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关键词： NLRP3 inflammasome   NEK7   NLRP3-NEK7   Inhibitors  

摘要： Aberrant activation of NLRP3 inflammasome is involved in various inflammatory diseases, making it a promising target for therapeutic intervention. NEK7, a member of the NIMA-related kinase (NEK) family, functions as a key NLRP3-binding protein and plays a crucial role in the regulation of NLRP3 inflammasome assembly and activation. Thus, disrupting NLRP3-NEK7 interactions by targeting NEK7 could be a promising strategy to inhibit the activation of NLRP3 inflammasome. In this work, a series of novel urea derivatives were designed and synthesized based on the reported NEK7 inhibitors. Among these, compound 23 exhibited potent activity against IL-1/3 release with low cytotoxicity. Moreover, compound 23 enhanced the thermal stability of NEK7 and disrupted the NLRP3-NEK7 interaction, thereby regulating NLRP3 inflammasome assembly.

摘要： Immunotherapy has emerged as a powerful strategy for combating cancer by harnessing the patient immune system to recognize and eliminate malignant cells. The major histocompatibility complex class I (MHC-I) has a pivotal role in the recognition step. These surface proteins present cancer-specific neoantigens to CD8+ T cells, which triggers activation and T cell-mediated killing. However, cancer cells can often evade immune detection by downregulating MHC-I surface expression, which renders the immune response less effective. In turn, this resistance mechanism offers an opportunity to bolster MHC-I surface expression therapeutic interventions. Here, we conducted an initial comprehensive evaluation of previously purported small molecule MHC-I inducers and identified heat shock protein 90 (Hsp90) inhibitors as privileged inducers of MHC-I surface expression. With a core scaffold in hand, we employed an click chemistry-based derivatization strategy to generate 380 novel compounds in the same family. New agents from this library showed high levels of induction, with one of the triazole-based analogs, , also enhancing T cell activation and exhibiting lower toxicity, which could potentiate some immunotherapeutic modalities. Moreover, we demonstrated the potential of a click chemistry-based diversification strategy for the discovery of small molecules to counter immune evasion.

关键词： IFN beta   ferroptosis   cGAS-STING   TRIM22   RSL3  

摘要： Background Cyclic GMP-AMP synthase (cGAS)-stimulator-of-interferon genes (STING) pathway is a cytosolic DNA sensor system. The production of this pathway, interferon-beta (IFN beta), could suppress the growth of tumor cells, yet it is unclear whether ferroptosis is involved in IFN beta-induced cell *** The effects of IFN beta on ferroptosis were analyzed in HT1080, 4T1, HCT116 and 786-O cells. HT1080 and 4T1 cells treated with IFN beta were subjected to RNA-Seq analysis. STAT1, STAT3, TRIM21, and TRIM22 were silenced by siRNAs to examine their effects on IFN beta-induced ferroptosis. The cGAS-STING signaling pathway-activated mice were used to evaluate the effects of IFN beta on ferroptosis in vivo. HT1080 cells, three-dimensional (3D) spheroids, and the xenograft mouse models were treated with IFN beta, RSL3, or IFN beta combination with RSL3 to analyze whether IFN beta enhances RSL3-induced *** Here, we found that IFN beta could promote intracellular Fe2+ and lipid peroxidation levels, and decrease GSH levels in tumor cells. RNA sequencing data revealed that IFN beta induced a transcriptomic disturbance in ferroptosis-related genes. Knockdown of tripartite motif-containing 22 (TRIM22) suppressed the levels of intracellular Fe2+ and lipid ROS. It also reduced heme oxygenase (HMOX1) protein levels and increased ferroptosis suppressor protein 1 (FSP1) levels in HT1080 cells treated with IFN beta. Furthermore, our results illustrated that IFN beta enhanced the RAS-selective lethal 3 (RSL3)-induced ferroptosis and the inhibitory effect of RSL3 on GPX4. Meanwhile, compared to the groups treated with either IFN beta or RSL3 alone, the combination treatment of IFN beta and RSL3 significantly inhibited the growth of HT1080 three-dimensional (3D) spheroids and tumor in a mouse xenograft *** Our work reveals a role for IFN beta in promoting ferroptosis and provides evidence that IFN beta could be used with RSL3 to increase cytotoxic ef

摘要： The standard of care in high-grade gliomas has remained unchanged in the past 20 years. Efforts to replicate effective immunotherapies in non-cranial tumors have led to only modest therapeutical improvements in glioblastoma (GB). Here, we demonstrate that intratumoral administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8 T cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical GB mouse models. This tumor-reactive CD8 T cell response is further supported by intratumoral rIL-12-sensing dendritic cells (DCs) and is accompanied by the co-stimulatory receptor 4-1BB expression on both cell types. Given that DCs and CD8 T cells are functionally suppressed in the tumor microenvironments of and recurrent glioma patients, we tested whether anti-tumor response at the rIL-12-inflamed tumor site could be enhanced with 4-1BBL, the ligand of 4-1BB. 4-1BBL was delivered using an adeno-associated virus (AAV) vector targeting GFAP-expressing cells and resulted in prolonged survival of rIL-12 treated GB-bearing mice. This study establishes that tumor antigen-specific CD8 T cell activity can be directed using an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity.

关键词： Edaravone dexborneol   Cerebral small vessel disease   Pericyte   Extracellular matrix   Fibrosis  

摘要： BackgroundChronic cerebral hypoperfusion (CCH) is a critical pathophysiological mechanism underlying cerebral small vessel disease (CSVD). Accumulating evidence have demonstrated that resident pericytes and deposit extracellular matrix (ECM) and play a key role in mediating fibrosis in hypoxic changes. Edaravone dexborneol (EDB) is known to target multiple pathways involved in *** constructed the CCH mouse models that were subjected to either PBS or EDB at different concentrations. Measures of cognitive function, neuronal damage, white matter lesion (WML), the fibrous profiles of pericytes and ECM protein were investigated to assess the effect of EDB. RNA sequencing of OGD in pericytes was performed to identify a key signaling *** observed that both medium and high concentrations of EDB could ameliorate CCH-induced cognitive impairment and emotional disorders. Neuronal damage in cortical layer and hippocampus and WML in corpus callosum were improved by EDB, which was consistent with the tends of fibrous pericytes and ECM proteins in these regions. RNA sequencing suggested that TGF-beta 1/IL-11 plays an important role in mechanism of pericytes fibrosis. Subsequently, the results of sequencing were confirmed in both cellular and mouse *** findings reveal the role of pericyte-mediated fibrosis in depositing ECM in the pathogenesis of CSVD. EDB could improve symptoms and the underlying pathogenesis of CCH mice and decrease the expression of the fibrous profiles of pericytes and ECM proteins, which may be regulated by TGF-beta 1/ IL-11. EDB treatment, targeting pericytes fibrosis, may be a novel therapeutic strategy for CSVD.

关键词： CCR7   CD25   Integrin   Interleukin 2   T cell biology   chemokine receptor   heparan sulfate   signaling  

摘要： IL-2, a central regulator of immune function, binds to its receptor subunit CD25 (IL-2Rα), promoting IL-2 interaction with β and γ subunits to trigger the canonical IL-2 signaling pathway. An anti-mouse CD25 antibody, PC61, triggers alternative IL-2 signaling, leading to integrin activation. PC61 induces a complex formed by the IL-2-dependent association of CD25 with CCR7, suggesting that the formation of this complex initiates alternative IL-2 signaling. Here, we used structure-based design together with combinatorial screening to identify an IL-2 mutant (denoted IL-2(E52K)) that spares canonical IL-2 signaling but disrupts both PC61-induced complex formation and integrin activation while retaining the full CD25 affinity of the parent molecule. We also report that heparan sulfate (HS), a physiological ligand of IL-2 that triggers alternative signaling, induced IL-2-dependent CD25-CCR7 association, whereas IL-2(E52K) failed to support both HS-induced CD25-CCR7 complex formation and integrin activation. Thus, both anti-CD25 antibody and HS require common features of IL-2 needed for CD25-CCR7 complex assembly and resulting integrin activation. Collectively, these data show that IL-2 promotes CD25 interaction with CCR7, thereby forming the signal initiating complex. Furthermore, canonical and alternative IL-2 signaling can be decoupled by an IL-2 mutation, creating a tool to specify the biological role of alternative IL-2 signaling in immune responses.

关键词： COVID-19   Clinical trials   Immunotherapy   Infectious disease  

摘要： BACKGROUND. Lymphopenia and failure of lymphocytes to mount an early IFN-gamma response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function. METHODS. We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality. RESULTS. CYT107 was well tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without a significant difference between CYT107 and placebo. Patients with COVID-19 receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (P = 0.067). There were significantly fewer treatment-emergent adverse events in CYT107versus placebo-treated patients (P < 0.001), consistent with a beneficial drug effect. Importantly, CYT107-treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (P = 0.014). CONCLUSION. Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections.

关键词： ischemic stroke   IL-3/IL-3Rα cross talk   VEGFDNEGFR3   astrocytes   microglia   neuroinflammation  

摘要： Astrocyte-derived IL-3 activates the corresponding receptor IL-3Rα in *** cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer's disease in *** this study we investigated the role of IL-3/IL-3Rα cross-talk and its regulatory mechanisms in ischemic *** stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery(MCA)for 60 min followed by reperfusion(I/R).Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation(OGD/Re)were used as in vitro models of brain *** showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3Rα protein levels,accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type ***,astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells,thereby mediating neuronal cell *** using metabolomics and multiple biochemical approaches,we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A,a rate-limiting enzyme for the mitochondrial β-oxidation,and increased levels of glycerophospholipids,the major components of cellular membranes,causing reduced accumulation of lipid droplets,thus reduced pro-inflammatory activation and necrosis,as well as increased phagocytosis of ***,exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3Rα,improving microglial lipid metabolic levels via upregulation of CPT1A,restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation,ultimately contributing to brain recovery from I/R *** results demonstrate that VEGFDNEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives pro-inflammato

摘要： Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Furthermore, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-alpha 4(37 improve gut barrier functions, and we hypothesized that combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups;however, dual-treated RMs showed slightly better control of viral replication at the latest time points afterATI. Additionally, following ATI, dual-treated RMs showed immunological benefits, including T cell preservation and lower PD-1+ central memory T cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) after ATI. Finally, 16S rRNA-Seq revealed better recovery from dysbiosis in treated animals, and the butyrate- producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-alpha 4(37 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.