Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.

Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.

Improving saccharification efficiency of corn stover through ferric chloride-deep eutectic solvent pretreatment.

An effective deep eutectic solvent (DES) and Iron(III) chloride (FeCl3) combination pretreatment system was developed to improve the removal efficiency of lignin and hemicellulose from corn stover (CS) and enhance its saccharification. N-(2-hydroxyethyl)ethylenediamine (NE) was selected as the hydrogen-bond-donor for preparing ChCl-based DES (ChCl:NE), and a mixture of ChCl:NE (60 wt%) and FeCl3 (0.5 wt%) was utilized for combination pretreatment of CS at 110 ℃ for 50 min. FeCl3/ChCl:NE effectively removed lignin (87.0 %) and xylan (55.9 %) and the enzymatic hydrolysis activity of FeCl3/ChCl:NE-treated CS was 5.5 times that of CS. The reducing sugar yield of pretreated CS was 98.6 %. FeCl3/ChCl:NE significantly disrupted the crystal structure of cellulose in CS and improved the removal of lignin and hemicellulose, enhancing the conversion of cellulose and hemicellulose into monomeric sugars. Overall, this combination of FeCl3 and DES pretreatment methods has high application potential for the biological refining of lignocellulose.

The NP protein of Newcastle disease virus dictates its oncolytic activity by regulating viral mRNA translation efficiency.

Newcastle disease virus (NDV) has been extensively studied as a promising oncolytic virus for killing tumor cells in vitro and in vivo in clinical trials. However, the viral components that regulate the oncolytic activity of NDV remain incompletely understood. In this study, we systematically compared the replication ability of different NDV genotypes in various tumor cells and identified NP protein determines the oncolytic activity of NDV. On the one hand, NDV strains with phenylalanine (F) at the 450th amino acid position of the NP protein (450th-F-NP) exhibit a loss of oncolytic activity. This phenotype is predominantly associated with genotype VII NDVs. In contrast, the NP protein with a leucine amino acid at this site in other genotypes (450th-L-NP) can facilitate the loading of viral mRNA onto ribosomes more effectively than 450th-F-NP. On the other hand, the NP protein from NDV strains that exhibit strong oncogenicity interacts with eIF4A1 within its 366-489 amino acid region, leading to the inhibition of cellular mRNA translation with a complex 5' UTR structure. Our study provide mechanistic insights into how highly oncolytic NDV strains selectively promote the translation of viral mRNA and will also facilitate the screening of oncolytic strains for oncolytic therapy.

Intervertebral Disk Degeneration and Bone Mineral Density: A Bidirectional Mendelian Randomization Study.

This study aimed to investigate the causal relationship between bone mineral density (BMD) and intervertebral disk degeneration (IVDD) using a two-sample bidirectional Mendelian randomization analysis. Summary-level data from the Genome-Wide Association Study (GWAS) were used. Instrumental variables (IVs) for IVDD were selected from the large-scale Genome-Wide Association Study (GWAS) (20,001 cases and 164,682 controls). Bone mineral density (BMD) at five different sites (heel (n = 426,824), total body (TB) (n = 56,284), forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), and lumbar spine (LS) (n = 28,498)) was used as a phenotype for OP. Bidirectional causality between IVDD and BMD was assessed using inverse variance weighting (IVW) and other methods. Related sensitivity analyses were performed. Myopia was also analyzed as a negative control result to ensure the validity of IVs. Heel bone mineral density (heel BMD), total body bone mineral density (TB-BMD), femoral neck bone mineral density (FN-BMD), and lumbar spine bone mineral density (LS-BMD) have a direct causal relationship on intervertebral disk degeneration (IVDD) [heel BMD-related analysis: beta = 0.06, p = 0.03; TB-BMD-related analysis: beta = 0.18, p = 8.72E-08; FN-BMD-related analysis: beta = 0.15, p = 4.89E-03; LS-BMD-related analysis: beta = 0.16, p = 1.43E-04]. There was no evidence of a significant causal effect of IVDD on BMD. In conclusion, our study found a significant positive causal effect of lower BMD on IVDD, and we identified significant causal effects of heel, TB-, FN-, and LS-BMD on IVDD, but there was no evidence of a significant causal effect of IVDD on BMD.

Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling.

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41-/-) or type 1 interferon receptor IFNAR1 (Ifnar1-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.

Pan-cancer analysis of aldolase B gene as a novel prognostic biomarker for human cancers.

Aldolase B (ALDOB) gene is essential for the process of glycolysis and differentially expressed in cancers. The aims of this study were to explore the potential role of ALDOB in pan-cancer, in order to deepen the research on the pathological mechanism of cancer. Hence, we used several online tools (TIMER2, GEPIA2, UALCAN, cBioPortal, and MXPRESS) and R language to identify the correlation between the ALDOB expression and survival analysis, genetic alteration, DNA methylation, and immune cell infiltration based on The Cancer Genome Atlas project. The results showed that ALDOB was lowly expressed in pan-cancer. Survival analysis revealed that low expression of ALDOB was markedly related with poor clinical prognosis, while the genetic alteration within ALDOB changed along with the difference of overall survival (OS) and disease-free survival (DFS) prognosis in several cancers. A possible relationship between DNA methylation and ALDOB expression for several tumors was found. Besides, ALDOB expression was confirmed to be associated with tumor immune cell infiltration, especially in breast invasive carcinoma (BRCA), esophageal carcinoma (ESCA), and testicular germ cell tumors (TGCT) cases. Further, the enrichment analysis demonstrated that metabolic pathway was closely related to ALDOB expression. Our results provide a comprehensive pan-cancer analysis and suggest ALDOB could act as a promising tumor predictive biomarker for human cancer.

Dopamine inhibits group 2 innate lymphoid cell-driven allergic lung inflammation by dampening mitochondrial activity.

Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.

Betaine supplementation alleviates dextran sulfate sodium-induced colitis via regulating the inflammatory response, enhancing the intestinal barrier, and altering gut microbiota.

Inflammatory bowel disease (IBD) is a multifaceted and recurrent immune disorder that occurs in the gastrointestinal tract. Betaine is a natural compound that exerts beneficial anti-inflammatory effects. However, the role of betaine in protecting IBD is still unclear. Therefore, the aim of our study was to investigate the anti-inflammatory effect of betaine in dextran sulfate sodium (DSS)-induced colitis. The results showed that betaine greatly increased the body weight and decreased the disease activity index score of DSS-treated mice. Furthermore, betaine effectively downregulated the protein levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα) and upregulated tight junction proteins (occludin and ZO-1) in the mice. Additionally, betaine exposure remarkably restricted the DSS-induced phosphorylation of IκB and NF-κB p65 in mice. Similarly, betaine pretreatment improved the inflammatory response and intestinal barrier of Caco-2 cells. Betaine altered the gut microbiota composition, markedly decreasing the relative abundance of Firmicutes and Proteobacteria and considerably increasing the relative abundance of Bacteroidota and Campylobacterota in DSS-induced mice. In conclusion, betaine could attenuate colitis via regulating the inflammatory response, enhancing the intestinal barrier, and altering gut microbiota and is conducive to developing new drugs for treating human diseases.

Adenosine Alleviates Necrotizing Enterocolitis by Enhancing the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Newborns.

Necrotizing enterocolitis (NEC) is a common disorder in premature infants that is characterized by hyperinflammation and severe necrosis in the intestine. The pathogenesis of NEC remains to be elucidated. In this study, we demonstrate that adenosine, a metabolite more abundant in infants than in adults, plays an important role in the prevention of NEC. Administration of adenosine or its analog, adenosine-5'-N-ethyluronamide (NECA), dramatically relieved the severity of NEC in neonatal mice. Meanwhile, adenosine treatment significantly enhanced the immunosuppressive function, antibacterial activity, and migration of myeloid-derived suppressor cells (MDSCs). However, depletion of MDSCs or inhibition of their migration using the CXCR2 inhibitor SB225002 almost completely abrogated the protective effect of adenosine on NEC. Mechanistic studies showed that MDSCs in newborns expressed abundant adenosine receptor A2B (A2BR) that elicits intracellular cAMP signaling and its downstream target NF-κB. Importantly, intestinal tissues from patients with NEC showed significantly lower infiltration of A2BR-positive MDSCs than those from healthy donors. These observations revealed that adenosine-induced MDSCs represent an essential immune axis for intestinal homeostasis in newborns.

Downregulation of HULC Induces Ferroptosis in Hepatocellular Carcinoma via Targeting of the miR-3200-5p/ATF4 Axis.

Hepatocellular carcinoma is a malignant tumor that poses a serious threat to human health. Ferroptosis, which represents an identified type of regulated iron-dependent cell death, may play an important role in hepatocellular carcinoma. However, it is unclear as to whether ferroptosis is involved with the mechanisms of lncRNA HULC in liver cancer cells. Here, we show that knockdown of HULC increases ferroptosis and oxidative stress in liver cancer cells. We also found changes in some related miRNAs in cells treated with HULC siRNA. Differential miRNA expression levels were determined with the use of high-throughput sequencing and prediction target genes identified using bioinformatics analysis. HULC was found to function as a ceRNA of miR-3200-5p, and miR-3200-5p regulates ferroptosis by targeting ATF4, resulting in the inhibition of proliferation and metastasis within HCC cells. In summary, these findings illuminate some of the molecular mechanisms through which downregulation of HULC induces liver cancer cell ferroptosis by targeting the miR-3200-5p/ATF4 axis to modulate the development of hepatocellular carcinoma.

Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis.

Cancer-associated fibroblasts (CAFs) are one of the most enriched components of Hepatocellular carcinoma (HCC) microenvironment, which are tightly related to the metastasis and invasion of HCC. We identified a mechanism by which CAF-derived chemokine CCL5 enhanced HCC metastasis by triggering the HIF1α/ZEB1 axis. We demonstrated that CAFs derived from HCC tissues promoted the migration and invasion of HCC cells and facilitated metastasis to the lung of NOD/SCID mice. Then the chemokine antibody array elucidated the higher chemokine CCL5 level secreted by CAFs than by paracancerous tissue fibroblasts (PTFs). Mechanistically, we found that CAF-derived CCL5 inhibited the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) by binding to specific receptors, maintained HIF1α under normoxia, thereby up-regulated the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and induced epithelial-mesenchymal transition (EMT), ultimately validating its ability to promote lung metastasis of HCC. And this novel mechanism may have association with poor prognosis. Taken together, targeting CAF-derived CCL5 mediated HIF1α/ZEB1 cascade possibly propose a new therapeutic route for HCC.

Angiotensin II enhances group 2 innate lymphoid cell responses via AT1a during airway inflammation.

Group 2 innate lymphoid cells (ILC2s) have emerged as critical mediators in driving allergic airway inflammation. Here, we identified angiotensin (Ang) II as a positive regulator of ILC2s. ILC2s expressed higher levels of the Ang II receptor AT1a, and colocalized with lung epithelial cells expressing angiotensinogen. Administration of Ang II significantly enhanced ILC2 responses both in vivo and in vitro, which were almost completely abrogated in AT1a-deficient mice. Deletion of AT1a or pharmacological inhibition of the Ang II-AT1 axis resulted in a remarkable remission of airway inflammation. The regulation of ILC2s by Ang II was cell intrinsic and dependent on interleukin (IL)-33, and was associated with marked changes in transcriptional profiling and up-regulation of ERK1/2 phosphorylation. Furthermore, higher levels of plasma Ang II correlated positively with the abundance of circulating ILC2s as well as disease severity in asthmatic patients. These observations reveal a critical role for Ang II in regulating ILC2 responses and airway inflammation.

Adenosine restrains ILC2-driven allergic airway inflammation via A2A receptor.

Although group 2 Innate Lymphoid Cells (ILC2s) play important roles in driving the pathogenesis of allergic airway inflammation, the molecular mechanisms regulating ILC2 responses remain to be fully elucidated. Adenosine signaling is emerging as an important factor to limit excessive inflammation and tissue damage, its role in ILC2-driven airway inflammation remains to be understood. Here we identify adenosine as a negative regulator of ILC2s and allergic airway inflammation. Elevation of adenosine was observed in lungs after protease papain challenge. Adenosine receptor A2A was abundantly expressed in lung ILC2s. The adenosine analog NECA significantly suppress ILC2s responses and relieved airway inflammation induced by IL-33 or papain. Conversely, blockage of adenosine synthesis by CD73 inhibitor APCP or deficiency of A2A aggravated murine airway inflammation. Adoptive transfer of ILC2s into immunodeficiency NCG mice demonstrated that the regulation of ILC2 by adenosine was cell intrinsic. Mechanistic studies showed that the effects of adenosine on ILC2s were associated with changes in transcriptional profiling, and the elevation of intracellular cAMP and resulted NF-κB downregulation. These observations indicate that adenosine-A2A signaling is a negative regulator of ILC2s, which confers protection against airway inflammation and represents a novel therapeutic target for controlling asthma.

Bilirubin represents a negative regulator of ILC2 in allergic airway inflammation.

Group 2 innate lymphoid cells (ILC2s) play an important role in allergic airway inflammation. Despite recent advances in defining molecular mechanisms that control ILC2 development and function, the role of endogenous metabolites in the regulation of ILC2s remains poorly understood. Herein, we demonstrated that bilirubin, an end product of heme catabolism, was a potent negative regulator of ILC2s. Bilirubin metabolism was found to be significantly induced during airway inflammation in mouse models. The administration of unconjugated bilirubin (UCB) dramatically suppressed ILC2 responses to interleukin (IL)-33 in mice, including cell proliferation and the production of effector cytokines. Furthermore, UCB significantly alleviated ILC2-driven airway inflammation, which was aggravated upon clearance of endogenous UCB. Mechanistic studies showed that the effects of bilirubin on ILC2s were associated with downregulation of ERK phosphorylation and GATA3 expression. Clinically, newborns with hyperbilirubinemia displayed significantly lower levels of ILC2 with impaired function and suppressed ERK signaling. Together, these findings indicate that bilirubin serves as an endogenous suppressor of ILC2s and might have potential therapeutic value in the treatment of allergic airway inflammation.

lncRNA MIR155HG Accelerates the Progression of Sepsis via Upregulating MEF2A by Sponging miR-194-5p.

Long noncoding RNA MIR155HG exerts important effects in the progression of multiple diseases. This study investigated the functions of MIR155HG in sepsis development. Blood samples were collected from 28 patients with sepsis and 28 without sepsis. The murine cardiac muscle cell line (HL-1) and macrophage cell line (RAW 264.7) treated with lipopolysaccharide (LPS) were used as the in vitro sepsis models. The levels of MIR155HG, miR-194-5p, and MEF2A were determined using real-time-quantitative polymerase chain reaction. Cell counting kit-8 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays were used to assess cell viability and apoptosis, respectively. The association between miR-194-5p and MIR155HG or MEF2A was confirmed using a dual-luciferase reporter assay. The levels of inflammatory cytokines were detected using enzyme-linked immunosorbent assay (ELISA). In this study, we demonstrated that MIR155HG expression was significantly increased in sepsis blood samples, RAW 264.7, and HL-1 cells treated with LPS. Silencing of MIR155HG promoted cell viability and obstructed cell apoptosis and inflammation of RAW 264.7 and HL-1 cells treated with LPS. MiR-194-5p depletion abrogated cell viability promotion and suppressive effect on cell apoptosis and inflammation caused by MIR155HG knockdown. In addition, MIR155HG upregulated MEF2A through interaction with miR-194-5p. Finally, rescue assays indicated that MEF2A overexpression abolished the inhibitory effect on sepsis progression induced by MIR155HG deletion. In conclusion, MIR155HG promotes sepsis progression in an in vitro sepsis model by modulating the miR-194-5p/MEF2A axis. This discovery provides a promising biomarker for sepsis therapy.

PPARγ enhances ILC2 function during allergic airway inflammation via transcription regulation of ST2.

Group 2 innate lymphoid cells (ILC2s) represent the major player during hyperresponsive airway inflammation. Peroxisome proliferator-activated receptor-γ (PPARγ) was highly expressed on ILC2 and its potential role in asthma has been suggested. However, the detailed mechanism underlying the effects of PPARγ on ILC2-induced airway inflammation remains to be fully understood. Here we identified PPARγ as a positive regulator of lung ILC2. Expression of PPARγ on ILC2 was dramatically induced upon interleukin-33 (IL-33) challenge. Deficiency of PPARγ in hematopoietic system in mice (PPARγfl/fl Vav1Cre) significantly impaired the function of ILC2 in lung, which led to apparent alleviation of airway inflammation in response to IL-33 or Papain challenge, when compared with those in PPARγfl/fl littermates control. Mechanistic studies identified IL-33 receptor ST2 as a transcriptional target of PPARγ. Overexpression of ST2 rescued the functional defects of ILC2 lacking PPARγ. Collectively, these results demonstrated PPARγ as an important regulator of ILC2 during allergic airway inflammation, which sheds new lights on the importance of PPARγ in asthma.

Critical Role of Intestinal Microbiota in ATF3-Mediated Gut Immune Homeostasis.

Secretory Ig A (sIgA) plays an important role in the maintenance of intestinal homeostasis via cross-talk with gut microbiota. The defects in sIgA production could elicit dysbiosis of commensal microbiota and subsequently facilitate the development of inflammatory bowel disease. Our previous study revealed activating transcription factor 3 (ATF3) as an important regulator of follicular helper T (TFH) cells in gut. ATF3 deficiency in CD4+ T cells impaired the development of gut TFH cells, and therefore diminished sIgA production, which increased the susceptibility to murine colitis. However, the potential role of microbiota in ATF3-mediated gut homeostasis remains incompletely understood. In this study, we report that both Atf3-/- and CD4creAtf3fl/fl mice displayed profound dysbiosis of gut microbiota when compared with their littermate controls. The proinflammatory Prevotella taxa, especially Prevotella copri, were more abundant in ATF3-deficient mice when compared with littermate controls. This phenotype was obviously abrogated by adoptive transfer of either TFH cells or IgA+ B cells. Importantly, depletion of gut microbiota dramatically alleviated the severity of colitis in Atf3-/- mice, whereas transfer of microbiota from Atf3-/- mice to wild-type recipients increased their susceptibility to colitis. Collectively, these observations indicate the importance of IgA-microbiota interaction in ATF3-mediated gut homeostasis.

Interference of miR-107 with Atg12 is inhibited by HULC to promote metastasis of hepatocellular carcinoma.

Highly upregulated in liver cancer (HULC) had a significant predictive effect on tumor growth and metastasis of hepatocellular carcinoma (HCC); however, the mechanisms of HULC on HCC still need to be clarified. We attempted to determine the roles of HULC and miR-107 in autophagy and invasion of HCC. HULC siRNA reduced the level of autophagy. The impact of HULC siRNA on invasion can be reversed by activating autophagy in HCC cell lines. Further studies on HULC and autophagy were conducted. An interacting sequence between HULC and miR-107, as well as miR-107 and Atg12, was predicted by software. The relationship of each pair of molecules was confirmed by luciferase reporter assays. The negative impacts of miR-107 on autophagy and invasion were proved in HCC cell lines. The inhibitor of miR-107-promoted invasion can also be reversed by Atg12 siRNA. The changes of miR-107, Atg12, epithelial-mesenchymal transition, and autophagy in transplanted tumors of mouse models also confirmed the results in HCC cell lines. Finally, we find that HULC acts as an endogenous sponge, which abolishes the binding of miR-107 on the Atg12 3'-UTR and promotes autophagy and metastasis of HCC.