were the most common agents causing the PP. In the treatment of most PP patients (73.2%), switching biologic agents was favoured, with TNF inhibitor (TNFi) chosen in 46.03% and non-TNFi in 26.9% of cases. The three most frequently selected drugs were etanercept (24.6%), secukinumab (9.5%) and adalimumab (8.7%). Only 5.17% of patients who switched to another TNFi showed progression. The odds ratios (s) for SSZ, HCQ, and LEF use were significantly higher in RA controls than in PP patients (P = 0.033, OR = 0.15; P = 0.012, OR = 0.15; and P = 0.015, OR = 0.13, respectively). In the PP group with SpA, the number of smokers was significantly higher (P = 0.003, OR: 2.0, 95% CI: 1.05, 3.81). CONCLUSION: Contrary to expectations based on earlier research suggesting that paradoxical reactions develop with the class effect of biological agents, the response of patients who were shifted to another TNFi was favourable.

Vitamin D deficiency enhances vascular oxidative stress, inflammation, and angiotensin II levels in the microcirculation of diabetic patients.

Low vitamin D (vitD) levels have been reported to be a risk factor for diabetes-related cardiovascular complications. This study examined the effects of vitD deficiency on oxidative stress (OS), inflammation, and levels of the vasoconstrictor angiotensin II (Ang II) in the microvascular tissue of type 2 diabetic patients. Patients were categorized into (i) vitD non-deficient diabetics (DNP, n = 10) and (ii) vitD-deficient diabetics (DDP, n = 10), based on their serum 25(OH)D levels. Subcutaneous fat tissues with intact blood vessels were collected during lower limb surgical procedures. The blood vessel were isolated; measurements of the antioxidant enzyme superoxide dismutase (SOD) activity, OS marker malondialdehyde (MDA), Ang II, and the inflammatory marker, TNF-α of the microvascular tissues were determined. Elevated MDA levels and reduced SOD activity, with higher levels of TNF-α and Ang II were observed in the microvascular tissues of DDP compared to DNP. VitD deficiency did not associate with glycemic parameters (fasting blood glucose and glycated hemoglobin) levels. In conclusion, vitD deficiency was correlated with higher microvascular tissue OS, inflammation, and Ang II levels in type 2 diabetic patients. This may contribute to early vasculopathy that occurs in diabetic patients, thus, may contribute to the planning of therapeutic strategies to delay or prevent cardiovascular complications.

Transcriptomic responses of peripheral blood mononuclear cells to cyclosporin and etanercept in a female infant with juvenile generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. An early onset of the diseases is correlated with mutations among IL36RN, CARD14, AP1S3, MPO and SERPINA3 genes. Systemic biological agents including anti-TNF-α, anti-IL-17, anti-IL-12/IL-23, anti-IL1R, anti-IL1ß and anti-IL-36R act as novel treatment methods for GPP. Herein we report a female infant clinically diagnosed with GPP since she was 10-month-old. Results of whole-exome sequencing (WES) and Sanger sequencing revealed a reported heterozygous IL36RN (c.115+6T>C) and another reported heterozygous SERPINA3 frame-shifting variant (c.1247_1248del). Initial cyclosporin treatment for the patient led to a partial remission of the symptoms. However, the patient reached nearly total remission of pustules and erythema after anti-TNF-α inhibitor etanercept treatment. Results of further RNA sequencing (RNA-seq) done on peripheral blood mononuclear cells correlated with the clinical responses, showing that cyclosporin suppressed a portion of the neutrophil-related genes, while most genes associated with neutrophil activation, neutrophil-mediated immunity and degranulation were downregulated by the subsequent etanercept treatment. We report this case to demonstrate WES and RNA-seq in combination could come in handy in reaching a precise diagnosis and in evaluating or even predicting the molecular alterations underlying clinical treatment effectiveness.

Wnt3a/YTHDF1 Regulated Oxaliplatin-Induced Neuropathic Pain Via TNF-α/IL-18 Expression in the Spinal Cord.

Oxaliplatin is widely used in cancer treatment, however, many patients will suffer from neuropathic pain (NP) induced by it at the same time. Therefore exploring the mechanism and founding novel target for this problem are needed. In this study, YTHDF1 showed upregulation in oxaliplatin treated mice. As m6A is known as conserved and it widely functions in numerous physiological and pathological processes. Therefore, we focused on exploring the molecular mechanism of whether and how YTHDF1 functions in NP induced by oxaliplatin. IHC and western blotting were conducted to measure proteins. Intrathecal injection for corresponding siRNAs in C57/BL6 mice or spinal microinjection for virus in YTHDF1flox/flox mice were applied to specially knockdown the expression of molecular. Von Frey, acetone test and ethyl chloride (EC) test were applied to evaluate NP behavior. YTHDF1, Wnt3a, TNF-α and IL-18 were increased in oxaliplatin treated mice, restricted the molecular mentioned above respectively can significantly attenuate oxaliplatin-induced NP, including the mechanical allodynia and cold allodynia. Silencing YTHDF1 and inhibiting Wnt3a and Wnt signaling pathways can reduce the enhancement of TNF-α and IL-18, and the decreasing of the upregulation of YTHDF1 can be found when inhibiting Wnt3a and Wnts signaling pathways in oxaliplatin treated mice. Our study indicated a novel pathway that can contribute to oxaliplatin-induced NP, the Wnt3a/YTHDF1 to cytokine pathway, which upregulating YTHDF1 functioned as the downstream of Wnt3a signal and promoted the translation of TNF-α and IL-18 in oxaliplatin treated mice.