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Tolerogenic dendritic cells (tol-DCs) play essential roles in immune-related diseases and induce immune tolerance by shaping T-cell responses. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in the immune system. However, the potential roles and underlying mechanisms of lncRNAs in tol-DCs remain unclear. RNA in-situ hybridization, histochemistry, and qRT-PCR were performed to determine the distribution and expression of NEAT1 in DCs. Flow cytometry was used to analyze the tolerogenic function of DCs. Small sequencing, followed by bioinformatic analysis, was performed to determine the target genes of NEAT1. The mechanism of NEAT1 was explored using a luciferase reporter, chromatin immunoprecipitation assays, and Immunofluorescence. experiments were used to investigate the induction of immune tolerance via NEAT1-knockdown DCs. Our results show that lncRNA NEAT1 can induce tolerogenic phenotype in DCs. Mechanistically, small RNA-seq analysis revealed that NEAT1 knockdown preferentially affected the expression of miR-3076-3p. Furthermore, NEAT1 used the NLRP3 inflammasome as a molecular decoy for miR-3076-3p, thus facilitating the expression of tolerogenic phenotype in DCs. Moreover, the transcription factor E2F1 acted as a repressor of NEAT1 transcription via activity of H3K27ac. Our results also indicate that NEAT1 knockdown in DCs can induce immune tolerance in models of experimental autoimmune myocarditis and heart transplantation. Taken together, our study shows the mechanism used by NEAT1 in inducing tol-DCs and highlights the therapeutic potential of targeting NEAT1 for the treatment of immune-related diseases.

In recent years, significant progress has been made in lung cancer treatment paradigms with the continuous unraveling of the tumor microenvironment and the ongoing advancement of immunotherapy. As an emerging immunotherapy modality, Immune Cell Engagers (ICEs) aim to effectively mobilize the body’s antitumor immune response by targeting tumors and activating immune effector cells such as T cells, NK cells, and myeloid cells. Recent studies have indicated that T-cell engagers (TCEs), exemplified by bispecific T-cell engagers (BiTEs), can enhance T-cell immunological activity within the lung cancer microenvironment and demonstrate significant antitumor effects in both in vitro and in vivo experiments. However, the highly heterogeneous nature of the lung cancer microenvironment and its complex immunosuppressive networks limit the therapeutic efficacy of ICEs. Meanwhile, key challenges remain in improving target cell specificity, lowering toxicity to non-target cells, and optimizing pharmacokinetics. This review systematically summarizes the mechanisms of action and recent advances of ICEs in lung cancer immunotherapy, explores innovative development directions for next-generation ICEs, and highlights their significant potential in driving paradigm shifts in lung cancer immunotherapy.

The aging process and age‐related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain‐derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno‐associated virus (AAV)‐mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet‐induced and genetic models. Here we examined the efficacy and safety of a built‐in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle‐aged mice. Twelve‐month‐old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging‐associated metabolic declines characterized by: preventing aging‐associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety‐like and depression‐like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.

By shaping T cell immunity, tolerogenic dendritic cells (tDCs) play critical roles in the induction of immune tolerance after transplantation. However, the role of long noncoding RNAs (lncRNAs) in the function and immune tolerance of dendritic cells (DCs) is largely unknown. Here, we found that the lncRNA MALAT1 is upregulated in the infiltrating cells of tolerized mice with cardiac allografts and activated DCs. Functionally, MALAT1 overexpression favored a switch in DCs toward a tolerant phenotype. Mechanistically, ectopic MALAT1 promoted dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) expression by functioning as an miR155 sponge, which is essential for the tolerogenic maintenance of DCs and the DC-SIGN-positive subset with more potent tolerogenic ability. The adoptive transfer of MALAT1-overexpressing DCs promoted cardiac allograft survival and protected from the development of experimental autoimmune myocarditis, accompanied with increasing antigen-specific regulatory T cells. Therefore, overexpressed MALAT1 induces tDCs and immune tolerance in heart transplantation and autoimmune disease by the miRNA-155/DC-SIGH/IL10 axis. This study highlights that the lncRNA MALAT1 is a novel tolerance regulator in immunity that has important implications in settings in which tDCs are preferred.

Background Human norovirus (HNV) is the predominant pathogen causing outbreaks of acute gastroenteritis globally. Despite significant efforts to combat norovirus infections, there is currently no FDA approved vaccine or antiviral drug available. Consequently, the development of effective antiviral agents is of critical importance. Methods and results In this study, a series of 41 5-cyano-2-thiacetyl aromatic pyrimidinone compounds were designed and synthesized. A cell viability-based screening for anti-murine norovirus (MNV) compounds was conducted, revealing that compound 29 (hereafter used as Co-29) exhibited antiviral activity against MNV. Co-29 demonstrated effective inhibition of MNV CW3 RNA replication, exhibiting an EC 50 of 58.22 μM. An RdRp enzyme activity assay indicated that Co-29 directly inhibits RdRp activity to both MNV and HNV. Molecular docking studies suggested that Co-29 interacts with the palm region of RdRp via hydrogen bonding with specific residues, which are conserved in RdRps across MNV and HNV norovirus variants. Conclusions In conclusion, our study suggests that the newly synthesized Co-29 may serve as a potential antiviral candidate or lead compound for future studies.

Metastasis remains one of the greatest challenges involved in treating gastric cancer (GC). Ropivacaine (Rop) is not only a well-documented local anesthetic medicament but also has been reported to exert an antitumor role in cancer development. This study explored the effects of ropivacaine on the growth, migration and invasion of gastric cancer and the underlying mechanisms. Cell Counting Kit-8 (CCK8) assay was conducted to test the effect of Rop on the proliferation of AGS and BGC-823 GC cells. Moreover, cell apoptosis, migration and invasion were examined by flow cytometry and transwell assay, respectively. The expression of miR-520a-3p was determined by qRT-PCR. miRNA targeting sites were analyzed using bioinformatics analysis and dual-luciferase reporter assay. Protein levels of WEE1 and PI3K/AKT were detected by Western blot. Furthermore, the tumor-forming experiment of nude mice was used to detect the growth of cells in vivo. Rop inhibited proliferation but promoted apoptosis of GC cells. Besides, the migration and invasion of GC cells were also inhibited by Rop. Moreover, miR-520a-3p expression was enhanced by Rop, and transfection with miR-520a-3p mimic decreased cell proliferation, migration and invasion. The upregulation of miR-520a-3p was partly contributed to the inhibitory effect of ropivacaine on GC cell lines. Finally, Rop inactivated WEE1 and PI3K/AKT pathway via upregulation of miR-520a-3p. Our results suggested that Rop decreased growth, migration and invasion of GC cells via regulating miR-520a-3p expression and further inactivated WEE1 and PI3K/AKT signaling pathways.

Background The unique mechanism of diabetic atherosclerosis has been a central research focus. Previous literature has reported that the inflammatory response mediated by dendritic cells (DCs) plays a vital role in the progression of atherosclerosis. The objective of the study was to explore the role of DCs in diabetes mellitus complicated by atherosclerosis. Methods ApoE −/− mice and bone marrow-derived DCs were used for in vivo and in vitro experiments, respectively. Masson’s staining and Oil-red-O staining were performed for atherosclerotic lesion assessment. The content of macrophages and DCs in plaque was visualized by immunohistochemistry. The expression of CD83 and CD86 were detected by flow cytometry. The fluctuations in the RNA levels of cytokines, chemokines, chemokine receptors and adhesions were analyzed by quantitative RT-PCR. The concentrations of IFN-γ and TNF-α were calculated using ELISA kits and the proteins were detected using western blot. Coimmunoprecipitation was used to detect protein–protein interactions . Results Compared with the ApoE −/− group, the volume of atherosclerotic plaques in the aortic root of diabetic ApoE −/− mice was significantly increased, numbers of macrophages and DCs were increased, and the collagen content in plaques decreased. The expression of CD83 and CD86 were significantly upregulated in splenic CD11c + DCs derived from mice with hyperglycemia. Increased secretion of cytokines, chemokines, chemokine receptors, intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) also were observed. The stimulation of advanced glycation end products plus oxidized low-density lipoprotein, in cultured BMDCs, further activated toll-like receptor 4, protein kinase C and receptor of AGEs, and induced immune maturation of DCs through the RAGE-TLR4-PKCβ 1 signaling pathway that was bound together by intrinsic structures on the cell membrane. Administering LY333531 significantly increased the body weight of diabetic ApoE −/− mice, inhibited the immune maturation of spleen DCs, and reduced atherosclerotic plaques in diabetic ApoE −/− mice. Furthermore, the number of DCs and macrophages in atherosclerotic plaques was significantly reduced in the LY333531 group, and the collagen content was increased. Conclusions Diabetes mellitus aggravates chronic inflammation, and promotes atherosclerotic plaques in conjunction with hyperlipidemia, which at least in part through inducing the immune maturation of DCs, and its possible mechanism of action is through the RAGE-TLR4-pPKCβ 1 signaling pathway.

Objective Vulnerable plaques with fibrous cap thickness (FCT) of ≤65 μm are prone to rupture and/or thrombosis. However, plaques with FCT > 65 μm cause acute myocardial infarction and even sudden death. We aimed to investigate the relationship between 65 < FCT ≤ 80 μm and plaque rupture and/or thrombosis using optical coherence tomography (OCT). Methods OCT was performed on culprit lesions in 502 consecutively enrolled patients to identify FCT. Patients were classified into three groups according to FCT: Group A (FCT ≤ 65 μm, n  = 147), Group B (65 < FCT ≤ 80 μm, n  = 84) and Group C (FCT > 80 μm, n  = 271). Clinical and laboratory data was collected from the inpatient medical record system. Results Plaques with thinner FCT, especially < 65 μm, were more susceptible to rupture and/or thrombosis ( P  < 0.001). Plaques with FCT between 65 and 80 μm had a higher probability of rupture and/or thrombosis than those with FCT > 80 μm ( P  < 0.001). In multivariable analysis, FCT ≤ 65 μm and 65 < FCT ≤ 80 μm were independent predictors for plaque rupture ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 8.082, 95% CI = 4.861 to 13.435, P  < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 2.463, 95% CI = 1.370 to 4.430, P  = 0.003), thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 25.224, 95% CI = 13.768 to 46.212, P  < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 3.675, 95% CI = 2.065 to 6.542, P  < 0.001) and plaque rupture with thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 22.593, 95% CI = 11.426 to 44.674, P  < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 4.143, 95% CI = 1.869 to 9.184, P  < 0.001). Conclusions OCT-assessed 65 < FCT ≤ 80 μm was independently associated with increased risk of plaque rupture and/or thrombosis compared with FCT > 80 μm.

It is challenging to genetically manipulate fat in adults. We demonstrate that intraperitoneal (i.p.) injection of an engineered adeno-associated virus (AAV) serotype Rec2 leads to high transduction of multiple visceral fat depots at a dose of 1 to 2 orders lower than commonly used doses for systemic gene delivery. To target adipose tissue, we develop a single AAV vector harboring two expression cassettes: one using the CBA promoter to drive transgene expression and one using the liver-specific albumin promoter to drive a microRNA-targeting WPRE sequence that only exists in this AAV vector. This dual-cassette vector achieves highly selective transduction of visceral fat while severely restricting off-target transduction of liver. As proof of efficacy, i.p. administration of an adipose-targeting Rec2 vector harboring the leptin gene corrects leptin deficiency, obesity, and metabolic syndromes of / mice. This study provides a powerful tool to genetically manipulate fat for basic research and gene therapies of genetic and acquired diseases.

Viral-mediated gene therapy presents many challenges in the clinic, including the potential for physiological effects that overshoot the intended goals. In a new report by Matthew During and his colleagues, the authors devise a scheme by which packaging of a microRNA into the virus, expressed under the control of a physiological response induced by the viral transgene, allows coordinated dampening of the transgene expression when the therapeutic response achieves a certain threshold. Hypothalamic brain-derived neurotrophic factor (BDNF) is a key element in the regulation of energy balance. Here we investigated the therapeutic efficacy of BDNF by gene transfer in mouse models of obesity and diabetes. Gene transfer of BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure that BDNF protein expression was appropriately decreased as weight loss progressed, thus preventing cachexia, we developed a molecular autoregulatory system involving a single recombinant adeno-associated virus vector harboring two expression cassettes, one constitutively driving BDNF and the other driving a specific microRNA targeting BDNF . The microRNA element was controlled by a promoter (that controlling the Agrp gene encoding agouti-related peptide) responsive to BDNF-induced physiological changes. Hence, as body weight decreased and agouti-related protein is induced, microRNA expression was activated, inhibiting transgene expression. In contrast to the progressive weight loss associated with a nonregulated approach, this microRNA-approach led to a sustainable plateau of body weight after notable weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms, thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.