Copy number variation (CNV) is a genetic structural polymorphism important for phenotypic diversity and important economic traits of livestock breeds, and it plays an important role in the desired gen Show more
Copy number variation (CNV) is a genetic structural polymorphism important for phenotypic diversity and important economic traits of livestock breeds, and it plays an important role in the desired genetic variation. This study used whole genome sequencing to detect the CNV variation in the genome of 6 local Tibetan sheep groups. We detected 69,166 CNV events and 7230 copy number variable regions (CNVRs) after merging the overlapping CNVs, accounting for 2.72% of the reference genome. The CNVR length detected ranged from 1.1 to 1693.5 Kb, with a total length of 118.69 Mb and an average length of 16.42 Kb per CNVR. Functional GO cluster analysis showed that the CNVR genes were mainly involved in sensory perception systems, response to stimulus, and signal transduction. Through CNVR-based Vst analysis, we found that the CACNA2D3 and CTBP1 genes related to hypoxia adaptation, the HTR1A gene related to coat color, and the TRNAS-GGA and PIK3C3 genes related to body weight were all strongly selected. The findings of our study will contribute novel insights into the genetic structural variation underlying hypoxia adaptation and economically important traits in Tibetan sheep. Show less
Vascular dementia (VD), associated with cerebrovascular injury, is characterized by severe cognitive impairment. Jianpi Tianjing Decoction (JTD) has been widely used to treat VD. However, its molecula Show more
Vascular dementia (VD), associated with cerebrovascular injury, is characterized by severe cognitive impairment. Jianpi Tianjing Decoction (JTD) has been widely used to treat VD. However, its molecular targets and mechanisms of action in this treatment remain unclear. This study integrated network pharmacology and proteomics to identify targets and mechanisms of JTD in the treatment of VD and to provide new insights and goals for clinical treatments. Systematic network pharmacology was used to identify active chemical compositions, potential targets, and mechanisms of JTD in VD treatment. Then, a mouse model of VD was induced via transient bilateral common carotid artery occlusion to verify the identified targets and mechanisms of JTD against VD using 4D label-free quantitative proteomics. By screening active chemical compositions and potential targets in relevant databases, 187 active chemical compositions and 416 disease-related compound targets were identified. JTD may suppress VD development via multiple components, targets, and pathways. It may thus serve as a complementary treatment option for patients with VD. Show less
Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC) with a low 5-year survival rate, which may be associated with the presence of metastatic tumors Show more
Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC) with a low 5-year survival rate, which may be associated with the presence of metastatic tumors at the time of diagnosis, especially lymph node metastasis (LNM). This study aimed to construct a LNM-related gene signature for predicting the prognosis of patients with LUAD. RNA sequencing data and clinical information of LUAD patients were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Samples were divided into metastasis (M) and nonmetastasis (NM) groups based on LNM status. Differentially expressed genes (DEGs) between M and NM groups were screened, and then WGCNA was applied to identify key genes. Furthermore, univariate Cox and LASSO regression analyses were conducted to construct a risk score model, and the predictive performance of model was validated by GSE68465, GSE42127, and GSE50081. The protein and mRNA expression level of LNM-associated genes were detected by human protein atlas (HPA) and GSE68465. A prognostic model based on eight LNM-related genes (ANGPTL4, BARX2, GPR98, KRT6A, PTPRH, RGS20, TCN1, and TNS4) was developed. Patients in the high-risk group had poorer overall survival than those in the low-risk group, and validation analysis showed that this model had potential predictive value for patients with LUAD. HPA analysis supported the upregulation of ANGPTL4, KRT6A, BARX2, RGS20 and the downregulation of GPR98 in LUAD compared with normal tissues. Our results indicated that the eight LNM-related genes signature had potential value in the prognosis of patients with LUAD, which may have important practical implications. Show less
Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity Show more
Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity in the Chinese indigenous Qingyuan partridge chicken. A cohort of 180 healthy 119-day-old chickens was subjected to a randomized assignment into three groups, identified as the control, R200, and R400 groups, with respective supplementation of 0, 200, and 400 mg/kg of rutin. The results revealed insignificance in growth performance, namely, average daily gain, average daily feed intake, and feed-to-gain ratio, across the various treatment groups ( Show less
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC Show more
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC and ELISA assays showed that GDF15 in trophoblast tissue and serum of pregnant women who miscarried was significantly lower than in those who had a live birth. GDF15 deficiency was associated with embryo resorption in GDF15 knockout mice through CRIPSR editing. In addition, the migration and invasion ability of HTR-8/SVneo and JEG-3 cells were promoted by GDF15. Mechanistically, GDF15 increased Smad1/5 phosphorylation, resulting in upregulating SNAI1/2, VIMENTIN and downregulating E-CADHERIN. A dual-luciferase reporter assay confirmed that Smad-binding elements (SBE) and/or GC-rich motifs were activated and target genes such as SNAI1/2, SERPINE1, and TIMP3 were transcriptionally regulated by GDF15/Smad5 signaling. Therefore, our data revealed a crucial role of GDF15 on invasion of trophoblast by upregulating the activity of TGF-β/Smad1/5 pathway. Show less
Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, a Show more
Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making. Using viral techniques in genetically modified male mice combined with molecular techniques, we identify and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic (IL) region of the cortex. Here, we describe a novel population of MC4R-expressing neurons in the IL of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are stimulated by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks. Together, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake in male mice. Show less
Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunct Show more
Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derived suppressor cells (MDSCs) promoted SS. However, NLRP3 inflammasome activation of MDSCs in SS and its regulated components are unclear. Splenic MDSCs were purified by immunomagnetic beads and cultured. Western blot was used to assess NLRP3 inflammasomes. Interleukin-1β (IL-1β) and IL-18 were measured using enzyme-linked immunosorbent assay. Here we showed that the NLRP3 inflammasome was activated in non-obese diabetic (NOD) mice with SS-like manifestations. We found that NLRP3 inflammasome activation was augmented in MDSCs of SS mice and NLRP3 inflammasome activation was suppressed in IL-27-deficient NOD mice. Consistent with findings of SS mice in vivo, we observed that NLRP3 inflammasome activation by adenosine triphosphate and lipopolysaccharide was remarkably intensified in MDSCs with IL-27 treatment in vitro. Collectively, our data highlighted that IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental SS. Show less
Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low Show more
Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23. Show less
Goat milk is increasingly recognized by consumers due to its high nutritional value, richness in short- and medium-chain fatty acids, and richness in polyunsaturated fatty acids (PUFA). Exogenous supp Show more
Goat milk is increasingly recognized by consumers due to its high nutritional value, richness in short- and medium-chain fatty acids, and richness in polyunsaturated fatty acids (PUFA). Exogenous supplementation of docosahexaenoic acid (DHA) is an important approach to increasing the content of PUFA in goat milk. Several studies have reported benefits of dietary DHA in terms of human health, including potential against chronic diseases and tumors. However, the mechanisms whereby an increased supply of DHA regulates mammary cell function is unknown. In this study, we investigated the effect of DHA on lipid metabolism processes in goat mammary epithelial cells (GMEC) and the function of H3K9ac epigenetic modifications in this process. Supplementation of DHA promoted lipid droplet accumulation increased the DHA content and altered fatty acid composition in GMEC. Lipid metabolism processes were altered by DHA supplementation through transcriptional programs in GMEC. ChIP-seq analysis revealed that DHA induced genome-wide H3K9ac epigenetic changes in GMEC. Multiomics analyses (H3K9ac genome-wide screening and RNA-seq) revealed that DHA-induced expression of lipid metabolism genes ( Show less
To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning Show more
To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aβ pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment. Show less
Cyclic adenosine monophosphate (cAMP) levels are directly activated by adenylate cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have sh Show more
Cyclic adenosine monophosphate (cAMP) levels are directly activated by adenylate cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have shown that isoforskolin (ISOF) can effectively activate AC1 and AC2 in vitro, improve pulmonary ventilation and reduce the inflammatory response in COPD model rats, supporting that ISOF may be a potential drug for the prevention and treatment of COPD, but the mechanism has not been explored in detail. The potential pharmacological mechanisms of ISOF against COPD were analyzed by network pharmacology and multi-omics based on pharmacodynamic study. To use specific agonists, inhibitors and/or SiRNA for gene regulation function studies, combined qPCR, WB were applied to detect changes in mRNA and protein expression of important targets PIK3C3, AKT, mTOR, SPP1 and AQP4 which related to ISOF effect on COPD. And the key inflammatory factors detected by ELISA. Bioinformatics suggested that the anti-COPD pharmacological mechanism of ISOF was related to PI3K-AKT signaling pathway, and suggested target protein like PIK3C3, AQP4, SPP1, AKT, mTOR. Using the AQP4 inhibitor,or inhibiting SPP1 expression by siRNA-SPP1 could block the PIK3C3-AKT-mTOR pathway and ameliorate chronic inflammation. ISOF showed cAMP-promoting effect then suppressed AQP4 expression, together with decreased level of IL-1β, IL-6, and IL-8. These findings demonstrate ISOF controlled the cAMP-regulated PIK3C3-AKT-mTOR pathway, thereby alleviating inflammatory development in COPD. The cAMP/AQP4/PIK3C3 axis also modulate Th17/Treg differentiation, revealed potential therapeutic targets for this disease. Show less
Genome-wide association studies have reported 23 gene loci related to abdominal aortic aneurysm (AAA)-a potentially lethal condition characterized by a weakened dilated vessel wall. This study aimed t Show more
Genome-wide association studies have reported 23 gene loci related to abdominal aortic aneurysm (AAA)-a potentially lethal condition characterized by a weakened dilated vessel wall. This study aimed to identify proteomic signatures and pathways related to these risk loci to better characterize AAA genetic susceptibility. Plasma concentrations of 4870 proteins were determined using a DNA aptamer-based array. Linear regression analysis estimated the associations between the 23 risk alleles and plasma protein levels with adjustments for potential confounders in a race-stratified analysis of 1671 Black and 7241 White participants. Significant proteins were then evaluated for their prediction of clinical AAA (454 AAA events in 11 064 individuals), and those significantly associated with AAA were further interrogated using Mendelian randomization analysis. Risk variants proximal to Low levels of neogenin and kit ligand may be novel risk factors for AAA development in potentially causal pathways. These findings provide insights and potential targets to reduce AAA susceptibility. Show less
Myopia has emerged as a major public health concern globally, which is tightly associated with scleral extracellular matrix (ECM) remodeling and choroidal vasculopathy. Choroidal vasculopathy has grad Show more
Myopia has emerged as a major public health concern globally, which is tightly associated with scleral extracellular matrix (ECM) remodeling and choroidal vasculopathy. Choroidal vasculopathy has gradually been recognized as a critical trigger of myopic pathology. However, the precise mechanism controlling choroidal vasculopathy remains unclear. Transfer RNA-derived fragments (tRFs) are known as a novel class of small non-coding RNAs that plays important roles in several biological and pathological processes. In this study, we investigated the role of tRF-22-8BWS72092 (tRF-22) in choroidal vasculopathy and myopia progression. The tRF-22 expression pattern under myopia-related stresses was detected by qRT-PCR. MTT assays, EdU incorporation assays, Transwell migration assays, and Matrigel assays were conducted to detect the role of tRF-22 in choroidal endothelial cell function in vitro. Isolectin B4 staining and choroidal sprouting assay ex vivo were conducted to detect the role of tRF-22 in choroidal vascular dysfunction in vivo. Immunofluorescent staining, western blot assays and ocular biometric parameters measurement were performed to examine whether altering tRF-22 expression in choroid affects scleral hypoxia and ECM remodeling and myopia progression in vivo. Bioinformatics analysis and luciferase activity assays were conducted to identify the downstream targets of tRF-22. RNA-sequencing combined with m6A-qPCR assays were used to identify the m6A modified targets of METTL3. Gain-of-function and Loss-of-function analysis were performed to reveal the mechanism of tRF-22/METTL3-mediated choroidal vascular dysfunction. The results revealed that tRF-22 expression was significantly down-regulated in myopic choroid. tRF-22 overexpression alleviated choroidal vasculopathy and retarded the progression of myopia in vivo. tRF-22 regulated choroidal endothelial cell viability, proliferation, migration, and tube formation ability in vitro. Mechanistically, tRF-22 interacted with METTL3 and blocked m Our study reveals that the intervention of choroidal vasculopathy via tRF-22-METTL3- Axin1/Arid1b axis is a promising strategy for the treatment of patients with myopic pathology. Show less
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
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and peria Show more
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and periarticular manifestations, RA is also a systematic disease associated with organ-specific extra-articular manifestation. Increasing evidence indicates that RA patients are susceptible to diabetes mellitus (DM), and RA aggravates metabolic disordered in DM, indicating the close association between RA and DM. Many factors involved in RA stimulate insulin resistance and DM development. These factors include proinflammatory cytokines (such as TNF-α, IL-6, IL-1β), RA autoantibodies (such as rheumatoid factor, cyclic citrullinated peptide antibodies), excess RA related adipokines (such as leptin, resistin, ANGPTL4), C-creative protein, and other protein (such as TXNDC5, NLRP3, RBP4). Furthermore, commonly used RA drugs, such as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), and glucocorticoids, provide potential benefits in improving insulin resistance and inhibiting DM development. This review discusses the mechanistic and therapeutic links between RA and DM, aiming to provide valuable information for the prevention and treatment of DM in RA patients. Show less
Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice Show more
Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle. Show less
Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder characterized by cardiomyocyte hypertrophy and cardiac fibrosis. Pathological cardiac remodeling in the myocardium of HCM Show more
Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder characterized by cardiomyocyte hypertrophy and cardiac fibrosis. Pathological cardiac remodeling in the myocardium of HCM patients may progress to heart failure. An in-depth elucidation of the lineage-specific changes in pathological cardiac remodeling of HCM is pivotal for the development of therapies to mitigate the progression. Here, we performed single-nucleus RNA-seq of the cardiac tissues from HCM patients or healthy donors and conducted spatial transcriptomic assays on tissue sections from patients. Unbiased clustering of 55,122 nuclei from HCM and healthy conditions revealed 9 cell lineages and 28 clusters. Lineage-specific changes in gene expression, subpopulation composition, and intercellular communication in HCM were discovered through comparative analyses. According to the results of pseudotime ordering, differential expression analysis, and differential regulatory network analysis, potential key genes during the transition towards a failing state of cardiomyocytes such as FGF12, IL31RA, and CREB5 were identified. Transcriptomic dynamics underlying cardiac fibroblast activation were also uncovered, and potential key genes involved in cardiac fibrosis were obtained such as AEBP1, RUNX1, MEOX1, LEF1, and NRXN3. Using the spatial transcriptomic data, spatial activity patterns of the candidate genes, pathways, and subpopulations were confirmed on patient tissue sections. Moreover, we showed experimental evidence that in vitro knockdown of AEBP1 could promote the activation of human cardiac fibroblasts, and overexpression of AEBP1 could attenuate the TGFβ-induced activation. Our study provided a comprehensive analysis of the lineage-specific regulatory changes in HCM, which laid the foundation for targeted drug development in HCM. Show less
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state accor Show more
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state according to their respective environment. Show less
Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-r Show more
Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases. A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes ( In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies. Show less
TNFAIP3-interacting protein 2 (TNIP2) is known as a negative regulator of NF-κB signaling and inhibit inflammatory response and apoptosis, and is also involved in RNA metabolism. In this study, we inv Show more
TNFAIP3-interacting protein 2 (TNIP2) is known as a negative regulator of NF-κB signaling and inhibit inflammatory response and apoptosis, and is also involved in RNA metabolism. In this study, we investigated the potential role of TNIP2 in amyloidogenesis critically associated with Alzheimer's disease (AD). We found a significant decline of TNIP2 protein level in both mouse and cell model of AD. In SH-SY5Y and HEK cells that stably express human full-length APP695 (SY5Y-APP and HEK-APP), TNIP2 overexpression decreased the protein levels of β-secretase (BACE1) and C99, as well as Aβ peptides (including Aβ40 and Aβ42), while those of α-secretase (ADAM10) and the related C83 remained unchanged. We further found that TNIP2 promoted the degradation of BACE1 mRNA and was able to bound to the 3' untranslated region (3'UTR) with the reduced luciferase activity. These results indicated that TNIP2 effectively inhibited amyloidogenic processing by regulating the 3'UTR-associated mRNA decay of BACE1. Show less
Qi Jiang, Ruolan Miao, Yuhuan Wang+8 more · 2023 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Polycystic ovary syndrome (PCOS) is one of the most common, heterogenous endocrine disorders and is the leading cause of ovulatory obstacle associated with abnormal folliculogenesis. Dysfunction of ov Show more
Polycystic ovary syndrome (PCOS) is one of the most common, heterogenous endocrine disorders and is the leading cause of ovulatory obstacle associated with abnormal folliculogenesis. Dysfunction of ovarian granulosa cells (GCs) is recognized as a major factor that underlies abnormal follicle maturation. Angiopoietin-like 4 (ANGPTL4) expression in GCs differs between patients with and without PCOS. However, the role and mechanism of ANGPTL4 in impaired follicular development are still poorly understood. Here, the case-control study was designed to investigate the predictive value of ANGPTL4 in PCOS while cell experiments in vitro were set for mechanism research. Results found that ANGPTL4 levels in serum and in follicular fluid, and its expression in GCs, were upregulated in patients with PCOS. In KGN and SVOG cells, upregulation of ANGPTL4 inhibited the proliferation of GCs by blocking G1/S cell cycle progression, as well as the molecular activation of the EGFR/JAK1/STAT3 cascade. Moreover, the STAT3-dependent CDKN1A(p21) promoter increased CDKN1A transcription, resulting in remarkable suppression effect on GCs. Together, our results demonstrated that overexpression of ANGPTL4 inhibited the proliferation of GCs through EGFR/JAK1/STAT3-mediated induction of p21, thus providing a novel epigenetic mechanism for the pathogenesis of PCOS. Show less
Human papillomavirus belongs to papovaviridae family papillomavirus A, a spherical deoxyribonucleic acid (DNA) virus, which can cause the proliferation of squamous epithelial cells of human skin or mu Show more
Human papillomavirus belongs to papovaviridae family papillomavirus A, a spherical deoxyribonucleic acid (DNA) virus, which can cause the proliferation of squamous epithelial cells of human skin or mucous membranes. With the rapid increase in the incidence of condyloma acuminatum among STDs and the increase in diseases caused by HPV infection, HPV infection has seriously endangered human health. In this paper, the in vitro detection of HPV E1 protein was realized using AgNCs-dsDNA. And through the test of this detection method, we calculated that the detection limit of this method is 0.886 nM. Compared with other methods for detecting E1 protein in vitro, this method has high sensitivity and simple operation. In addition, the detection method also has good anti-interference and selectivity, and can realize the detection of E1 in serum samples. The transfection efficiency of BLV-miR-B4-3p mimics at different time points was determined by quantitative real-time PCR (qPCR); the transcriptome sequencing of lymphocytes transfected with different concentrations of BLV-miR-B4-3p mimics was performed, and differential gene clustering was performed on the sequencing results. And the BLV-miR-B4-3p target gene prediction and transcriptome analysis results were verified by qPCR. The effects of BLV-miR-B4-3p on the transcriptional levels of immune-related cytokines in human lymphocytes were analyzed. Transcriptome sequencing analysis showed that after BLV-miR-B4-3p entered lymphocytes, a total of 556 differentially expressed genes were obtained. GO enrichment and KEGG analysis results showed that BLV-miR-B4-3p could independently activate influenza. The signaling pathway ultimately affects the body's immune system process, stress response, defense response, immune response, and other biological processes. After BLV-miR-B4-3p enters lymphocytes, it will lead to abnormal lymphocyte immune function, including the mRNA expression of TNF-α in Th1 cytokines which was significantly increased (P < 0.05), and the expression of IL-10 in Th2 cytokines was significantly increased (P < 0.05). The mRNA expression was significantly decreased (P < 0.05), and the mRNA expression of IL-27 was significantly increased (P < 0.001), which did not affect the mRNA expression of lymphocyte proliferation and activation-related regulators. The tumor suppressor breast cancer 1 (BRCA1) and antimicrobial peptide CAMP were significantly increased, and decreased (P < 0.001), and the expression of pro-apoptotic factor Caspase9 showed a significant downward trend (P < 0.05). Show less
Chicken is considered an ideal model species to study the synthesis of polyunsaturated fatty acids (PUFAs) due to its appropriate proportions of fatty acids and abundant content of PUFAs, suitable for Show more
Chicken is considered an ideal model species to study the synthesis of polyunsaturated fatty acids (PUFAs) due to its appropriate proportions of fatty acids and abundant content of PUFAs, suitable for human consumption. However, the molecular mechanisms regulating poultry PUFA synthesis remain unclear. Here, we systematically explored the transcriptional regulation activity of the gene family related to PUFA synthesis in chicken by carrying out the Dual-Luciferase Reporter Assay. We identified the core promoter regions of members of the chicken PUFA synthesis-related gene family, including ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, ELOVL7, FADS1, FADS2, FADS6, SCD, and SCD5. Additionally, changes in relative fluorescence values of different truncated segments in the upstream regulatory region of these genes indicate the existence of regulatory regions. Furthermore, we predicted the transcription factors that bind to the identified core promoter regions of multiple genes, including Sp1, NF-1, C/EBPalpha, etc. These findings provide a basis for the molecular mechanisms regulating poultry PUFA synthesis and offer new scientific insight into the potential improvement of poultry meat quality in the future. Show less
The decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) is one of the important reasons for SOP. Inhibition of Wnt signaling in MSCs is closely related to SOP. Microtubule ac Show more
The decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) is one of the important reasons for SOP. Inhibition of Wnt signaling in MSCs is closely related to SOP. Microtubule actin crosslinking factor 1 (MACF1) is an important regulator in Wnt/β-catenin signal transduction. However, whether the specific expression of MACF1 in MSC regulates SOP and its mechanism remains unclear. We established MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-KI) mice, naturally aged male mice, and ovariectomized female mice models. Micro-CT, H&E staining, double calcein labeling, and the three-point bending test were used to explore the effects of MACF1 on bone formation and bone microstructure in the SOP mice model. Bioinformatics analysis, ChIP-PCR, qPCR, and ALP staining were used to explore the effects and mechanisms of MACF1 on MSCs' osteogenic differentiation. Microarray analysis revealed that the expression of MACF1 and positive regulators of the Wnt pathway (such as TCF4, β-catenin, Dvl) was decreased in human MSCs (hMSCs) isolated from aged osteoporotic than non-osteoporotic patients. The ALP activity and osteogenesis marker genes (Alp, Runx2, and Bglap) expression in mouse MSCs was downregulated during aging. Furthermore, Micro-CT analysis of the femur from 2-month-old MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-cKI) mice showed no significant trabecular bone changes compared to wild-type littermate controls, whereas 18- and 21-month-old MACF1 c-KI animals displayed increased bone mineral densities (BMD), improved bone microstructure, and increased maximum compression stress. In addition, the ovariectomy (OVX)-induced osteoporosis model of MACF1 c-KI mice had significantly higher trabecular volume and number, and increased bone formation rate than that in control mice. Mechanistically, ChIP-PCR showed that TCF4 could bind to the promoter region of the host gene miR-335-5p. Moreover, MACF1 could regulate the expression of miR-335-5p by TCF4 during the osteogenic differentiation of MSCs. These data indicate that MACF1 positively regulates MSCs osteogenesis and bone formation through the TCF4/miR-335-5p signaling pathway in SOP, suggesting that targeting MACF1 may be a novel therapeutic approach against SOP. MACF1, an important switch in the Wnt signaling pathway, can alleviate SOP through the TCF4/miR-335-5p signaling pathway in mice model. It might act as a therapeutic target for the treatment of SOP to improve bone function. 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 th Show more
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
Arabidopsis nucleoporin involved in the regulation of ethylene signaling via controlling of nucleocytoplasmic transport of mRNAs. The two-way transport of mRNAs between the nucleus and cytoplasm are c Show more
Arabidopsis nucleoporin involved in the regulation of ethylene signaling via controlling of nucleocytoplasmic transport of mRNAs. The two-way transport of mRNAs between the nucleus and cytoplasm are controlled by the nuclear pore complex (NPC). In higher plants, the NPC contains at least 30 nucleoporins. The Arabidopsis nucleoporins are involved in various biological processes such as pathogen interaction, nodulation, cold response, flowering, and hormone signaling. However, little is known about the regulatory functions of the nucleoporin NUP160 and NUP96 in ethylene signaling pathway. In the present study, we provided data showing that the Arabidopsis nucleoporin NUP160 and NUP96 participate in ethylene signaling-related mRNAs nucleocytoplasmic transport. The Arabidopsis nucleoporin mutants (nup160, nup96-1, nup96-2) exhibited enhanced ethylene sensitivity. Nuclear qRT-PCR analysis and poly(A)-mRNA in situ hybridization showed that the nucleoporin mutants affected the nucleocytoplasmic transport of all the examined mRNAs, including the ethylene signaling-related mRNAs such as ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, and EIN3. Transcriptome analysis of the nucleoporin mutants provided clues suggesting that the nucleoporin NUP160 and NUP96 may participate in ethylene signaling via various molecular mechanisms. These observations significantly advance our understanding of the regulatory mechanisms of nucleoporin proteins in ethylene signaling and ethylene response. Show less
Icariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summa Show more
Icariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. The PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. The study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aβ via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca This study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD. Show less
Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which a Show more
Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an Show less