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BackgroundIgA vasculitis (IgAV) is an immune-associated vasculitis, yet its exact etiology remains unclear. Here, we explore the interaction between IgAV and inflammatory factors using bidirectional Mendelian randomization (MR).MethodsWe conducted a bidirectional summary-level MR analysis to delineate the causality of C-reactive protein (CRP), procalcitonin (PCT), and 41 circulating inflammatory regulators with IgAV. Data on genetic variants related to inflammation were obtained from three genome-wide association studies (GWASs) on CRP, PCT, and human cytokines, whereas data on IgAV was from large meta-analyses of GWAS among 216 569 FinnGen Biobank participants. The primary MR analysis was performed using the inverse-variance weighted (IVW) approach, and the sensitivity analyses were carried out using MR-Egger, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier.ResultsThis study revealed the association of CRP higher levels with increased risk of IgAV through IVW method (Estimate odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.01-1.98, P = 0.04), MR-Egger (OR = 1.87, CI: 1.15-3.02, P = 0.01), weighted median (OR = 2.00, CI: 1.21-3.30, P = 0.01) and weighted mode (OR = 1.74, CI: 1.13-2.68, P = 0.02). Furthermore, elevated IL-8 was strongly implicated with a higher risk of IgAV (IVW OR = 1.42, CI: 1.05-1.92; P = 0.02). Conversely, genetically predicted IgAV was associated with decreased levels of TNF-β (IVW estimate β = -0.093, CI: -0.178 - -0.007; P = 0.033). Additionally, no such significant statistical differences for other inflammatory factors were found.ConclusionOur current study using bidirectional MR analysis provides compelling evidence for a causal effect of CRP, PCT, and circulating inflammatory regulators on IgAV. These findings contribute to a better understanding of the pathogenesis of IgAV and emphasize the potential of targeting inflammatory factors for therapeutic interventions.

Background The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear. Results Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8 + memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly. Conclusions Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation. Recovery from ischemic stroke involves dynamic interactions between immune cells and the brain. Here, the authors show that microglia reduction promotes long-term stroke recovery in mice by expanding reparative macrophages, enhancing vascular repair and white matter integrity.

Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that [CD8.sup.+][CD122.sup.+][CD49d.sup.lo] T regulatory-like cells ([CD8.sup.+] TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by [CD8.sup.+] TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for [CD8.sup.+] TRLs. Upon brain entry, [CD8.sup.+] TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor-like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in [CD8.sup.+] TRLs. While IL-10 induction was important for the Anti-inflammatory effects of [CD8.sup.+] TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of [CD8.sup.+] TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique [CD8.sup.+] TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.

As urban aging issues intensify, the impact of the built environment in urban neighborhoods on the physical and mental health of elderly residents has garnered increasing attention. Previous studies have demonstrated that the built environment is related to various health outcomes; however, most empirical research typically focuses on the objective physical environment, lacking measurements of subjective environmental perceptions. This study, using 24 neighborhoods in Shanghai as case studies, employed deep learning, big data methods, and surveys to collect 462 valid questionnaires from elderly residents. Structural equation modeling was applied to explore the relationship between the built environment and the physical and mental health of elderly residents, incorporating respondents’ subjective perceptions, physical activity, and neighborhood relationships as chain mediation effects. The results indicate that although there is no direct relationship between the built environment and the mental health of elderly residents, the built environment positively impacts mental health through enhancing subjective.

Background Specific targeting ability and good cell penetration are two critical requirements of tumor-targeted delivery systems. In the present work, we developed a novel matrix metalloprotein-triggered, cell-penetrating, peptide-modified, star-shaped nanoparticle (NP) based on a functionalized copolymer (MePEG-Peptide-Tri-CL), with the peptide composed of GPLGIAG (matrix metalloprotein-triggered peptide for targeted delivery) and r9 (cell-penetrating peptide for penetration improvement) to enhance its biological specificity and therapeutic effect. Results Based on the in vitro release study, a sustained release profile was achieved for curcumin (Cur) release from the Cur-P-NPs at pH 7.4. Furthermore, the release rate of Cur was accelerated in the enzymatic reaction. MTT assay results indicated that the biocompatibility of polymer NPs (P-NPs) was inversely related to the NP concentration, while the efficiency toward tumor cell inhibition was positively related to the Cur-P-NP concentration. In addition, Cur-P-NPs showed higher fluorescence intensity than Cur-NPs in tumor cells, indicating improved penetration of tumor cells. An in vivo biodistribution study further demonstrated that Cur-P-NPs exhibited stronger targeting to A549 xenografts than to normal tissue. Furthermore, the strongest tumor growth inhibition (76.95%) was observed in Cur-P-NP-treated A549 tumor xenograft nude mice, with slight pulmonary toxicity. Conclusion All results demonstrated that Cur-P-NP is a promising drug delivery system that possesses specific enzyme responsiveness for use in anti-tumor therapy.

Background Myocardial injury is the main manifestation of cardiovascular diseases, and previous studies have shown that propofol (PPF) regulates myocardial injury. However, the mechanism of PPF in regulating myocardial injury remains to be further explored. This work aims to analyze the effects of PPF on human cardiomyocyte injury and the underlying mechanism. Methods The regulatory and functional role of PPF and circAPBB2 in human cardiomyocyte injury were analyzed using an in vitro hypoxia/reoxygenation (H/R) cell model, which was established by treating human cardiomyocytes (AC16 cells) with H/R. The study evaluated AC16 cell injury by analyzing cytotoxicity, oxidative stress, inflammation and apoptosis of H/R‐induced AC16 cells. Quantitative real‐time polymerase chain reaction was performed to detect circAPBB2, miR‐18a‐5p and dual specificity phosphatase 14 (DUSP14) expression. Protein expression was analyzed by Western blot analysis assay. Dual‐luciferase reporter assay, RNA pull‐down assay and RNA immunoprecipitation assay were performed to identify the associations among circAPBB2, miR‐18a‐5p and DUSP14. Cytotoxicity was investigated by cell counting kit‐8 assay and lactate dehydrogenase activity detection kit. Oxidative stress was evaluated by cellular reactive oxygen species assay kit and superoxide dismutase activity assay kit. The production of tumor necrosis factor‐α and interleukin‐1β was evaluated by enzyme‐linked immunosorbent assays. Results The expression of circAPBB2 and DUSP14 was significantly decreased, while miR‐18a‐5p was increased in H/R‐induced AC16 cells when compared with controls. H/R treatment‐induced cytotoxicity, oxidative stress, inflammation and cell apoptosis were attenuated after circAPBB2 overexpression or PPF treatment, whereas these effects were restored by increasing miR‐18a‐5p expression. PPF treatment improved the inhibitory effect of ectopic circAPBB2 expression on H/R‐induced cell injury. MiR‐18a‐5p silencing ameliorated H/R‐induced AC16 damage by interacting with DUSP14. Mechanically, circAPBB2 acted as a miR‐18a‐5p sponge, and miR‐18a‐5p targeted DUSP14 in AC16 cells. Conclusion PPF synergized with circAPBB2 to protect AC16 cells against H/R‐induced oxidative stress, inflammation and apoptosis through the miR‐18a‐5p/DUSP14 pathway. Propofol synergized with circAPBB2 protected AC16 cells against H/R‐induced oxidative stress, inflammation and apoptosis through the miR‐18a‐5p/DUSP14 pathway.

Background Numerous studies have manifested long noncoding RNAs (lncRNAs) as biomarkers to determine the prognosis of multiple myeloma (MM) patients. Nevertheless, the prognostic role of lncRNAs in MM is still ambiguous. Herein, we performed a meta‐analysis to evaluate the predictive value of aberrantly expressed lncRNAs in MM. Methods A systemic literature search was performed in PubMed, EMBASE, Cochrane, and Web of Science databases until October 9, 2021, and the protocol was registered in the PROSPERO database (CRD42021284364). Our study extracted the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression‐free survival (PFS), or event‐free survival (EFS). Begg's and Egger's tests were employed to correct publication bias. Result Twenty‐six individual studies containing 3501 MM patients were enrolled in this study. The results showed that aberrant expression of lncRNAs was associated with poor OS and PFS of MM patients. The pooled HRs for univariate OS and PFS were 1.48 (95% CI = 1.17–1.88, p < 0.001) and 1.30 (95% CI = 1.18‐1.43, p < 0.001), respectively, whereas the pooled HRs for multivariate OS and PFS were 1.50 (95% CI = 1.16‐1.95, p < 0.001) and 1.59 (95% CI = 1.22‐2.07, p < 0.001), respectively. Subgroup analysis suggested that MALAT1, TCF7, NEAT1, and PVT1 upregulation were associated with poor OS (p < 0.05), PVT1, and TCF7 upregulation were implicated with worse PFS (p < 0.05), while only TCF7 overexpression was correlated with reduced EFS (p < 0.05). Moreover, the contour‐enhanced funnel plot demonstrated the reliability of our current conclusion, which was not affected by publication bias. Conclusion Aberrantly expressed particular lncRNAs are critical prognostic indicators in long‐term survival as well as promising biomarkers in progression‐free status. However, different cutoff values and dissimilar methods to assess lncRNA expression among studies may lead to heterogeneity.

ABSTRACT Background Bilirubin has anti‐inflammatory, antioxidant, and anti‐cancer properties, with an inverse relationship between its levels and cancer risk and prognosis. However, the prognostic value of serum bilirubin in acute myeloid leukemia (AML) remains uncertain. Methods This retrospective study analyzed pretreatment serum total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) in 284 AML patients and 316 healthy controls. The prognostic significance of serum bilirubin levels was determined using the Kaplan–Meier method and Cox proportional hazards model. Results Pretreatment TBIL and IBIL levels were significantly lower in AML patients compared to controls. TBIL and IBIL levels were significantly higher in the CR/CRh/CRi group than in the non‐CR/CRh/CRi group and increased significantly after chemotherapy. Elevated pretreatment TBIL and IBIL were associated with longer overall survival (OS) (p < 0.05) and progression‐free survival (PFS) (p < 0.05). Pretreatment IBIL was an independent prognostic factor for OS (hazard ratio [HR], 0.47; 95% confidence interval [CI] 0.28–0.79; p < 0.05) and PFS (HR, 0.53; 95% CI 0.33–0.85; p < 0.05). Conclusion Elevated pretreatment IBIL levels are correlated with improved OS and PFS, acting as an independent favorable prognostic indicator for AML.

To compare the efficacy and safety of gecacitinib (also known as jaktinib) with hydroxyurea (HU) in treating myelofibrosis (MF) patients. In this multicenter, randomized phase 3 trial (ZGJAK016), intermediate- or high-risk primarily JAK inhibitor naïve MF patients were assigned in a 2:1 ratio to receive either gecacitinib (100 mg twice a day, BID) or HU (500 mg BID). The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) from baseline at week 24. Secondary endpoints included the best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile. At 24 weeks, the SVR35 was reached by 64.8% of patients on gecacitinib (46/71), compared to 26.5% on HU (9/34), P  = 0.0002. The best spleen response rates were also superior for gecacitinib at 81.7%, vs 32.4% for HU, P  < 0.0001. The TSS50 rates were 62.0% for gecacitinib- and 50% for HU-treated patients. Among non-transfusion-dependent patients with baseline hemoglobin (HGB) ≤ 100 g/L, 31.0% (13/42) in the gecacitinib group showed a ≥20 g/L increase in HGB, compared to 15.0% (3/20) in HU group. The common grade ≥ 3 treatment-emergent adverse events (TEAEs), including anemia (26.8% vs 44.1%), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%), were less frequent with gecacitinib than HU. Treatment discontinuation due to TEAEs was lower in gecacitinib (7.0%) compared to HU (11.8%). Gecacitinib demonstrates superior efficacy and a more favorable safety profile compared to HU, making it a promising treatment option for managing MF, particularly in patients with anemia (This trial was registered with ClinicalTrials.gov, (NCT04617028)).