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Macrophage polarization facilitates the inflammatory response and intensified fibrosis in the silicosis microenvironment by a mechanism related to macrophage pyroptosis, although the upstream target remains poorly defined. Currently, there are few reports on the development of drugs that alleviate macrophage polarization by dampening pyroptosis. The present study aims to explore the mechanics of silica mediating macrophage polarization and to investigate whether quercetin (Que) can depolarize macrophages with this mechanism. Silica processing led to prominent M1 polarization of macrophages. Additionally, significant macrophage polarization could be detected in the lung tissue of mice with airway-perfused silica. Further investigation turned out that pronounced mitochondria damage, mtDNA cytoplasmic ectomy, and pyroptosis occurred in response to silica. Nevertheless, Que treatment could effectively attenuate silica-induced mitochondria damage and pyroptosis as demonstrated in vitro and in vivo. Further exploration presented Que could bind to TOM70 and restore silica-induced mitochondrial damage. More importantly, the M1 polarization of macrophage was depressed with the co-treatment of Que and silica, wherein the inflammatory response and pulmonary fibrosis were also mitigated without obvious damage to vital organs. In conclusion, these findings proved that silica leads to mitochondrial damage, thereby evoking pyroptosis and promoting macrophage M1 polarization. Que could bind to TOM70 and restore its function, suppressing mitochondrial damage and pyroptosis, and depolarizing macrophages to reduce fibrosis, which provides a promising strategy for silicosis treatment in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of exosomes and microRNA (miRNA) from placental mesenchymal stem cells on chemotherapy-damaged ovarian granulosa cells. Methods: Various public databases were searched for miRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene. After miRNA transfection into human ovarian granulosa cells, cell growth and expressions of the target miRNA and PTEN were detected. Cisplatin was utilized to induce damage to human ovarian granulosa cells, which were subsequently co-cultured with human placental mesenchymal stem cells and exosomes generated from mesenchymal stem cells, then apoptosis and expressions of PTEN and the target miRNA were detected. Results: After analyzing several databases, miRNA 139-5p (miR-139-5p) was chosen as the target miRNA for this research. Transfection of miR-139-5p mimics into human ovarian granulosa cells elevated miR-139-5p expression level (9 882.080±1 049.130), reduced PTEN protein expression level (0.78±0.11), and increased cell proliferation absorbance (0.85±0.07). Cisplatin treatment severely damaged human ovarian granulosa cells and increased apoptosis, cisplatin-treated cells had a higher apoptosis ratio compared to untreated cells [ (41.9±1.0)% vs (5.0±0.3)%, P <0.001]. In damaged human ovarian granulosa cells, co-cultured with human placental mesenchymal stem cells and exosomes increased miR-139-5p expression levels (1.31±0.04 and 1.20±0.03, respectively) and decreased apoptosis ratios [(20.0±0.4)% and (22.3±1.1)%, respectively]. Conclusion: Placental mesenchymal stem cell-derived exosomes repair damages of cisplatin-induced ovarian granulosa cell and could target PTEN gene through miR-139-5p, which might be a potential option for the treatment of chemotherapy-induced ovarian dysfunction.

Background: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer., Methods: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors., Results: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, β-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis., Conclusion: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methods: Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action., Results: CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3)., Conclusion: The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs., (© 2024. The Author(s).)

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Increasing evidence indicated that neuroinflammation was involved in progression of Parkinson's disease (PD). Long noncoding RNAs (lncRNAs) played important roles in regulating inflammatory processes in multiple kinds of human diseases such as cancer diabetes, cardiomyopathy, and neurodegenerative disorders. The mechanisms by which lncRNAs regulated PD related inflammation and dopaminergic neuronal loss have not yet been fully elucidated. In current study, we intended to explore the function and potential mechanism of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in regulating inflammasome activation in PD. Functional assays confirmed that knockdown of KCNQ1OT1 suppress microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and attenuated dopaminergic neuronal loss in PD model mice. As KCNQ1OT1 located in both cytoplasm and nucleus of microglia, we demonstrated that KCNQ1OT1 promoted microglial NLRP3 inflammasome activation by competitive binding with miR-186 in cytoplasm and inhibited pri-miR-186 mediated NLRP3 silencing through recruitment of DiGeorge syndrome critical region gene 8 (DGCR8) in nucleus, respectively. Our study found a novel lncRNA-pri-miRNA/mature miRNA-mRNA regulatory network in microglia mediated NLRP3 inflammasome activation and dopaminergic neuronal loss, provided further insights for the treatment of Parkinson's disease., Competing Interests: Declaration of competing interest All the authors of this paper declare no conflicts of interests., (Copyright © 2024. Published by Elsevier B.V.)

Yaks live in the Qinghai-Tibet Plateau for a long time where oxygen is scarce, but can ensure the smooth development of testis and spermatogenesis. The key lies in the functional regulation of the Sertoli cells under hypoxia. In this study, we sequenced yak Sertoli cells cultured in normal oxygen concentration (Normoxia) and treated with low oxygen concentration (Hypoxia) by whole transcriptomics, and screened out 194 differentially expressed mRNAs (DEmRNAs), 934 differentially expressed LncRNAs (DELncRNAs) and 129 differentially expressed miRNAs (DEmiRNAs). GO and KEGG analysis showed that these differential genes were mainly concentrated in PI3K-AKT, MAPK, RAS, and other signaling pathways, and were associated with glucose metabolism, tight junction, steroid hormone synthesis, cell fusion, and immunity of yak Sertoli cells. We constructed the gene interaction network of yak Sertoli cells in hypoxia and screened out the relationship pairs related to glucose metabolism and tight junction. The results suggested that the changes in energy metabolism, tight junction, and immune regulation of yak Sertoli cells under hypoxia might provide favorable conditions for spermatogenesis. This study provides data for further study on the role of non-coding RNA in testis development and spermatogenesis of yak., (© 2024. The Author(s).)

Intervertebral disc degeneration (IVDD) is a prevalent chronic condition causing spinal pain and functional impairment. This study investigates the role of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in regulating IVDD. Using RNA-seq, we analyzed differential expressions of lncRNA and miRNA in nucleus pulposus tissues from various mouse groups. We identified key regulatory molecules, MALAT1 and miRNA-138-5p, which contribute to IVDD. Further experiments demonstrated that MALAT1 can up-regulate SLC7A11 expression by competitively binding to miR-138-5p, forming a MALAT1/miR-138-5p/SLC7A11 coexpression regulatory network. This study elucidates the molecular mechanism by which hUCMSC-derived EVs regulate IVDD and could help develop novel therapeutic strategies for treating this condition. Our findings demonstrate that hUCMSCs-EVs inhibit ferroptosis in nucleus pulposus cells, thereby improving IVDD. These results highlight the therapeutic potential of hUCMSCs-EVs in ameliorating the development of IVDD, offering significant scientific and clinical implications for new treatments.

Objectives: To investigate the structural characteristics of intestinal flora in children with sepsis and its association with inflammatory response., Methods: A prospective cohort study was conducted. The children with sepsis who were admitted from December 2021 to January 2023 were enrolled as the sepsis group, and the children with non-sepsis who were admitted during the same period were enrolled as the non-sepsis group. The two groups were compared in terms of the distribution characteristics of intestinal flora, peripheral white blood cell count (WBC), C reactive protein (CRP), and cytokines, and the correlation of the relative abundance of fecal flora with WBC, CRP, and cytokines was analyzed., Results: At the genus level, compared with the non-sepsis group, the sepsis group had significantly lower relative abundance of Akkermansia , Ruminococcus , and Alistipes and significantly higher relative abundance of Enterococcus , Streptococcus , and Staphylococcus ( P <0.05). At the phylum level, Proteobacteria was the dominant phylum (37.46%) in the group of children with a score of ≤70 from the Pediatric Critical Illness Score (PICS), and Firmicutes was the dominant phylum in the group of children with a score of 71-80 or 81-90 from the PICS (72.20% and 43.88%, respectively). At the genus level, among the 18 specimens, 5 had a relative abundance of >50% for a single flora. Compared with the non-sepsis group, the sepsis group had significant higher levels of WBC, CRP, interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α ( P <0.05). The Spearman's rank correlation analysis showed that at the genus level, the relative abundance of Ruminococcus , Alistipes , and Parasutterella in the sepsis group was negatively correlated with the levels of WBC, CRP, and IL-6 ( P <0.05); the relative abundance of Enterococcus was positively correlated with the CRP level ( P <0.01); the relative abundance of Streptococcus and Staphylococcus was positively correlated with the levels of CRP and IL-6 ( P <0.05); the relative abundance of Streptococcus was positively correlated with WBC ( P <0.05)., Conclusions: Intestinal flora disturbance is observed in children with sepsis, and its characteristics vary with the severity of the disease. The structural changes of intestinal flora are correlated with inflammatory response in children with sepsis.

Interleukin-27 (IL-27) is known to play opposing roles in immunology. The present paper considers, specifically, the role IL-27 plays in cancer immunotherapy when combined with immune checkpoint inhibitor anti-PD-1. We first develop a mathematical model for this combination therapy, by a system of Partial Differential Equations, and show agreement with experimental results in mice injected with melanoma cells. We then proceed to simulate tumor volume with IL-27 injection at a variable dose F and anti-PD-1 at a variable dose g. We show that in some range of "small" values of g, as f increases tumor volume decreases as long as fc (g) and increases in a range where f>F c (g), where F c (g) is a monotone increasing function of g. This demonstrates that IL-27 can be both anti-cancer and pro-cancer, depending on the ranges of both anti-PD-1 and IL-27., Competing Interests: Declaration of competing interest There is no interest of conflict., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Gastric carcinoma, being one of the most prevalent types of solid tumors, has emerged as the third leading cause of death worldwide. The symptoms of gastric cancer (GC) are typically complex, which makes early detection challenging. Immune checkpoint inhibition has become the new standard targeted therapy for advanced or metastatic GC. It is currently being explored in various combinations, both with and without chemotherapy, across multiple therapies in clinical trials. Immunotherapy can stimulate immune responses in GC patients, leading to the destruction of cancer cells. Compared with traditional therapies, immunotherapy has shown strong effectiveness with tolerable toxicity levels. Hence, this innovative approach to the treatment of advanced GC has gained popularity. In this review, we have outlined the recent advancements in immunotherapy for advanced GC, including immune checkpoint inhibitors, cancer vaccines, vascular endothelial growth factor-A inhibitors, and chimeric antigen receptor T-cell therapy. Our current emphasis is on examining the immunotherapies presently employed in clinical settings, addressing the existing challenges associated with these therapeutic approaches, and exploring promising strategies to overcome their limitations.

Tumor-derived exosomes (TDEs) play critical roles in many aspects of cancer progression. There have been several advances in cancer immunotherapy in recent years. A major challenge, however, has been addressed to the role of TDEs in tumor cell immune escape through their influence on the antitumor immunity of natural killer (NK) cells, a key type of immune cell. In this review, we present our overview of the effects of different TDEs on NK cell activation and NK cell toxicity. Studies on mechanism suggest that TDEs mainly affect the immune response of NK cells by inhibiting activated receptors on the surface of NK cells and downregulating the NK recognition ligand MICA/B on the tumor cell surface. In addition, a summary was documented on how to restore the cytotoxicity of NK cells and improve the drug's ability to recognize tumor cells, and a detailed explanation was also provided on the mechanism of action of the drug.

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Objective: The effect of probiotics supplementation on the gut microbiota in Helicobacter pylori (H. pylori) eradication therapy is controversial. Therefore, this review aimed to illustrate changes in the gut microbiota after standard eradication therapy with probiotics supplements., Materials and Methods: A computerized literature search in PubMed, Cochrane Library, Web of Science, and Embase database was performed up to February 1st, 2022, with English language restriction. The extracted outcomes were analyzed, including gut microbiota, adverse effects, and eradication rate., Results: 13 studies reported data on 777 participants who were finally eligible for this systematic review. All of them are randomized controlled trials investigating the effect of H. pylori eradication with probiotics supplementation therapy on gut microbiota. Probiotics supplementation seems to play a positive role in restoring the gut microbiota during H. pylori eradication therapy. However, the changes in the gut microbiota are still controversial. The included studies had significant heterogeneity in the study population, diagnostic methods of H. pylori infection, and detection techniques of the gut microbiota and probiotics species., Conclusions: The results provided a basis for the rational selection of probiotics in the H. pylori eradication process. Probiotic supplementation might keep the balance of gut microbiota and reduce the gastrointestinal adverse effects of antibiotics, but whether it could improve the eradication rate or not is a debatable point. Therefore, more research is needed to provide evidence.

CD200 is overexpressed in many solid tumors and considered as an immune checkpoint molecule dampening cancer immunity. In this study, we found that CD200R -/- mice were significantly more potent in rejecting these CD200 + tumors. scRNA sequencing demonstrated that tumors from CD200R -/- mice had more infiltration of CD4 + and CD8 + T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effector cells are crucial in inhibiting tumor growth in CD200R -/- mice. Mechanistically, we found that CD200R signaling regulates the expression of chemokines in tumor-associated myeloid cells (TAMCs). In the absence of CD200R, TAMCs increased expression of CCL24 and resulted in increased infiltration of eosinophils, which contributes to anti-tumor activity. Overall, we conclude that CD200R signaling contributes to unfavorable TME through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has implications in developing CD200-CD200R targeted immunotherapy of solid tumors., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Dairy foods are crucial for adequate calcium intake in young children, but scarce data are available on the effects of formula milk on bone acquisition. This cluster-randomized controlled trial investigated the effects of the supplementation of formula milk on bone health in rural children accustomed to a low-calcium diet between September 2021 and September 2022. We recruited 196 healthy children aged 4-6 years from two kindergartens in Huining County, Northwest China. A class-based randomization was used to assign them to receive 60 g of formula milk powder containing 720 mg calcium and 4.5 µg vitamin D or 20-30 g of bread per day for 12 months, respectively. Bone mineral density (BMD) and bone mineral content (BMC) at the left forearm and calcaneus, bone biomarkers, bone-related hormones/growth factors, and body measures were determined at baseline, 6, and 12 months. A total of 174 children completed the trial and were included in the analysis. Compared with the control group, formula milk intervention showed significant extra increments in BMD (3.77% and 6.66%) and BMC (4.55% and 5.76%) at the left forearm at 6th and 12th months post-intervention (all p < 0.001), respectively. Similar trends were observed in BMD (2.83%) and BMC (2.38%) in the left calcaneus at 6 months ( p < 0.05). The milk intervention (vs. control) also showed significant changes in the serum concentrations of osteocalcin level (-7.59%, p = 0.012), 25-hydroxy-vitamin-D (+5.54%, p = 0.001), parathyroid hormone concentration (-15.22%, p = 0.003), and insulin-like growth factor 1 (+8.36%, p = 0.014). The percentage increases in height were 0.34%, 0.45%, and 0.42% higher in the milk group than in the control group after 3-, 6-, and 9-month intervention, respectively ( p < 0.05). In summary, formula milk supplementation enhances bone acquisition at the left forearm in young Chinese children.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

CD24 is a GPI anchored cell surface glycoprotein whose function as a co-stimulatory molecule has been implicated. However, the function of CD24 on antigen presenting cells during T cell responses is not well understood. Here we show that in the CD24-deficient host, adoptively transferred CD4 + T cells undergo inefficient expansion and have accelerated cell death in lymph nodes, which results in insufficient priming of T cells. Insufficient expansion of T cells in the CD24-deficient host was not due to host anti-CD24 response by NK, T and B lymphocytes. Transgenic expression of CD24 on DC in CD24 -/- mice restored T cell accumulation and survival in draining lymph nodes. Consistent with these findings, MHC II tetramer staining also revealed that an antigen-specific polyclonal T cell response was reduced in lymph nodes of CD24 -/- mice. Taken together, we have revealed a novel role of CD24 on DC in optimal T cell priming in lymph nodes. These data suggest that CD24 blockade should lower unwanted T cell responses such as those in autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Yu, Liu and Bai.)

Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal-organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8 + T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.

Background: Myocardial ischemia-reperfusion injury (MIRI) caused by the reperfusion therapy of myocardial ischemic diseases is a kind of major disease that threatens human health and lives severely. There are lacking of effective therapeutic measures for MIRI. MicroRNAs (miRNAs) are abundant in mammalian species and play a critical role in the initiation, promotion, and progression of MIRI. However, the biological role and molecular mechanism of miRNAs in MIRI are not entirely clear., Methods: We used bioinformatics analysis to uncover the significantly different miRNA by analyzing transcriptome sequencing data from myocardial tissue in the mouse MIRI model. Multiple miRNA-related databases, including miRdb, PicTar, and TargetScan were used to forecast the downstream target genes of the differentially expressed miRNA. Then, the experimental models, including male C57BL/6J mice and HL-1 cell line, were used for subsequent experiments including quantitative real-time polymerase chain reaction analysis, western blot analysis, hematoxylin and eosin staining, flow cytometry, luciferase assay, gene interference, and overexpression., Results: MiR-582-5p was found to be differentially upregulated from the transcriptome sequencing data. The elevated levels of miR-582-5p were verified in MIRI mice and hypoxia/reperfusion (H/R)-induced HL-1 cells. Functional experiments revealed that miR-582-5p promoted apoptosis of H/R-induced HL-1 cells via downregulating cAMP-response element-binding protein 1 (Creb1). The inhibiting action of miR-582-5p inhibitor on H/R-induced apoptosis was partially reversed after Creb1 interference., Conclusions: Collectively, the research findings reported that upregulation of miR-582-5p promoted H/R-induced cardiomyocyte apoptosis by inhibiting Creb1. The potential diagnostic and therapeutic strategies targeting miR-582-5p and Creb1 could be beneficial for the MIRI treatment., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Enantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

Cancer vaccines-based cancer immunotherapy has drawn widespread concern. However, insufficient cancer antigens and inefficient antigen presentation lead to low immune response rate, which greatly restrict the practical application of cancer vaccines. Here, inspired by intracellular proteasome-mediated protein degradation pathway, we report an antigen presentation simplification strategy by extracellular degradation of antigen proteins into peptides with proteolytic enzyme for improving the utilization of cancer antigens and arousing restricted cancer immunity. The pre-degraded antigen peptides are first validated to exhibit an increased capacity on antigen-presenting cell (APC) stimulation compared with proteins and still reserve antigen specificity and major histocompatibility complex (MHC) affinity. Furthermore, by coordinating the pre-degraded peptides with calcium phosphate nanoparticles (CaP), a CaP-peptide vaccine (CaP-Pep) is constructed, which is verified to induce an efficient personalized immune response in vivo for multi-model anti-cancer therapy. Notably, this bioinspired strategy based on extracellular enzymatic hydrolysis for vaccine construction is not only applicable for multiple types of cancers, but also shows great potential in expanding immunology fields and translational medicine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8 + T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer., (Copyright © 2022 Elsevier B.V. All rights reserved.)

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8 + T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4 + T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8 + T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Objective: We evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial., Methods: Patients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate., Results: We enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively., Conclusions: S-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT., Trial Registration: ClinicalTrial.gov NCT02301481., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhao, Yang, Chi, Zhao, Jiang, Jiang, Tang, Li, Liu, Dou, Zou, Xue, Ren, Tian, Che, Guo, Bai, Sun, Wang, Song, Liu, Fang, Li and Jin.)

CD24 is a glycosyl-phosphatidylinositol (GPI) anchored cell surface glycoprotein with a variety of immunomodulatory functions such as inhibition of thymic generation of autoreactive T cells, regulation of antigen presenting cell functions, and mediation of autoimmunity. Given the autoimmune nature of FoxP3 + regulatory T cells and their importance in autoimmune diseases, we hypothesize that CD24 regulates the generation and functions of Treg cells. Through the analysis of the Treg repertoire in two strains of CD24-deficient mice, we found that CD24 does not globally affect the thymic generation of Treg cells. However, CD24 is abundantly expressed on Treg cells, and CD24 antibody treatment of Treg cells enhances their suppressive functions. Concurrently, we observed CD24-deficient Treg cells exhibit increased suppressive functions and produce more IL-10 compared to their wild type counterparts. In addition, CD24-deficient Treg cells exhibited more potent suppressive capacity in inhibiting the development of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, CD24 on Treg cells regulates their suppressive functions. Our findings can partially explain the resistance of EAE development in CD24-deficient mice and CD24 polymorphism-associated susceptibility of human autoimmune diseases. Further investigations regarding mechanisms of CD24 regulation of Treg function may lead to a new approach for the immunotherapy of human autoimmune diseases., Competing Interests: None., (AJTR Copyright © 2022.)

A Gram-stain negative, aerobic, rod-shaped bacterium, designated 126 T , was isolated from the intestinal content of a sea cucumber, Apostichopus japonicus, in China. Strain 126 T was found to grow optimally at 25-28 °C and pH 7.5-8.0 in marine 2216 E medium, with tolerance of 1-7% (w/v) NaCl. Strain 126 T is motile by means of one to several polar flagella. The dominant fatty acids of strain 126 T were identified as C 16:1 ω7c/C 16:1 ω6c (29.5%), C 18:1 ω7c/C 18:1 ω6c (19.8%) and C 16:0 (16.7%). The respiratory quinone was found to be Q-8. The polar lipid profile was found to be mainly composed of phosphatidylglycerol and phosphatidylethanolamine. The total length of the draft genome is approximately 4.2 × 10 6  bp, encoding 3655 genes and 3576 coding sequences. The G + C content of the genomic DNA is 48.0%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 126 T belongs to the genus Neiella and is closely related to Neiella marina J221 T (96.5%). Genomic comparisons of 126 T to N. marina J221 T revealed that they had similar genome size, G + C content and complement of clusters of orthologous groups. However, average nucleotide identity and digital DNA-DNA hybridization values between strains126 T and N. marina J221 T was 75.5% and 19.7%, which could distinguish the strains. On the basis of these phenotypic and genotypic data, strain 126 T is concluded to represent a novel species, for which the name Neiella holothuriorum sp. nov. is proposed. The type strain is 126 T (= GDMCC 1.2530 T  = KCTC 82829 T )., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Erythropoietin (EPO), a central protein of erythropoiesis, plays an important role during hypoxia adaptation and is regulated by hypoxia-inducible factor (HIF). However, there is no report on EPO-producing cells and their regulatory mechanisms in yak (Bos grunniens). To understand EPO production and regulation of yak, kidneys from different age of yak were collected and expression of EPO, hypoxia-inducible factor 1 alpha (HIF-1α), and hypoxia-inducible factor 2 alpha (HIF-2α) were detected. Then renal tubule epithelial cells (RTECs) and peritubular interstitial fibroblast-like (RIFs) cells were isolated and cultured to determine their EPO production abilities. Subsequently, the cells were treated with dimethyloxalylglycine (DMOG) and Geldanamycin (GA), which are inhibitors of prolyl-4-hydroxylase domain (PHD) and heat shock protein 90 (HSP90) respectively, and siRNAs of HIF-1α and HIF-2α to explore their effect on EPO production and regulation. The results showed that expressions of EPO, HIF-1α, and HIF-2α were different in the different age groups of yak. High DMOG concentration caused a corresponding increase in the levels of HIF-1α and HIF-2α in RIFs and RTECs, however, EPO levels increased in RIFs only and was not detected at any concentration in RTECs; suggesting that EPO was produced in RIFs. Upon treating RIFs with siRNAs of HIF-1α and HIF-2α, we found that EPO was regulated by PHD through HIF-2α. In addition, increasing GA concentration caused a decrease in expression of HSP90, HIF-1α, HIF-2α, and EPO in RIFs. In conclusion, these findings support our proposition that PHD regulates EPO via HIF-2α in yak RIFs, while HSP90 impelled EPO expression., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

BRD4, a chromatin modifier frequently upregulated in a variety of neoplasms including hepatocellular cancer (HCC), promotes cancer cell growth by activating oncogenes through its interaction with acetylated histone tails of nucleosomes. Here, we determined the anti-HCC efficacy of AZD5153, a potent bivalent BRD4 inhibitor, and elucidated its underlying molecular mechanism of action. AZD5153 treatment inhibited HCC cell proliferation, clonogenic survival and induced apoptosis in HCC cells. In vivo , AZD5153-formulated lipid nanoemulsions inhibited both orthotopic and subcutaneous HCCLM3 xenograft growth in NSG mice. Mapping of BRD4- chromosomal targets by ChIP-seq analysis identified the occupancy of BRD4 with the promoters, gene bodies, and super-enhancers of both mRNA and noncoding RNA genes, which were disrupted upon AZD5153 treatment. RNA-seq analysis of polyadenylated RNAs showed several BRD4 target genes involved in DNA replication, cell proliferation, and anti-apoptosis were repressed in AZD5153-treated HCC cells. In addition to known tumor-promoting genes, e.g., c- MYC , YAP1 , RAD51B , TRIB3 , SLC17A9 , JADE1 , we found that NAPRT , encoding a key enzyme for NAD + biosynthesis from nicotinic acid, was also suppressed in HCC cells by the BRD4 inhibitor. Interestingly, AZD5153 treatment upregulated NAMPT , whose product is the rate-limiting enzyme for NAD + synthesis from nicotinamide. This may explain why AZD5153 acted in concert with FK866, a potent NAMPT inhibitor, in reducing HCC cell proliferation and clonogenic survival. In conclusion, our results identified novel targets of BRD4 in the HCCLM3 cell genome and demonstrated anti-HCC efficacy of AZD5153, which was potentiated in combination with an NAMPT inhibitor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Kuo, Li, Koenig, Pan, Yan, Bai, Lee and Ghoshal.)

Background: Protein glycosylated hemoglobin, hemoglobin A1c (HbA1c) binds hemoglobin (Hb) in red blood cells to blood glucose. However, the relationship between Hb and HbA1c remains unclear., Aim: To elucidate their relationship in a nondiabetic population aged ≥ 16 years in the United States, using data from the 1999-2018 National Health and Nutrition Examination Survey., Methods: This study was based on data from 44560 adults aged ≥ 16 years, excluding those with diabetes. The relationship was estimated using a multivariate regression. We also used piecewise linear regression for subgroup analysis based on age and sex stratification and analysis of the threshold effects of Hb on HbA1c., Results: Hb and HbA1c levels were negatively correlated in the unadjusted model (β = -0.01; 95%CI: -0.01, -0.01). The correlation was significantly negative when the regression model was minimally regulated and stratified by age and sex, and remained negative when the model was further regulated (more than 10%) to identify covariates with the HbA1c level influence estimates. In subgroup analyses based on age and sex stratification, the association remained negative when the covariates were controlled. A nonlinear relationship was observed between them when the Hb levels reached the tipping point (13.2 g/dL) (adjusted odds ratio, -0.04; 95%CI: -0.05, -0.03) and when the Hb levels exceeded 13.2 g/dL (adjusted odds ratio, -0.10; 95%CI: -0.10, -0.09)., Conclusion: Our study shows that normal Hb levels are negatively correlated with HbA1c in nondiabetic Americans aged ≥ 16 years., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Influenza is an infectious respiratory disease caused by the influenza viruses. Older people, infants and people with underlying medical conditions could have a higher risk of severe influenza symptoms and complications. The co-infection of Coronavirus Diseases 2019 (COVID-19) with influenza viruses could lead to the complication of prevention, diagnosis, control, treatment, and recovery of COVID-19. Influenza vaccine and COVID-19 vaccine overlapped in target populations, vaccination time, and inoculation units. Although there was insufficient evidence on the immunogenicity and safety of co-administration of influenza vaccine and COVID-19 vaccine, World Health Organization and some countries recommended co-administration of inactivated influenza vaccine and COVID-19 vaccine. This review summarized domestic and international vaccination policies and research progress, and put forward corresponding suggestions in order to provide scientific support for the formulation of vaccination strategy on seasonal influenza vaccine and COVID-19 vaccine.

Aim: To explore the expression of cGAS/STING signaling components in Mooren's ulcer (MU)., Methods: Samples were obtained from ten MU patients, and eight residual corneal-scleral rings of healthy donor corneas for controls. Human corneal epithelial cells (HCECs) were used to evaluate the effect of cGAS/STING signaling pathway. Immunohistochemistry (IHC) and Western blot were used to examine the expression of cGAS, STING, and phosphorylated interferon regulatory factor 3 (p-IRF3) in MU tissues. The expression of interferon-β (IFN-β) and interferon-stimulated genes (ISGs) was quantified by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA)., Results: The protein levels of cGAS and STING in MU samples were significantly elevated when compared with the healthy controls by Western blot and IHC. After stimulation with cGAMP, real-time PCR and ELISA showed a dramatic increase of IFN-β and ISGs (containing CXCL10, IFIT1, and IL-6) in HCECs. Moreover, HCECs treated with cGAMP was characterized by increased phosphorylation and more nuclear translocation of IRF3. Meanwhile, increased p-IRF3 was observed in MU samples via IHC and Western blot., Conclusion: The pronounced expression of cGAS/STING signaling components in the patients with MU and probably contribute to the onset and development of MU., (International Journal of Ophthalmology Press.)

Colorectal cancer (CRC) is one of the most common malignancies of the digestive system. Recent studies have revealed the importance of RNA-binding proteins (RBPs) in tumorigenesis, but their role in CRC remains unclear. The present study systematically analyzed the relationships between RBPs and CRC using data from The Cancer Genome Atlas. We detected 483 differentially expressed RBPs and identified a series of pathways and processes using GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. Analyzing protein-protein interactions and modules identified the edges and modules of RBPs. Univariate and multivariate Cox regression analyses were then used to construct a prognostic model that included 13 RBPs. Survival analyses indicated that the overall survival (OS) was significantly lower for CRC patients in the high-risk group than for those in the low-risk group, and that high risk scores were associated with poor OS. Finally, we constructed a nomogram that included 13 RBPs for calculating the estimated survival probabilities of CRC patients at 1, 2, and 3 years. Calibration plots indicated good conformity between the predicted and observed outcomes. This study has revealed that the expression of RBPs differs between CRC and normal tissues. A prognostic model based on 13 RBP coding genes has been developed that can provide independent prognoses of CRC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Xiao-fen Bai and Jing-wen Liu.)

Tumor heterogeneity, often leading to metastasis, limits the development of tumor therapy. Personalized therapy is promising to address tumor heterogeneity. Here, a vesicle system was designed to enhance innate immune response and amplify personalized immunotherapy. Briefly, the bacterial outer membrane vesicle (OMV) was hybridized with the cell membrane originated from the tumor (mT) to form new functional vesicles (mTOMV). In vitro experiments revealed that the mTOMV strengthened the activation of innate immune cells and increased the specific lysis ability of T cells in homogeneous tumors. In vivo experiments showed that the mTOMV effectively accumulated in inguinal lymph nodes, then inhibited lung metastasis. Besides, the mTOMV evoked adaptive immune response in homologous tumor rather than the heterogeneous tumor, reversibly demonstrating the effects of personalized immunotherapy. The functions to inhibit tumor growth and metastasis accompanying good biocompatibility and simple preparation procedure of mTOMV provide their great potential for clinical applications.

CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200 + Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R -/- mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R -/- or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ + and TNF-α + T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R -/- tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R -/- mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Talebian, Yu, Lynch, Liu, Carson and Bai.)

Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes-S1 and S2-based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC., (© 2021. The Author(s).)

The morbidity and mortality of myocardial ischemia-reperfusion injury (MIRI) have increased in modern society. Noncoding RNAs (ncRNAs), including lncRNAs, circRNAs, piRNAs and miRNAs, have been reported in a variety of studies to be involved in pathological initiation and developments of MIRI. Hence this review focuses on the current research regarding these ncRNAs in MIRI. We comprehensively introduce the important features of lncRNAs, circRNAs, piRNA and miRNAs and then summarize the published studies of ncRNAs in MIRI. A clarification of lncRNA-miRNA-mRNA, lncRNA-transcription factor-mRNA and circRNA-miRNA-mRNA axes in MIRI follows, to further elucidate the crucial roles of ncRNAs in MIRI. Bioinformatics analysis has revealed the biological correlation of mRNAs with MIRI. We provide a comprehensive perspective for the roles of these ncRNAs and their related networks in MIRI, providing a theoretical basis for preclinical and clinical studies on ncRNA-based gene therapy for MIRI treatment.

A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97 : 3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.

Circular RNAs (circRNAs) are evolutionarily conserved and abundant non-coding RNAs whose functions and regulatory mechanisms remain largely unknown. Here, we identify and characterize an epigenomically distinct group of circRNAs (TAH-circRNAs), which are transcribed to a higher level than their host genes. By integrative analysis of cistromic and transcriptomic data, we find that compared with other circRNAs, TAH-circRNAs are expressed more abundantly and have more transcription factors (TFs) binding sites and lower DNA methylation levels. Concordantly, TAH-circRNAs are enriched in open and active chromatin regions. Importantly, ChIA-PET results showed that 23-52% of transcription start sites (TSSs) of TAH-circRNAs have direct interactions with cis-regulatory regions, strongly suggesting their independent transcriptional regulation from host genes. In addition, we characterize molecular features of super-enhancer-driven circRNAs in cancer biology. Together, this study comprehensively analyzes epigenomic characteristics of circRNAs and identifies a distinct group of TAH-circRNAs that are independently transcribed via enhancers and super-enhancers by TFs. These findings substantially advance our understanding of the regulatory mechanism of circRNAs and may have important implications for future investigations of this class of non-coding RNAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Tang, Peng, Li, Qian, Zhao, Ding, Du, Li, Zhang, Bai, Zhu, Feng, Wang, Pan and Li.)

With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include 'Variation information', 'Regulatory information', 'Related genes', 'Chromatin accessibility' and 'Chromatin interaction'. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)