Body conformation is the most direct production index, which can fully reflect pig growth status and is closely related to critical economic traits. In this study, we conducted a genome-wide associati Show more
Body conformation is the most direct production index, which can fully reflect pig growth status and is closely related to critical economic traits. In this study, we conducted a genome-wide association study (GWAS) on body conformation traits in a population of 1518 Duroc × (Landrace × Yorkshire) commercial pigs. These traits included body length (BL), body height (BH), chest circumference (CC), abdominal circumference (AC), and waist circumference (WC). Both the mixed linear model (MLM) and fixed and random model circulating probability unification (FarmCPU) approaches were employed for the analysis. Our findings revealed 60 significant single nucleotide polymorphisms (SNPs) associated with these body conformation traits in the crossbred pig population. Specifically, sixteen SNPs were significantly associated with BL, three SNPs with BH, thirteen SNPs with CC, twelve SNPs with AC, and sixteen SNPs with WC. Moreover, we identified several promising candidate genes located within the genomic regions associated with body conformation traits. These candidate genes include Show less
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Show more
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and β-catenin and promotes the phase separation for β-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing β-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent. 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
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
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation Show more
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aβ generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aβ generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aβ generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aβ generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1β, APP, CTF-β, BACE1 and Aβ Show less
Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigrat Show more
Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model. Twenty-four male Sprague-Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations. All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05). Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model. Show less
Bidirectional communication between the developing conceptus and endometrium is essential for pregnancy recognition and establishment in ruminants. We dissect the transcriptomic dynamics of sheep conc Show more
Bidirectional communication between the developing conceptus and endometrium is essential for pregnancy recognition and establishment in ruminants. We dissect the transcriptomic dynamics of sheep conceptus and corresponding endometrium at pre- and peri-implantation stages using single-cell RNA sequencing. Spherical blastocysts contain five cell types, with 68.62% trophectoderm cells. Strikingly, elongated conceptuses differentiate into 17 cell types, indicating dramatic cell fate specifications. Cell-type-specific gene expression delineates the features of distinctive trophectoderm lineages and indicates that the transition from polar trophectoderm to trophoblast increases interferon-tau expression and likely drives elongation initiation. We identify 13 endometrium-derived cell types and elucidate their molecular responses to conceptus development. Integrated analyses uncover multiple paired transcripts mediating the dialogues between extraembryonic membrane and endometrium, including IGF2-IGF1R, FGF19-FGFR1, NPY-NPY1R, PROS1-AXL, and ADGRE5-CD55. These data provide insight into the molecular regulation of conceptus elongation and represent a valuable resource for functional investigations of pre- and peri-implantation ruminant development. Show less
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current stra Show more
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies employing protein growth factors pose challenges in terms of both reproducibility and cost. In this study, we developed a novel DNA-based modulator to regulate FGFR signaling in NPCs, thereby facilitating the long-term maintenance of stemness and promoting neurogenesis. This DNA-based FGFR-agonist effectively stimulated FGFR1 phosphorylation and activated the downstream ERK signaling pathway in human embryonic stem cell (HESC)-derived NPCs. We replaced the basic fibroblast growth factor (bFGF) in the culture medium with our DNA-based FGFR-agonist to artificially modulate FGFR signaling in NPCs. Utilizing a combination of cell experiments and bioinformatics analyses, we showed that our FGFR-agonist could enhance NPC proliferation, direct migration, and promote neurosphere formation, thus mimicking the functions of bFGF. Notably, transcriptomic analysis indicated that the FGFR-agonist could specifically influence the transcriptional program associated with stemness while maintaining the neuronal differentiation program, closely resembling the effects of bFGF. Furthermore, our culture conditions allowed for the successful propagation of NPCs through over 50 passages while retaining their ability to efficiently differentiate into neurons. Collectively, our approach offers a highly effective method for expanding NPCs, thereby providing new avenues for disease-in-dish research and drug screening aimed at combating neural degeneration. Show less
Axin1 takes an important part in a variety of signaling pathway, such as MEKK1, GSK3β, and β-catenin, and plays a variety of physiological functions; but its effects on the brain-blood barrier (BBB) a Show more
Axin1 takes an important part in a variety of signaling pathway, such as MEKK1, GSK3β, and β-catenin, and plays a variety of physiological functions; but its effects on the brain-blood barrier (BBB) and stroke remain unclear. To explore the effects and underlying mechanisms of Axin1 on the BBB in ischemic stroke, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Human brain microvascular endothelial cells (HBMEC) were subjected to oxygen/glucose deprivation/reoxygenation (OGD/R) to imitate ischemia/reperfusion (I/R) injury. We found that Axin1 was upregulated in HBMEC after OGD without reoxygenation, and downregulated in the injured hemisphere after MCAO without reperfusion. Tight junction (TJ) proteins were upregulated both in HBMEC after OGD without reoxygenation and in ischemic penumbra of the injured hemisphere in rats after MCAO without reperfusion. TJ proteins were downregulated after MCAO/R in rats. Overexpression of Axin1 upregulated the levels of TJ proteins, which alleviated BBB permeability, reduced infarction volume, and ultimately improved neurological behavioral indicators after I/R injury. Furthermore, inhibiting phosphorylation of Axin1 at Thr485 notably increased the expression of Snail and decreased the expression of TJ proteins. Our findings demonstrate that Axin1 participates in BBB protection and improvement of neurological functions during ischemic stroke by regulating TJ proteins. Axin1 may serve as a potential novel candidate to protect BBB and relieve brain injury. 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
Currently, the prevalence of allergic rhinitis (AR) remains high and there is a great need to develop better and safer ways to alleviate AR symptoms. The Adults aged from 18 to 60 years old and previo Show more
Currently, the prevalence of allergic rhinitis (AR) remains high and there is a great need to develop better and safer ways to alleviate AR symptoms. The Adults aged from 18 to 60 years old and previously suffered from AR were recruited and received GUANKE probiotics treatment for 4 weeks. The questionnaires of Total nasal symptom scores (TNSS), total non-nasal symptom score (TNNSS), and rhinitis control assessment test (RCAT) were used to assess the effectiveness before and after treatment. The serum allergen-specific IgE and cytokines were also determined at baseline and after 4 weeks of probiotics administration. The results showed that TNSS and TNNSS were significantly reduced and the RCAT score was significantly increased compared to baseline. The sub-symptom score of rhinorrhea, itching, sneezing, and tearing in each questionnaire also showed significant changes, and the serum IgE level was markedly decreased. We further measured inflammatory-related proteins in serum and found that a total of 20 proteins (6 upregulated and 14 downregulated) were significantly changed compared to baseline, including IL-4, IL-7, IL-20, IL-33, CXCL1, CXCL5, CXCL6, CXCL11, CCL4, CCL23, TGF-alpha, LAP-TGF-beta-1, MMP-1, MMP-10, AXIN1, NT-3, OSM, SCF, CD6, and NRTN. Enrichment analysis showed that these significantly altered proteins were mainly enriched in cytokine and chemokine-related signaling pathways. Taken together, this study demonstrated the Show less
The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the ca Show more
The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis. Nine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method. Per standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02-1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01-1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94-1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547. This study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis. Show less
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet- Show more
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents. 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
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
17α-Methyltestosterone (MT), a synthetic environmental endocrine disruptor with androgenic effects, has been shown to disrupt the reproductive system and inhibit germ cell maturation in
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
Obesity is a global epidemic around the world. Reticulon-4B (Nogo-B) is an endoplasmic reticulum-resident protein. Our previous work demonstrated that Nogo-B deficiency inhibited obesity and decreased Show more
Obesity is a global epidemic around the world. Reticulon-4B (Nogo-B) is an endoplasmic reticulum-resident protein. Our previous work demonstrated that Nogo-B deficiency inhibited obesity and decreased the size of white adipocytes. However, the underlying molecular mechanism of Nogo-B in white adipogenesis remains poorly understood. This study aims to explore the effect of Nogo-B in white adipogenesis, as well as its underlying molecular mechanisms. The study adopted mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes to induce white adipogenesis and investigate the effect of Nogo-B on adipogenesis using qRT-PCR, Western blotting, immunofluorescence, lipid quantification, and Oil Red O staining. During white adipogenesis, Nogo-B expression was increased accompanied by upregulation of adipogenic markers. In contrast, Nogo-B deficiency inhibited white adipocyte markers expression and lipid accumulation. Furthermore, the mechanism study showed that Nogo-B deficiency decreased the destruction complex [AXIN1-APC-glycogen synthase kinase 3β (GSK3β)] levels through activating protein kinase B 2 (AKT2), resulting in β-catenin translocating into the nucleus and inhibiting the expression of adipogenic markers. Moreover, Nogo-B deficiency promoted the expression of brown/beige adipocytes markers while improving mitochondrial thermogenesis by activating β-catenin pathway. In addition, Nogo-B deficiency reduced the levels of inflammatory molecules during white adipogenic differentiation. This study revealed that Nogo-B deficiency inhibited white adipogenesis through AKT2/GSK3β/β-catenin pathway. Meanwhile, Nogo-B deficiency increased the expression of brown/beige adipocyte markers and promoted mitochondrial thermogenesis. In addition, Nogo-B deficiency reduced inflammatory cytokine levels caused by adipogenesis. Collectively, blocking Nogo-B expression may be a potential strategy to suppress white adipogenesis. Show less
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-2 Show more
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-27 in the heart and serum until day 14 in murine cardiac ischemia‒reperfusion injury models. However, whether IL-27 is involved in chronic inflammation-mediated ventricular remodeling remains unclear. In the present study, we found that MI triggered high IL-27 expression in murine cardiac macrophages. The increased expression of IL-27 in serum is correlated with cardiac dysfunction and aggravated fibrosis after MI. Furthermore, the addition of IL-27 significantly activated the JAK/STAT signaling pathway in cardiac fibroblasts (CFs). Meanwhile, IL-27 treatment promoted the proliferation, migration and extracellular matrix (ECM) production of CFs induced by angiotensin II (Ang II). Collectively, high levels of IL-27 mainly produced by cardiac macrophages post MI contribute to the activation of CFs and aggravate cardiac fibrosis. 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
Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Show more
Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing Show less
The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabet Show more
The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis. Genetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments. Genetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52-0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83-0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR. This MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future. Show less
Mi Li, Xian Wang, Lijie Yang+3 more · 2023 · Technology and health care : official journal of the European Society for Engineering and Medicine · added 2026-04-24
Microglia express phosphatidylinositol 3-kinase (PI3K) has been implicated in the induction and maintenance of long-term potentiation (LTP) and in hippocampal synaptic plasticity. However, there are f Show more
Microglia express phosphatidylinositol 3-kinase (PI3K) has been implicated in the induction and maintenance of long-term potentiation (LTP) and in hippocampal synaptic plasticity. However, there are few studies on the interference of PI3K signal pathway in microglia. The study goal is to gain a better understanding of the mechanism by which EA affects synapses provides insights into how electroacupuncture (EA) modulates synaptic plasticity in learning and memory. Rat models of posttraumatic stress disorder (PTSD) were used to explore the effects of EA on microglial PI3K pathway, brain-derived neurotrophic factor (BDNF) and LTP, and the target and mechanism underlying the effects of EA on PI3K from the perspective of protein ubiquitination. EA induced microglial BDNF expression by activating the PI3K-AKT pathway, thereby facilitating LTP and synaptic plasticity. EA inhibited lincRNA 02023 to rescue the binding of WWP2 to PTEN, thereby promoting PTEN ubiquitination and degradation. The mechanism of EA improving the learning and memory ability of PTSD rats may be that it can promote the competitive combination of WWP2 and PTEN by inhibiting Linc RNA02023, and then lead to microglial PI3K and its pathway activation, BDNF up-regulation, and finally induce LTP and repair damaged synaptic plasticity. Show less
This study aims to confirm whether apolipoprotein C3 (ApoC3) can regulate the inflammatory response and tissue damage in acute lung injury (ALI) and explore its regulatory pathway. ALI mouse model was Show more
This study aims to confirm whether apolipoprotein C3 (ApoC3) can regulate the inflammatory response and tissue damage in acute lung injury (ALI) and explore its regulatory pathway. ALI mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). ApoC3 levels were detected by real-time quantitative polymerase chain reaction, immunohistochemistry, and western blot assays. The levels of various inflammatory factors were detected by enzyme-linked immunosorbent assay and western blot analysis. Finally, the expression of toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) signaling pathway-related protein [TLR2, myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor-associated kinase 1 (IRAK1), NF-κB p65, and inhibitor of kappa B alpha (IκBα)], SLP adaptor and CSK interacting membrane protein (SCIMP), spleen tyrosine kinase (Syk), and phosphorylated (p)-Syk was detected by western blot analysis. ApoC3 was overexpressed in ALI mouse lung tissue and cell inflammation model. Silencing ApoC3 reduced inflammatory factors and alleviated lung tissue damage in ALI mice. Silencing ApoC3 reduced inflammatory factors and downregulated the expression of TLR2, MyD88, IRAK1, NF-κB p65, and increased IκBα expression in LPS-treated RAW264.7 cells. Moreover, co-transfection of si-TLR2 and shApoC3 further enhanced the inhibitory effects on the levels of inflammatory factors induced by silencing ApoC3. ApoC3 overexpression increased the levels of inflammatory factors and protein expression of SCIMP and p-Syk, while silencing TLR2 reversed the promotive effects of ApoC3 overexpression on above factors. In LPS-induced ALI mouse model and inflammatory cell model, downregulation of ApoC3 reduced inflammatory factors and relieved tissue damage. This process might be achieved through the TLR pathway. Show less