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关键词： aryl hydrocarbon receptor   checkpoint control   gamma interferon   immunotoxicology   long noncoding RNA   lung cancer   polycyclic aromatic hydrocarbons  

摘要： Although immune checkpoint inhibitors show great promise, not all patients respond, and many do not achieve durable responses. Consequently, further investigations into potentially targetable molecules that regulate immune checkpoints are warranted. Previous studies in several cancers demonstrated that interferons produced by tumor-infiltrating leukocytes regulate immunosuppressive PD-L1, PD-L2, and IDO1 through JAK/STAT signaling. Here, we investigated a novel role for an immunosuppressive environmental chemical receptor, previously implicated in smoking-related cancers, in IFN signaling in human lung adenocarcinoma (LUAD) cells. Deletion of the aryl hydrocarbon receptor (AhR) from A549 LUAD cells significantly decreased baseline JAK2, STAT1, STAT3, IRF1 (a JAK/STAT target), PD-L1, PD-L2, and IDO1 expression. IFNy and IFNy increased the expression of JAK/STAT and immune checkpoint genes and proteins, but these increases were significantly diminished or absent in AhR-knockout cells. The AhR similarly controls IFN-induced, JAK/STAT-driven increases in multiple MHC class I- and class II-related genes. AhR control of type I and type II interferon signaling is mediated through up-regulation of an lncRNA, the IFNstimulated non-coding RNA 1 (INCR1), and through repression of an RNA-binding protein, heterogeneous nuclear STAT-related and immune checkpoint gene transcripts. The data suggest that the AhR is a key mediator of tumor immunosuppression through regulation of IFN-induced INCR1 and JAK/STAT signaling and, thereby, expression of immune checkpoints. However, that immunosuppression may be tempered by AhR control of MHC expression. Given the multiple roles of JAK/STAT signaling in the immune system, the results immunity.

关键词： melanoma   tetrandrine   MHC-I   autophagy   proteasome   TPC2 channel  

摘要： MHC-I-mediated antigen presentation is pivotal in antitumor immunity, enabling the recognition and destruction of tumor cells by CD8+ T cells. Both the proteasome and autophagy serve as essential cellular degradation mechanisms that regulate the stability and functionality of MHC-I molecules. In melanoma, modulating the pathways that affect MHC-I antigen presentation is pivotal and can profoundly influence the therapeutic outcomes of immunotherapy. Our initial effort of this study was a screening process to identify natural compounds capable of amplifying MHC-I surface expression on B16 melanoma cells. Utilizing flow cytometry with fluorescently tagged antibodies, we identified tetrandrine (Tet), a bisbenzylisoquinoline alkaloid derived from the root of Stephania tetrandra, as a potent enhancer of MHC-I-mediated antigen presentation in B16 melanoma cells. We demonstrate that tetrandrine (2.5, 5, 7.5 mu M) dose-dependently upregulates both surface and total MHC-I protein levels in B16 or A375 melanoma cells by simultaneously inhibiting autophagy and proteasomal activity, two key pathways involved in MHC-I degradation. This dual inhibition stabilizes MHC-I molecules, leading to enhanced tumor antigen presentation and improved recognition by CD8+ T cells. In co-culture systems, tetrandrine treatment increased CD8+ T cell activation and cytotoxicity against melanoma cells, evidenced by elevated IFN-gamma secretion and increased tumor cell apoptosis. Administration of tetrandrine (50 mgkg-1d-1, i.g., for 15 days) significantly suppressed melanoma growth in mouse models accompanied by increased CD8+ T cell infiltration and activation within the tumor microenvironment. Notably, tetrandrine synergized with anti-PD-1 immune checkpoint therapy, leading to enhanced tumor growth inhibition compared to either treatment alone. We revealed that tetrandrine (7.5 mu M) blocked the lysosomal calcium efflux channel TPC2, disrupting lysosomal calcium homeostasis

关键词： Reverse Shoulder Arthroplasty   mDSA   HDA   GDA   HLA   GLA   lateralization   distalization  

摘要： Background: The focus in reverse shoulder arthroplasty (RSA) has been on the lateralization and distalization of prosthesis positioning, influenced by implant design and surgical technique. There's no consensus on the optimal amount of lateralization and distalization or the best radiographic parameters for evaluating placement. This study examines the correlation and the predictive value between previously described modified distalization shoulder angle (DSA) and lateralization shoulder angle (LSA) with postoperative outcomes, which aim to differentiate the contributions of the humeral and glenoid components in the global distalization and lateralization of the RSA. The LSA was divided into the glenoid lateralization angle and the humeral lateralization angle;the modified distalization shoulder angle was divided into the glenoid distalization angle and the humeral distalization angle. Our hypothesis was that these new angles play a marginal role in predicting clinical outcomes. Materials and methods: Retrospective analysis of 83 RSA patients from 2017 to 2021 at San Pietro Fatebenefratelli Hospital, Rome. Angles were measured using true anteroposterior radiographs. Clinical outcomes were assessed using the Constant-Murley Score, a visual analog scale (VAS) for pain, and range of motion. Results: A weak correlation was found between the modified angles and clinical outcomes. Modified DSA (mDSA) correlated positively with internal rotation and negatively with VAS score. Glenoid distalization angle correlated positively with abduction, forward flexion, and Constant-Murley Score. Humeral distalization angle correlated positively with internal rotation and negatively with VAS. Glenoid lateralization angle and humeral lateralization angle showed negative correlation with internal rotation and positive correlation with VAS. Conclusion: Modified DSA and LSA show marginal correlation with postoperative outcomes and have limited predictive value. Further research with larger

关键词： K & imath   z & imath   l & imath   rmak   Ye & scedil   il & imath   rmak   Macroinvertebrates   Black Sea   River mouth   Estuary  

摘要： This study investigates the K & imath;z & imath;l & imath;rmak and Ye & scedil;ilirmak estuarine ecosystems in Turkey, which provide significant freshwater and nutrient inputs to the Samsun Shelf area along the midsouthern Black Sea. The objective was to determine the current ecological status and to detect any significant differences between two estuarine ecosystems (restored-K & imath;z & imath;l & imath;rmak-and natural-Ye & scedil;il & imath;rmak) in terms of macrobenthic invertebrates and environmental variables. Macrobenthic invertebrates were collected with a 500 mu m mesh size kick-net. A total of four samplings, one in each season, were collected during February, May, August, and November of 2017. A total of 90 taxa, mainly oligochaetas and chironomids, were identified, composed of 51 species in K & imath;z & imath;l & imath;rmak and 60 in Ye & scedil;il & imath;rmak. Orthocladius (Orthocladius) dentifer, O. (O.) clarkei, O. (O.) dorenus, O. (O.) wetterenesis, O. (O.) mixtus, and Mystacides longicornis were found to be new records for Turkey. The distribution of macrobenthic invertebrates was compared between season, estuary, grain size and stations. In K & imath;z & imath;l & imath;rmak and Ye & scedil;il & imath;rmak, the region characterized as estuarine was found to be small transitional waters. In K & imath;z & imath;l & imath;rmak, a high similarity was observed among stations, accompanied by relatively low diversity across sampling sites. This phenomenon is thought to be a natural consequence of the reconstruction activities along the river, which have deleteriously affected the ecosystem. The Ye & scedil;il & imath;rmak estuary has a more diverse macrobenthic community and appeared to be better preserved than the K & imath;z & imath;l & imath;rmak area.

关键词： Mosquitoes   Granulocytes   Plasmodium   Hemocytes   Malarial parasites   Oocysts   Parasitic diseases   Malaria  

摘要： Tumor Necrosis Factor-alpha (TNF-alpha) is a proinflammatory cytokine and a master regulator of immune cell function in vertebrates. While previous studies have implicated TNF signaling in invertebrate immunity, the roles of TNF in mosquito innate immunity and vector competence have yet to be functionally explored. Herein, we confirm the identification of a conserved TNF-alpha pathway in Anopheles gambiae consisting of the TNF-alpha ligand, Eiger, and its cognate receptors Wengen and Grindelwald. Through gene expression analysis, RNAi, and in vivo injection of recombinant TNF-alpha, we provide direct evidence for the requirement of TNF signaling in regulating mosquito immune cell function by promoting granulocyte midgut attachment, increased granulocyte abundance, and oenocytoid rupture. Moreover, our data demonstrate that TNF signaling is an integral component of anti-Plasmodium immunity that limits malaria parasite survival. Together, our data support the existence of a highly conserved TNF signaling pathway in mosquitoes that mediates cellular immunity and influences Plasmodium infection outcomes, offering potential new approaches to interfere with malaria transmission by targeting the mosquito host.

关键词： Antioxidant   COX-2   Docking   Neuroprotective   NLRP3   Piperazine   Scopolamine   TNF-alpha  

摘要： Oxidative stress-induced neuro-inflammatory events are common in neurodegenerative illnesses, addressing neuro-inflammation and oxidative distress could be an effective approach for ameliorating the typical effects associated with scopolamine-induced neurodegeneration. Elevated levels of tumor necrosis factor-alpha (TNF-alpha), nuclear factor-B (p-NF-B), and pyrin domain-containing protein 3 were associated with changes in antioxidant enzyme levels NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3). The present study aimed to synthesize a series of piperazine derivatives and evaluate their neuroprotective effects in mice with scopolamine-induced learning and memory impairments. The synthesized derivatives 2(a-i) were characterized spectroscopically using proton NMR (H-1-NMR) and carbon-13 NMR which were then tested for their antioxidant potential. Based on the strong antioxidant activity of compounds 2b, 2f and 2h were selected for further investigation of their neuroprotective potential. The result of the study indicated the neuroprotective role of 2b, 2f, and 2h which reduced neuro-inflammation, oxidative stress, and memory impairment. Among these three derivatives 2h significantly reduced the elevated level of cyclooxygenase-2 (COX-2, p-NF-B, and TNF-alpha). Molecular docking analysis supported our hypothesis by showing strong binding affinity of all synthesized compounds with selected targets (COX-2 and TNF-alpha). Overall, our findings suggest that these derivatives could serve as lead compounds for further drug development aimed at controlling neuro-inflammation and neurodegeneration.

摘要： Background Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy. Methods FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end-point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV1, time-to-first COPD composite exacerbation event and safety. Results The intent-to-treat population included 135 patients (tozorakimab, n=67;placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV1 (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI)-15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV1 (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements versus placebo in change from baseline in pre-bronchodilator FEV1 (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV1 (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated. Conclusion Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of pa

关键词： CTL   lipopeptide   MHC class I   TAP  

摘要： A novel subset of classical major histocompatibility complex class I molecules has recently been identified in rhesus monkeys that mediates the presentation of N-myristoylated lipopeptides, rather than conventional peptides, to CD8+ cytotoxic T lymphocytes (CTLs). For example, the rhesus Mamu-B*098 allomorph binds an N-terminal 5-mer fragment (C14 fatty acid-Gly-Gly-Ala-Ile-Ser;C14nef5) derived from the N-myristoylated SIV Nef protein and activates C14nef5-specific CTLs. Additionally, a transporter for antigen presentation (TAP)-independent cell-surface expression was observed for Mamu-B*098 in the in vitro transfection experiments, leading us to hypothesize that TAP-independent pathways may exist for CTL activation. To address this directly, we generated transgenic mice expressing Mamu-B*098 and analyzed its function under TAP-deficient conditions. We first confirmed that its expression level was unchanged on the surface of TAP-deficient cells compared with that of TAP-sufficient cells. Second, the CD8+ T cell population, but not the CD4+ T cell population, increased in TAP knockout (KO) mice as a result of the acquisition of Mamu-B*098 expression. Third, C14nef5-specific, Mamu-B*098-restricted CD8+ T cells were readily inducible in Mamu-B*098 transgenic/TAP KO but not in nontransgenic/TAP KO mice. Finally, the CD8+ T cells expressed cytolytic granule contents and functioned as CTLs. These findings provide evidence that in addition to conventional peptide-specific CTL responses that require TAP, an alternative TAP-independent pathway for CTL activation exists in primates. This novel pathway may be valuable when TAP is targeted by pathogenic viruses for immune evasion. We propose that the established concept of major histocompatibility complex class I biology may require modifications to incorporate TAP-independent pathways of lipopeptide-specific CTL responses.

关键词： IFN-γ   helminth   microbiota   intestinal immunity   stroma   neutrophils  

摘要： IFN-gamma function during a type-2 helminth infection remains enigmatic. Westfall et al. found an unexpected role for IFN-gamma in limiting tissue damage during intestinal infection by Heligmosomoides polygyrus bakeri (Hpb). IFN-gamma produced by CD8+ T cells stimulates stromal cells directly to recruit neutrophils, where they prevent tissue damage caused by the worms.