It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed Show more
It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed on exploring diabetic wound healing to protect patients from adverse events. We recently found interleukin-7 (IL-7), a growth factor for B-cells and T-cells, and its receptor was significantly upregulated in high glucose-induced fibroblasts and skin of diabetic mice. Moreover, IL-7 stimulated fibroblasts secreted ANGPTL4, which inhibited angiogenesis of endothelial cells resulting in delayed wound healing. In our previous study, fibroblasts, endothelial cells and keratinocytes were exposed to normal glucose (5.5 mM) or high glucose (30 mM) medium for 24 h, and RNA sequencing showed that IL-7 and IL-7R were significantly upregulated in fibroblasts. To remove the effect of high glucose and explore the influence of IL-7, exogenous rMuIL-7 used to treat normal mice led to delayed wound healing by inhibiting angiogenesis. Vitro experiments revealed that IL-7-induced fibroblasts inhibited endothelial cell proliferation, migration and angiogenesis. Further experiments showed that fibroblast angiopoietin-like-4 (ANGPTL4) secretion exhibited the inhibitory effect which was blocked by culture with the corresponding neutralizing antibody. Overall, our study revealed signaling pathways associated with diabetic wound healing and provided the foothold for further studies on delayed wound healing in this patient population. Mechanism that high glucose activates IL-7-IL-7R-ANGPTL4 signal pathway in delayed wound healing. High glucose upregulates IL-7 and IL-7R in dermal fibroblasts. IL-7 stimulates dermal fibroblasts secreting Angptl4 which inhibits proliferation, migration and angiogenesis of endothelial cells in a paracrine way. Show less
The goose is an economically important poultry species and was one of the first to be domesticated. However, studies on population genetic structures and domestication in goose are very limited. Here, Show more
The goose is an economically important poultry species and was one of the first to be domesticated. However, studies on population genetic structures and domestication in goose are very limited. Here, we performed whole genome resequencing of geese from two wild ancestral populations, five Chinese domestic breeds, and four European domestic breeds. We found that Chinese domestic geese except Yili geese originated from a common ancestor and exhibited strong geographical distribution patterns and trait differentiation patterns, while the origin of European domestic geese was more complex, with two modern breeds having Chinese admixture. In both Chinese and European domestic geese, the identified selection signatures during domestication primarily involved the nervous system, immunity, and metabolism. Interestingly, genes related to vision, skeleton, and blood-O2 transport were also found to be under selection, indicating genetic adaptation to the captive environment. A forehead knob characterized by thickened skin and protruding bone is a unique trait of Chinese domestic geese. Interestingly, our population differentiation analysis followed by an extended genotype analysis in an additional population suggested that two intronic SNPs in Show less
This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease Show more
This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients. Show less
Huanan Li, Peifen Li, Shanyi Li+4 more · 2023 · Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · added 2026-04-24
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was Show more
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was used for analysis. Differentially expressed genes were screened with the criteria of false discovery rate<0.05 and l o g 2 F C >1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Genes encoding transcription factors were further screened for differential expression genes. Then, the expression of these genes during renal fibrosis was verified using unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis model and a public gene expression dataset (GSE104954). After TGF-β1 treatment for 6, 12 and 24 h, 552, 1209 and 1028 differentially expressed genes were identified, respectively. GO analysis indicated that these genes were significantly enriched in development, cell death, and cell migration. KEGG pathway analysis showed that in the early stage of TGF-β1 induction (TGF-β1 treatment for 6 h), the changes in Hippo, TGF-β and Wnt signaling pathways were observed, while in the late stage of TGF-β1 induction (TGF-β1 treatment for 24 h), the changes of extracellular matrix-receptor interaction, focal adhesion and adherens junction were mainly enriched. Among the 291 up-regulated differentially expressed genes treated with TGF-β1 for 6 h, 13 genes ( TGF-β1 induces differentially expressed genes in renal fibroblasts, among which Show less
Diabetic retinopathy (DR), one of the most common microangiopathic complications in diabetes, causes severe visual damage among working-age populations. Retinal vascular endothelial cells, the key cel Show more
Diabetic retinopathy (DR), one of the most common microangiopathic complications in diabetes, causes severe visual damage among working-age populations. Retinal vascular endothelial cells, the key cell type in DR pathogenesis, are responsible for abnormal retinal angiogenesis in advanced stages of DR. The roles of exosomes in DR have been largely unknown. In this study, we report the first evidence that exosomes derived from the vitreous humor of patients with proliferative DR (PDR-exo) promote proliferation, migration, and tube formation of human retinal vascular endothelial cells (HRVECs). We identified long noncoding RNA (lncRNA) LOC100132249 enrichment in PDR-exo via high-throughput sequencing. This lncRNA, also mainly derived from HRVECs, promoted angiogenesis both in vitro and in vivo. Mechanistically, LOC100132249 acted as a competing endogenous sponge of miRNA-199a-5p (miR-199a-5p), thus regulating the endothelial-mesenchymal transition promoter SNAI1 via activation of the Wnt/β-catenin pathway and ultimately resulting in endothelial dysfunction. In conclusion, our findings underscored the pathogenic role of endothelial-derived exosomes via the LOC100132249/miR-199a-5p/SNAI1 axis in DR angiogenesis and may shed light on new therapeutic strategies for future treatment of DR. This study provides the first evidence that exosomes derived from vitreous humor from patients with proliferative diabetic retinopathy participate in angiogenesis. The findings demonstrate an unreported long noncoding RNA (lncRNA), LOC100132249, by exosomal sequencing of vitreous humor. The newly found lncRNA LOC100132249, mainly derived from endothelial cells, promotes angiogenesis via an miRNA-199a-5p/SNAI1/Wnt/β-catenin axis in a pro-endothelial-mesenchymal transition manner. Show less
For patients with locally unresectable recurrent nasopharyngeal carcinoma who relapsed after 2 years of radiotherapy, re-radiotherapy is also the preferred treatment. However, for patients relapsed wi Show more
For patients with locally unresectable recurrent nasopharyngeal carcinoma who relapsed after 2 years of radiotherapy, re-radiotherapy is also the preferred treatment. However, for patients relapsed within 2 years, the use of re-radiotherapy would be greatly limited by its adverse effects. Consequently, finding a new strategy to prolong the time of re-radiotherapy for locally recurrent nasopharyngeal carcinoma is very necessary to reduce the related side effects and improve the curative effect. Anlotinib is an orally available small molecule multi-target tyrosine kinase inhibitor that primarily inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. However, whether recurrent nasopharyngeal carcinoma patients can be treated with anlotinib combined with ticeorgio (also called S-1) remains unknown. Herein, we report a nasopharyngeal carcinoma patient with local recurrence after radical radiotherapy who benefited from combination treatment of anlotinib with ticeorgio. Show less
Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, Show more
Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases. Show less
The crosstalk between intervertebral disc degeneration (IVDD) and type 2 diabetes mellitus (T2DM) has been investigated. However, the common mechanism underlying this phenomenon has not been clearly e Show more
The crosstalk between intervertebral disc degeneration (IVDD) and type 2 diabetes mellitus (T2DM) has been investigated. However, the common mechanism underlying this phenomenon has not been clearly elucidated. This study aimed to explore the shared gene signatures of IVDD and T2DM. The expression profiles of IVDD (GSE27494) and T2DM (GSE20966) were acquired from the Gene Expression Omnibus database. Five hub genes including ANGPTL4, CCL2, CCN3, THBS2, and INHBA were preliminarily screened. GO (Gene Ontology) enrichment analysis, functional correlation analysis, immune filtration, Transcription factors (TFs)-mRNA-miRNA coregulatory network, and potential drugs prediction were performed following the identification of hub genes. RNA sequencing, in vivo and in vitro experiments on rats were further performed to validate the expression and function of the target gene. Five hub genes (ANGPTL4, CCL2, CCN3, THBS2, and INHBA) were identified. GO analysis demonstrated the regulation of the immune system, extracellular matrix (ECM), and SMAD protein signal transduction. There was a strong correlation between hub genes and different functions, including lipid metabolism, mitochondrial function, and ECM degradation. The immune filtration pattern grouped by disease and the expression of hub genes showed significant changes in the immune cell composition. TFs-mRNA-miRNA co-expression networks were constructed. In addition, pepstatin showed great drug-targeting relevance based on potential drugs prediction of hub genes. ANGPTL4, a gene that mediates the inhibition of lipoprotein lipase activity, was eventually determined after hub gene screening, validation by different datasets, RNA sequencing, and experiments. This study screened five hub genes and ANGPTL4 was eventually determined as a potential target for the regulation of the crosstalk in patients with IVDD and T2DM. Show less
Linping Wang, Jingqi Zhang, Yue Zhao+5 more · 2023 · Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · Elsevier · added 2026-04-24
Studies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, β-secretase (BACE1), and amy Show more
Studies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, β-secretase (BACE1), and amyloid beta (Aβ) in vivo and in vitro. Previous studies by our research group have shown that this is partly caused by the negative regulation of BACE1 by miRNA29a/b1 (miR29a/b1). Despite the observed the role of nuclear factor kappa B (NF-κB) on many miRNAs, the upstream regulation of NF-κB protein on miR29 remains poorly understood. The purpose of this study was to better define the relationship between NF-κB and miR29a/b1 and the potentially relevant signaling pathways. On the one hand, we constructed the animal model of Al exposure by the intraperitoneal injection of aluminum-maltolate (Al(mal) We verified that NF-κB shows an increasing trend with Al accumulation in the brain of rats, which is accompanied by a downward trend of miR29a/b1. Notably, the suppression of NF-κB significantly increased miR29a/b1 and affected the expression of BACE1mRNA and downstream proteins. Al-induced NF-κB can negatively regulate the expression of miR29a/b1, which then significantly enhances the expression of BACE1 and Aβ plaques. Show less
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the im Show more
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the impacts of BCFAs inferred from yak ghee on the expression of qualities related to lipid metabolism, natural pathways, and intestinal microbiota in mice. The treatment group (purified BCFAs from yak ghee) exhibited a decrease in cholesterol levels; a decrease in Show less
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor Show more
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was Show less
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. 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 mu Show more
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
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole- Show more
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease. 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 examin Show more
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
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 Show more
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
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progressi Show more
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progression of DKD. The public transcriptomic datasets of the alloxan-induced DKD model and the streptozotocin-induced DKD model were retrieved to perform an integrative bioinformatic analysis of differentially expressed genes (DEGs) shared by two experimental animal models. The dominant biological processes and pathways associated with DEGs were identified through enrichment analysis. The expression changes of the key DEGs were validated in the classic db/db DKD mouse model. The downregulated and upregulated genes in DKD models were uncovered from GSE139317 and GSE131221 microarray datasets. Enrichment analysis revealed that metabolic process, extracellular exosomes, and hydrolase activity are shared biological processes and molecular activity is altered in the DEGs. Importantly, Hmgcs2, angptl4, and Slco1a1 displayed a consistent expression pattern across the two DKD models. In the classic db/db DKD mice, Hmgcs2 and angptl4 were also found to be upregulated while Slco1a1 was downregulated in comparison to the control animals. In summary, we identified the common biological processes and molecular activity being altered in two DKD experimental models, as well as the novel gene factors (Hmgcs2, Angptl4, and Slco1a1) which may be implicated in DKD. Future works are warranted to decipher the biological role of these genes in the pathogenesis of DKD. Show less
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophag Show more
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycan on Aβ Show less
Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in as Show more
Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in asthma patients, whereas the effects of fatty acids on the actual risk of asthma remain controversial. This study comprehensively investigated the causal effects of serum fatty acids on asthma risk using two-sample bidirectional Mendelian Randomization (MR) analysis. Genetic variants strongly associated with 123 circulating fatty acid metabolites were extracted as instrumental variables, and a large GWAS data of asthma was used to test effects of the metabolites on this outcome. The inverse-variance weighted method was used for primary MR analysis. The weighted median, MR-Egger regression, MR-PRESSO, and leave-one-out analyses were utilized to evaluate heterogeneity and pleiotropy. Potential confounders were adjusted by performing multivariable MR analyses. Reverse MR analysis was also conducted to estimate the causal effect of asthma on candidate fatty acid metabolites. Further, we performed colocalization analysis to examine the pleiotropy of variants within the fatty acid desaturase 1 (FADS1) locus between the significant metabolite traits and the risk of asthma. Cis-eQTL-MR and colocalization analysis were also performed to determine the association between RNA expression of FADS1 and asthma. Genetically instrumented higher average number of methylene groups was causally associated with a lower risk of asthma in primary MR analysis, while inversely, the higher ratio of bis-allylic groups to double bonds and the higher ratio of bis-allylic groups to total fatty acids, were associated with higher probabilities of asthma. Consistent results were obtained in multivariable MR when adjusted for potential confounders. However, these effects were completely eliminated after SNPs correlated with the FADS1 gene were excluded. The reverse MR also found no causal association. The colocalization analysis suggested that the three candidate metabolite traits and asthma likely share causal variants within the FADS1 locus. In addition, the cis-eQTL-MR and colocalization analyses demonstrated a causal association and shared causal variants between FADS1 expression and asthma. Our study supports a negative association between several PUFA traits and the risk of asthma. However, this association is largely attributed to the influence of FADS1 polymorphisms. The results of this MR study should be carefully interpreted given the pleiotropy of SNPs associated with FADS1. Show less
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical d Show more
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions Show less
Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired s Show more
Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired sufficiently after exposure has ceased. Therefore, this project aims to investigate the effects of BPA on the hepatic lipid metabolism function and its potential mechanisms in mice by comparing the BPA exposure model and the BPA exposure + cessation of drug treatment model. Herein, the male C57BL/6 mice were exposed in the dose of 50 μg/kg/day and 500 μg/kg/day BPA for 8 weeks, and then transferred to a standard chow diet for another 8 weeks to recover. Based on our previous RNA-seq study, we examined the expression patterns of some key genes. The results showed that the mice exposed to BPA manifested NAFLD features. Importantly, we also found that there was a significant expression reversion for 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 im Show more
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
Apolipoprotein C3 (APOC3) is known for its important functions in metabolism-related diseases. However, the function and molecular mechanism of APOC3 in polycystic ovarian syndrome (PCOS) have not bee Show more
Apolipoprotein C3 (APOC3) is known for its important functions in metabolism-related diseases. However, the function and molecular mechanism of APOC3 in polycystic ovarian syndrome (PCOS) have not been reported. Quantitative polymerase chain reaction and western blot assays were used to detect the expression of APOC3 in KGN cells. Small interference APOC3 (siAPOC3) was applied to reduce APOC3 expression, and the proliferation ability of human granulosa cell line (KGN cells) was measured by cell counting kit-8 and colony formation assays. The protein levels of key genes related to apoptosis were detected by western blot assay. The transcriptional regulator of APOC3 was predicted by the UCSC and PROMO website, and verified by dual luciferase assay. siAPOC3 and pcDNA3.1-specific protein 1 (SP1) vector were co-transfected into KGN cells to detect the function of SP1 and APOC3 in KGN cells. APOC3 was overexpressed in KGN cells, and siAPOC3 transfection significantly reduced the growth ability of KGN cells and increased the apoptosis ability of KGN cells. SP1 directly bound to the promoter of APOC3 and transcriptional regulated APOC3 expression. Overexpression of SP1 increased the growth ability of KGN cells and decreased the apoptosis ability of KGN cells, which were reversed after siAPOC3 transfection. The increased levels of toll-like receptor 2 (TLR2) and p65 phosphorylation (p-P65) nuclear factor kappa B (NF-κB) caused by SP1 overexpression were inhibited by siAPOC3 transfection. APOC3, transcriptionally regulated by SP1, promoted the growth of KGN cells, and inhibited the apoptosis by regulating TLR2/NF-κB signalling pathway. Show less
Aspergillus fumigatus (A. fumigatus) is an important fungal pathogen and its conidia can be inhaled and interact with airway epithelial cells; however, the release of inflammatory factors from bronchi Show more
Aspergillus fumigatus (A. fumigatus) is an important fungal pathogen and its conidia can be inhaled and interact with airway epithelial cells; however, the release of inflammatory factors from bronchial epithelial cells upon A. fumigatus infection and its regulation remained unclear. Here it was demonstrated that the release of IL-27, MCP-1 and TNF-α from BEAS-2B cells were upregulated upon stimulation by conidia, while mitogen-activated protein kinase signaling pathway was activated. Further, the inhibition of JNK, but not p38 and ERK, could inhibit inflammatory factors release and the LC3II formation in BEAS-2B cells induced by A. fumigatus conidia. In addition, an inhibitor of autophagy, bafilomycin A1 was able to significantly down-regulate the release of inflammatory factors in BEAS-2B cells upon A. fumigatus conidia, while rapamycin could reverse the effect of JNK inhibitor on IL-27 and TNF-α release. Taken together, these data demonstrated that JNK signal might play an important role in inflammatory factor release regulated by autophagy in bronchial epithelial cells against A. fumigatus infection. Show less
Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hyp Show more
Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hypothesized that increased CPS1 release during hypoosmosis is selective and associates with altered mitochondrial morphology. Both ex vivo and in vivo models were assessed. Mouse hepatocytes and livers were challenged with isotonic or hypoosmotic (35 mosM) buffer. Mice were injected intraperitoneally with water (10% body weight) with or without an antidiuretic. Mitochondrial and cytosolic fractions were isolated using differential centrifugation, then analyzed by immunoblotting to assess subcellular redistribution of four mitochondrial proteins: CPS1, ornithine transcarbamylase (OTC), pyrroline-5-carboxylate reductase 1 (PYCR1), and cytochrome c. Mitochondrial morphology alterations were examined using electron microscopy. Hypoosmotic treatment of whole livers or hepatocytes led to preferential or increased mitochondrial release, respectively, of CPS1 as compared with two mitochondrial matrix proteins (OTC/PYCR1) and with the intermembrane space protein, cytochrome c. Mitochondrial apoptosis-induced channel opening using staurosporine in hepatocytes led to preferential CPS1 and cytochrome c release. The CPS1-selective changes were accompanied by dramatic alterations in ultrastructural mitochondrial morphology. In mice, hypoosmosis/hyponatremia led to increased liver vascular congestion and increased CPS1 in bile but not blood, coupled with mitochondrial structural alterations. In contrast, isotonic increase of intravascular volume led to a decrease in mitochondrial size with limited change in bile CPS1 compared with hypoosmotic conditions and absence of the hypoosmosis-associated histological alterations. Taken together, hepatocyte CPS1 is selectively released in response to hypoosmosis/hyponatremia and provides a unique biomarker of mitochondrial injury. Show less
This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of caroti Show more
This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of carotid atherosclerotic plaque. For this purpose, 108 patients with coronary heart disease in our hospital from Jan 2021 to May 2022 were selected as the coronary heart disease (CHD) group and 80 patients with the healthy examination as the control group. Patients' serum levels of ANGPTL4 and SIRT1 were collected, and their stability of carotid atherosclerotic plaque was determined by carotid ultrasound. According to their stability results, patients were divided into three subgroups: No plaque, Stable plaque, and Unstable plaque. The serum ANGPTL4 and SIRT1 levels were analyzed in different groups, and the correlation between their serum levels and the stability of carotid atherosclerotic plaque was analyzed by rank correlation. Results showed that the CHD group's serum ANGPTL4 and SIRT1 levels were lower, with statistical significance (P<0.05); A statistically significant difference in serum ANGPTL4 and SIRT1 levels were observed among patients with No plaques, Stable plaques, and Unstable plaques (P<0.05); A negative correlation was observed between serum levels of ANGPTL4 and SIRT1 and the stability of carotid atherosclerotic plaque (r=-0.438, -0.717, P<0.001); Serum ANGPTL4 and SIRT1 can be used as the evaluation method of carotid atherosclerotic plaque stability. When ANGPTL4 ≤ 30.17mg/L and SIRT1 ≤ 6.91μg/L, patients were more likely to develop unstable plaques; When ANGPTL4 ≤ 30.40mg/L and SIRT1 ≤ 6.87μg/L, patients were more likely to develop plaques (instability and/or stability). In conclusion, the serum levels of ANGPTL4 and SIRT1 in patients with CHD decreased. ANGPTL4 and SIRT1 will participate in the formation and development of carotid plaque, which can be used as a serological evaluation index to evaluate the occurrence and carotid atherosclerotic plaque's stability. Show less