👤 Lihua Lu

The global coronavirus disease 2019 (COVID-19) pandemic has a detrimental impact on public health. COVID-19 usually manifests as pneumonia, which can progress into acute respiratory distress syndrome (ARDS) related to uncontrolled TH17 immune reaction. Currently, there is no effective therapeutic agent to manage COVID-19 with complications. The currently available anti-viral drug remdesivir has an effectiveness of 30% in SARS-CoV-2-induced severe complications. Thus, there is a need to identify effective agents to treat COVID-19 and the associated acute lung injury and other complications. The host immunological pathway against this virus typically involves the THαβ immune response. THαβ immunity is triggered by type 1 interferon and interleukin-27 (IL-27), and the main effector cells of the THαβ immune response are IL10-CD4 T cells, CD8 T cells, NK cells, and IgG1-producing B cells. In particular, IL-10 exerts a potent immunomodulatory or anti-inflammatory effect and is an anti-fibrotic agent for pulmonary fibrosis. Concurrently, IL-10 can ameliorate acute lung injury or ARDS, especially those caused by viruses. Owing to its anti-viral activity and anti-pro-inflammatory effects, in this review, IL-10 is suggested as a possible treatment agent for COVID-19. Show less

Several interleukins (ILs) have been demonstrated to participate in cardiac injury. This study aimed to investigate whether IL-27p28 plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by regulating inflammation and oxidative stress. Dox was used to establish a mouse cardiac injury model, and IL-27p28 was knocked out to observe its role in cardiac injury. In addition, monocytes were adoptively transferred to clarify whether monocyte-macrophages mediate the regulatory role of IL-27p28 in DOX-induced cardiac injury. IL-27p28 knockout significantly aggravated DOX-induced cardiac injury and cardiac dysfunction. IL-27p28 knockout also upregulated the phosphorylation levels of p65 and STAT1 and promoted M1 macrophage polarization in DOX-treated mice, which increased cardiac inflammation and oxidative stress. Moreover, IL-27p28-knockout mice that were adoptively transferred WT monocytes exhibited worse cardiac injury and cardiac dysfunction and higher cardiac inflammation and oxidative stress. IL-27p28 knockdown aggravates DOX-induced cardiac injury by worsening the M1 macrophage/M2 macrophage imbalance and its associated inflammatory response and oxidative stress. Show less

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83 Show less

Interleukin (IL) 27 is a member of the IL-12 family and is a heterodimeric cytokine composed of IL-27A and Epstein-Barr virus-induced 3 (EBI3). It plays an important role in regulating inflammation and cancer progression. IL-27A not only functions by dimerizing with EBI3 but also acts alone. Here, we report that IL-27A and EBI3 suppress spring viremia of carp virus (SVCV) replication in zebrafish. Expression analysis reveals that il-27a and ebi3 were significantly upregulated in the ZF4 cells by SVCV and poly(I:C), and in the zebrafish caudal fin (ZFIN) cells overexpressed with SVCV genes. Interestingly, il-27a and ebi3 were not modulated by IFNφ1, indicating that they are not IFN stimulated genes (ISGs). Furthermore, overexpression of IL-27A and EBI3 alone inhibited SVCV replication in the EPC cells, but less potent than co-expression of IL-27A and EBI3. Intriguingly, IL-27A could not induce the expression of irf3, ifn, isg15 and mx1. Taken together, our results demonstrate that IL-27A and EBI3 activate innate antiviral response in an IFN independent manner in zebrafish. Show less

Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in muscle metabolisms of triploid crucian carp (Carassius auratus) cultured at different concentrations of S. chinensis diets (sc0, sc0.125%, sc0.25%, sc0.5%, sc1%, sc2%) after 8 weeks. The serum antioxidant enzyme activities analysis showed that dietary S. chinensis could reduce oxidative stress and increase organismic antioxidant capacity. Meanwhile, the detected results of muscle components presented that the amino acids and two flavor nucleotides of GMP and IMP significantly elevated while muscle crude lipid significantly reduced in S. chinensis feeding groups. In addition, springiness, chewiness, and fiber density in S. chinensis feeding groups muscle were significantly upregulated while muscle fiber diameter and area showed an opposite trend. By comparative transcriptome analysis of the muscles, functional enrichments of differentially expressed genes showed that multiple terms were related to purine metabolism, glycerolipid metabolism, regulation of actin cytoskeleton, and peroxisome. Finally, some key hub genes such as egln, gst, ggct, su1b, pi3kr4, myh9, lpl, gcdh, mylk, and col4a were identified by weighted gene co-expression network analysis. Taken together, our findings facilitate the understanding of the molecular basis underlying the muscle quality effect of dietary S. chinensis in triploid crucian carp, which provides valuable insights into the nutritional strategies of the aquaculture industry. Show less

It has been found that high-lipid diets (HLDs) disrupt lipid metabolism in fish, leading to an excessive accumulation of lipids in various tissues of the fish body. The objective of this study was to investigate if the inclusion of lycopene (LCP) in an HLD may mitigate the adverse consequences of excessive dietary lipid intake in hybrid grouper (♀ Show less

Afterglow materials are attracting widespread attention owing to their distinctive and long-lived optical emission properties which create exciting opportunities in various fields. Recent research has led to the discovery of many new afterglow materials featuring high photoluminescence quantum yields (PLQY) and lifetimes of up to several hours under ambient conditions. Afterglow materials are typically categorized according to their luminescence mechanism, such as long-persistent luminescence (LPL), room temperature phosphorescence (RTP), or thermally activated delayed fluorescence (TADF). Through rational design and novel synthetic strategies to modulate spin-orbit coupling (SOC) and populate triplet exciton states (T Show less

Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. To describe the manifestations and management of 19 pediatric patients with LPL-FCS. LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy. Show less

Myostatin (encoded by mstn) negatively regulates skeletal muscle mass and affects lipid metabolism. To explore the regulatory effects of mstn on muscle development and lipid metabolism in Nile tilapia (Oreochromis niloticus), we used antisense RNA to transcriptionally knock-down mstn. At 180 days, the body weight and body length were significantly higher in the mstn-knock-down group than in the control group (p < 0.05). Additionally, fish with mstn-knock-down exhibited myofiber hyperplasia but not hypertrophy. Oil red O staining revealed a remarkable increase in the area of lipid droplets in muscle in the mstn-knockdown group (p < 0.05). Nutrient composition analyses of muscle tissue showed that the crude fat content was significantly increased in the mstn-knock-down group (p < 0.05). The contents of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids were all significantly increased in the mstn-knock-down group (p < 0.05). Comparative transcriptome analyses revealed 2420 significant differentially expressed genes between the mstn-knock-down group and the control group. KEGG analysis indicates that disruptions to fatty acid degradation, glycerolipid metabolism, and the PPAR signaling pathway affect muscle development and lipid metabolism in mstn-knock-down Nile tilapia: acaa2, eci1, and lepr were remarkably up-regulated, and acadvl, lpl, foxo3, myod1, myog, and myf5 were significantly down-regulated (p < 0.05). These results show that knock-down of mstn results in abnormal lipid metabolism, acceleration of skeletal muscle development, and increased adipogenesis and weight gain in Nile tilapia. Show less

Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency. A total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups. A total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy. This study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy. Show less

Diabetes mellitus (DM) affects bone metabolism and causes osteoporosis. Musashi 1 (MSI1), a member of the Musashi family, regulates protein expression by targeting protein mRNA and has been reported to play an important role in osteogenic differentiation. Therefore, this paper attempts to explore the role of MSI1 in diabetic osteoporosis and discussing its specific mechanism. The glucose concentration for high glucose (HG) and control MC3T3-E1 cells were 30 and 5.5 mM. MC3T3-E1 cells induced by high glucose (HG) were used to simulate diabetic osteoporosis in vivo. The interaction between MSI1 and microtubule actin crosslinking factor 1 (MACF1) was confirmed by RNA Immunoprecipitation (RIP). The mRNA and protein expressions of MSI1 and MACF1 in MC3T3-E1 cells and HG-induced MC3T3-E1 cells after indicated transfection were tested by Real-time quantitative polymerase chain reaction (RT-qPCR) assay and western blot. After transfection, the proliferation, apoptosis, and osteogenic differentiation of HG-induced MC3T3-E1 cells were detected by cell counting kit (CCK)-8, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), alkaline phosphatase (ALP) activity assay, and alizarin red staining. The expression of Wnt/β-catenin signaling pathway-related proteins in HG-induced MC3T3-E1 cells after transfection was detected by western blot. This work shows that MSI1 can combine with MACF1. The expression of MSI1 and MACF1 was increased in HG-induced MC3T3-E1 cells. Upregulation of MSI1 promoted the proliferative and differentiative capabilities, but inhibited the apoptosis of HG-insulted MC3T3-E1 cells, which could be reversed by MACF1 knockdown. MSI1 stabilizes MACF1 to suppress apoptosis and promote osteogenic differentiation in HG-induced MC3T3-E1 cells by inhibiting Wnt/β-catenin signaling pathway. Show less

Background Sarcomere gene mutation and myocardial fibrosis are both associated with poorer clinical outcomes in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the relationship between sarcomere gene mutation and myocardial fibrosis measured by both histopathology and cardiac magnetic resonance (CMR). Methods and Results Two hundred twenty-seven patients with HCM who underwent surgical treatment, genetic testing, and CMR were enrolled. We retrospectively analyzed basic characteristics, sarcomere gene mutation, and myocardial fibrosis measured by CMR and histopathology. In our study, the mean age was 43 years, and 152 patients (67.0%) were men. A total of 107 patients (47.1%) carried a positive sarcomere gene mutation. The myocardial fibrosis ratio was significantly higher in the late gadolinium enhancement (LGE)+ group (LGE+ 14.3±7.5% versus LGE- 9.0±4.3%; Show less

Emerging evidence indicates that the interactions and dynamic changes among tumor-associated macrophages (TAMs) are pivotal in molding the tumor microenvironment (TME), thereby influencing diverse clinical outcomes. However, the potential clinical ramifications of these evolutionary shifts in tumor-associated macrophages within pancreatic adenocarcinoma (PAAD) remain largely unexamined. Single-cell RNA sequencing (scRNA-seq) data were retrieved from the Tumor Immune Single-cell Hub. The Seurat and Monocle algorithms were employed to elucidate the progression of TAMs, using non-negative matrix factorization (NMF) to determine molecular classifications. Subsequently, the prognosis, biological characteristics, genomic modifications, and immune landscape across various clusters were interpreted. Furthermore, the sensitivity of potential therapeutic drugs between subtypes was predicted. Cellular experiments were conducted to explore the function of the NR1H3 gene in pancreatic cancer. These experiments encompassed gene knockdown, proliferation assessment, clone formation evaluation, transwell examination, and apoptosis analysis. Trajectory gene expression analysis of tumor-associated macrophages identified three disparate clusters, each associated with different clinical outcomes Compared to clusters C1 and C2, cluster C3 is seemingly at a less advanced pathological stage and associates with a relatively favorable prognosis. Further investigation revealed pronounced genetic instability in cluster C2, whereas cluster C3 demonstrated notable genetic stability. Cluster C1, characterized as "immune-hot," exhibits an abundance of immune cells and elevated immune checkpoint expression, suggesting its suitability for immunotherapy. Furthermore, several potential therapeutic agents have been pinpointed, potentially facilitating the clinical application of these insights. Cell assays indicated that NR1H3 knockdown markedly induced apoptosis and suppressed clonogenesis, migration, and proliferation of pancreatic cancer cells in the PTAU-8988 and PANC-1 cell lines. Overall, our study discerned three clusters with unique characteristics, defined by the evolution of TAMs. We propose customized therapeutic strategies for patients within these specific clusters to improve clinical outcomes and optimize clinical management. Show less

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease. Show less

Sepsis can cause various organ dysfunction, which heart failure may be associated with significant mortality. Recently, natural plant extracts have gradually attracted people's attention in the clinical treatment of cardiovascular diseases. Psoralidin (PSO) is one of the main bioactive compounds from the seeds of Psoralea corylifolia L and exhibits remarkable protective effects in diseases, including cancer, osteoporosis, and depression. Recently, NR1H3 is one of the emerging nuclear receptors targets for the various drugs. This study first reported the porotective role of PSO in septic myocardial injury, which was mainly attributed to the NR1H3-dependent manner. NR1H3 knockout mice subjected to cecal ligation and puncture (CLP) were used to investigate the involvement of NR1H3 in PSO protection. Our results showed that PSO prominently improved cardiac function, attenuated inflammation, inhibited oxidative stress, improved mitochondrial function, regulated ERS, suppressed apoptosis, and particularly increased NR1H3 and p-AMPK levels. However, NR1H3 knockout reversed the positive role of PSO in septic mice. Furthermore, activation of NR1H3 by T0901317 also increased the activity of AMPK and ACC in the HL-1 cardiomyocytes, indicating the regulatory relationship between NR1H3 and AMPK signaling. Together, this study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3/AMPK pathway. Show less

Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have demonstrated ferroptosis as a biological process highly dependent on selective autophagy, such as ferritinophagy, lipophagy, and clockophagy. Our study also revealed a role for ER-phagy-mediated ferroptosis in HCC cells treated with multi-targeted tyrosine kinase inhibitors (TKIs). In the current study, we found that the homologous circular RNA (circRNA) of the family with sequence similarity 134, member B ( Show less

This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes. Show less

Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers. Show less

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment. Show less

Paclitaxel (PTX) resistance is a key cause of chemotherapy failure in patients with triple negative breast cancer (TNBC). The aim of this study is to investigate the effect and mechanism of long non-coding RNA (lncRNA) on the PTX resistance of TNBC cells through autophagy. MDA-MB-231 cells are used to induce the PTX-resistant TNBC cell line MDA-MB-231.PR (MDR) by increasing dose intermittently. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA levels of phosphoinositide-3-kinase class 3 (PIK3C3), miR-361-5p and lncRNA PRKCQ-AS1 in the cells, and Western blot analysis was used to detect the protein expressions of PIK3C3, autophagy-related, drug-resistant and apoptosis-related genes. MDC staining detected the formation of autophagic vacuoles. The interactions between miR-361-5p and PIK3C3 and between lncRNA PRKCQ-AS1 and miR-361-5p were verified by dual-luciferase assay. Cell viability, apoptosis, migration and invasion were assessed by performing MTT, flow cytometry assay, and transwell assay. The mRNA level of miR-361-5p and the autophagy and drug resistance levels of TNBC PTX-resistant cells were significantly up-regulated. miR-361-5p could target autophagy-related gene PIK3C3, and overexpression of miR-361-5p could down-regulate PIK3C3 protein expression and autophagy level and PTX resistance of MDR cells. LncRNA PRKCQ-AS1 was selected through bioanalysis, and miR-361-5p could target lncRNA PRKCQ-AS1. In addition, lncRNA PRKCQ-AS1 level was up-regulated in TNBC PTX-resistant cells, and knockdown of lncRNA PRKCQ-AS1 could weaken autophagy and drug resistance level and could promote cell apoptosis. Overexpression of lncRNA PRKCQ-AS1 reversed the pro-apoptotic effect and down-regulation of autophagy and resistance levels was induced by miR-361-5p. In vivo experiments were performed to verify the role of lncRNA PRKCQ-AS1. We demonstrate that down-regulation of lncRNA PRKCQ-AS1 weakened PTX resistance and promoted cell apoptosis by miR-361-5p/PIK3C3 mediated autophagy. Show less

miRNA is a noncoding RNA found in recent years and more than one third of human genes are the target of miRNAs. miR-624, located on human chromosome 14, is associated with tumorigenesis. However, the role of miR-624 in human hepatocarcinogenesis is still unclear. Herein, our results indicate that miR-624 accelerates the growth of liver cancer cells Show less

Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME. Show less

Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear. This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits. Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits. We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty. Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways. Show less

Genome-wide association studies (GWAS) have identified genetic variants in SEC16 homolog B (SEC16B) locus to be associated with obesity and body mass index (BMI) in various populations. SEC16B encodes a scaffold protein located at endoplasmic reticulum (ER) exit sites that is implicated to participate in the trafficking of COPII vesicles in mammalian cells. However, the function of SEC16B in vivo, especially in lipid metabolism, has not been investigated. We generated Sec16b intestinal knockout (IKO) mice and assessed the impact of its deficiency on high-fat diet (HFD) induced obesity and lipid absorption in both male and female mice. We examined lipid absorption in vivo by acute oil challenge and fasting/HFD refeeding. Biochemical analyses and imaging studies were performed to understand the underlying mechanisms. Our results showed that Sec16b intestinal knockout (IKO) mice, especially female mice, were protected from HFD-induced obesity. Loss of Sec16b in intestine dramatically reduced postprandial serum triglyceride output upon intragastric lipid load or during overnight fasting and HFD refeeding. Further studies showed that intestinal Sec16b deficiency impaired apoB lipidation and chylomicron secretion. Our studies demonstrated that intestinal SEC16B is required for dietary lipid absorption in mice. These results revealed that SEC16B plays important roles in chylomicron metabolism, which may shed light on the association between variants in SEC16B and obesity in human. Show less

Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade. Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells. Show less

Oxaliplatin is a commonly used platinum drug for colorectal cancer (CRC). However, the treatment of CRC by oxaliplatin usually fails because of drug resistance, which results in a huge challenge in the therapy of CRC. Elucidation of molecular mechanisms may help to overcome oxaliplatin resistance of CRC. In our study, we revealed that KIAA1199 can promote oxaliplatin resistance of CRC. Mechanistically, KIAA1199 prevents oxaliplatin mediated apoptosis via up-regulated PARP1 derived from reduced endoplasmic reticulum stress induced by protein O-GlcNAcylation. In the meantime, KIAA1199 can also trigger epithelial mesenchymal transition by stabilizing SNAI1 protein via O-GlcNAcylation. Therefore, KIAA1199 has great potential to be a novel biomarker, therapeutic target for oxaliplatin resistance and metastasis of CRC. Show less

The poorly understood regulatory mechanisms impede gastric cancer therapy. Kruppel-like factors (KLFs) are associated with the development of various tumors, The studies on the role of the KLF transcription factor 13 (KLF13) in gastric cancer progression haven't been studied. The current study aimed to investigate the role of KLF13 in the migration and invasion of gastric cancer and the regulatory mechanism of KLF13 in gastric cancer progression. The research team performed a laboratory study. The study took place at the Zengcheng District People's Hospital of Guangzhou in Zengcheng, China. In addition to using normal gastric cells, GES1, and seven gastric cancer cell lines, the research team compared the fresh, gastric cancer tissues (T) and paired, adjacent, noncancerous gastric tissues (ANT) from eight patients undergoing surgical resection at the hospital. The research team also downloaded the data for 33 gastric cancer tissues and adjacent, normal gastric tissues from the Cancer Genome Atlas' TCGA database. The research team used: (1) short hairpin RNAs (shRNAs) to knock down KLF13, (2) wound healing and transwell invasion analyses to determine the effects of KLF13 on the migration and invasion of gastric cancer, and (3) a Luciferase reporter assay to determine the effects of KLF13 on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. KLF13 was upregulated in gastric cancer cells and tissues, and the patients with a high KLF13 expression had poor outcome. Downregulation of KLF13 significantly inhibited the migration and invasion of gastric cancer cells. Mechanistically, downregulation of KLF13 significantly inhibited NF-κB activity, and its targets such as: (1) snail family transcriptional repressor 1 (SNAI1 or Snail), (2) snail family transcriptional repressor 2 (SNAI2 or Slug), (3) zinc finger e-box binding homeobox 1 (ZEB1), (4) Smad interacting protein 1 (Sip1), (5) twist family basic helix-loop-helix (BHLH) transcription factor (Twist), (6) matrix metallopeptidase 2 (MMP2), and (7) MMP9. Tumor necrosis factor alpha (TNF-α) can activate NF-κB. Treating with TNF-α can reverse the effects of KLF13 downregulation on migration and invasion, confirming that KLF13 promotes the migration and invasion of gastric cancer cells through activating the NF-κB pathway. KLF13 promoted the migration and invasion of gastric cancer cells through activating the NF-κB pathway, providing a new target for gastric cancer therapy. Show less