Background:A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population.However,the relationsh...Background:A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population.However,the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus (GDM) has not been reported to date.The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development.Methods:We conducted a prospective,nested case-control study in a pregnancy cohort.First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy.Median ANGPTL2 levels were compared using Mann-Whitney U-test.Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles.Results:The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM (3.06 [2.59,3.65] ng/ml vs.2.46 [2.05,2.96] ng/ml,P =0.003).Fasting blood glucose was higher in women with GDM than that in women without GDM (5.0 ± 0.9 mmol/L vs.4.4 ± 0.6 mmol/L,P 〈 0.001).Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM (9.1 ± 3.5 mmol/L vs.6.2 ± 1.2 mmol/L,P 〈 0.001).A multivariate model adjusted for baseline characteristics,medical complications,and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy.Conclusions:At 1 1-13 weeks in pregnancies that develop GDM,the serum concentration of ANGPTL2 is increased,and it can be combined with maternal factors to provide effective early screening for GDM.展开更多
BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in ...BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in the development of MAFLD,with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma.Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers.However,imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints.Consequently,it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis.AIM To investigate the predictive value of angiopoietin-like protein 8(ANGPTL8)in MAFLD and its progression.METHODS We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department,Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology,during September 2021-July 2022.Using abdominal ultrasonography and MAFLD diagnostic criteria,among the 160 patients,80 patients(50%)were diagnosed with MAFLD.The MAFLD group was divided into the liver fibrosis group(n=23)and non-liver fibrosis group(n=57)by using a cut-off fibrosis-4 index≥1.45.Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression.Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression.RESULTS Compared with non-MAFLD patients,MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose(TyG)index(both P<0.05).Serum ANGPTL8(r=0.576,P<0.001)and TyG index(r=0.473,P<0.001)were positively correlated with MAFLD.Serum ANGPTL8 was a risk factor for MAFLD[odds ratio(OR):1.123,95%confidence interval(CI):1.066-1.184,P<0.001).Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD[area under the curve(AUC):0.832 and 0.886,respectively;both P<0.05].Compared with MAFLD patients without fibrosis,those with fibrosis had higher serum ANGPTL8 and TyG index(both P<0.05),and both parameters were positively correlated with MAFLD-associated fibrosis.Elevated serum ANGPTL8(OR:1.093,95%CI:1.044-1.144,P<0.001)and TyG index(OR:2.383,95%CI:1.199-4.736,P<0.013)were risk factors for MAFLD-associated fibrosis.Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD-associated fibrosis(AUC:0.812 and 0.835,respectively;both P<0.05).CONCLUSION The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD.They can serve as predictors for the risk of MAFLD and liver fibrosis,with the ANGPTL8+TyG index potentially exhibiting even higher predictive value.展开更多
Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholestero...Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis.However,little is known about the role of LRP2 in lipid homeostasis in insects.In the present study,we investigated the function of LRP2 in the migratory locust Locusta migratoria(LmLRP2).The mRNA of LmLRP2 is widely distributed in various tissues,including integument,wing pads,foregut,midgut,hindgut,Malpighian tubules and fat body,and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage.Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut.Using RNAi to silence LmLRP2 caused molting defects in nymphs(more than 60%),and the neutral lipid was found to accumulate in the midgut and surface of the integument,but not in the fat body,of dsLmLRP2-treated nymphs.The results of a lipidomics analysis showed that the main components of lipids(diglyceride and triglyceride)were significantly increased in the midgut,but decreased in the fat body and hemolymph.Furthermore,the content of total triglyceride was significantly increased in the midgut,but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs.Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells,and is required for lipid export from the midgut to the hemolymphand fat body in locusts.展开更多
BACKGROUND Recently,type 2 diabetic osteoporosis(T2DOP)has become a research hotspot for the complications of diabetes,but the specific mechanism of its occurrence and development remains unknown.Ferroptosis caused by...BACKGROUND Recently,type 2 diabetic osteoporosis(T2DOP)has become a research hotspot for the complications of diabetes,but the specific mechanism of its occurrence and development remains unknown.Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP.Polycytosine RNA-binding protein 1(PCBP1),an iron ion chaperone,is considered a protector of ferroptosis.AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes.METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose(HG)and/or ferroptosis inhibitors at different concentrations and times.Transmission electron microscopy was used to examine the morpho-logical changes in the mitochondria of osteoblasts under HG,and western blotting was used to detect the expression levels of PCBP1,ferritin,and the ferroptosis-related protein glutathione peroxidase 4(GPX4).A lentivirus silenced and overex-pressed PCBP1.Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin(OPG)and osteocalcin(OCN),whereas flow cytometry was used to detect changes in reactive oxygen species(ROS)levels in each group.RESULTS Under HG,the viability of osteoblasts was considerably decreased,the number of mitochondria undergoing atrophy was considerably increased,PCBP1 and ferritin expression levels were increased,and GPX4 expression was decreased.Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1,increased the expression levels of ferritin,GPX4,OPG,and OCN,compared with the HG group.Flow cytometry results showed a reduction in ROS,and an opposite result was obtained after silencing PCBP1.CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment.Moreover,PCBP1 may be a potential therapeutic target for T2DOP.展开更多
AIM:To confirm the role of angiopoietin-like protein 8(Angptl 8) in proliferative diabetic retinopathy(PDR).METHODS:The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy(NDR) patients(...AIM:To confirm the role of angiopoietin-like protein 8(Angptl 8) in proliferative diabetic retinopathy(PDR).METHODS:The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy(NDR) patients(idiopathic macular hole patients) were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay(ELISA).Experimental diabetes mice model was induced with streptozotocin.The expression of glycosylated hemoglobin and Angptl 8 in sera was detected.Recombinant Angptl 8 was re-infused into wild type(WT) diabetic mice and spatial frequency threshold and contrast sensitivity were measured.In vitro retinal pigment epithelium(RPE) were stimulated by recombinant Angptl 8 for 24 h.MMT assay were used to detect cell proliferation.At the same time,q RT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells.RESULTS:The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients(F=99.02,P〈0.0001 in sera;t=10.42,P〈0.0001 in aqueous).After successfully establishing the diabetic mice model,we found that glycosylated hemoglobin and Angptl 8 expression levels were increased.Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity(P〈0.01).In vitro,RPE cells stimulated by recombinant Angptl 8could increase the relative absorbance of MMT assay(1.486±0.042 vs 1.000±0.104,P〈0.05) and proliferating cell nuclear antigen(PCNA) expression(0.55±0.01 vs 0.29±0.03,P〈0.05).The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1(4.973±0.205 vs 2.720±0.197,P〈0.05),cyclin F(5.690±0.219 vs 4.297±0.292,P〈0.05) and E2 F2(2.297±0.102 vs 1.750±0.146,P〈0.05),and reducing the expression of proliferation-inhibiting factors cdkn1(2.370±0.074 vs 3.317±0.135,P〈0.05) and cdkn2(4.793±0.065 vs 5.387±0.149,P〈0.05).CONCLUSION:The expression of Angptl 8 is increased in PDR,and the increased Angptl 8 can promote proliferation and increase proliferation-related factors.展开更多
Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the int...Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.展开更多
Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 (ANGPTL3) can contribute to disorder of carbohydrate and lipid metabolism. The presen...Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 (ANGPTL3) can contribute to disorder of carbohydrate and lipid metabolism. The present study was conducted to investigate the change of ANGPTL3 expression during pregnancy toxemia, We firstly cloned the full-length cDNA of ANGPTL3 in Liuyang Black goats, revealing that goat ANGPTL3 had the typical structure of the angiopoietin-like family, and its mRNA was exclusively expressed in liver. Pregnancy toxemia of pregnant goat does with twins during late gestation was induced by being fasted for 72 h, and then they were recovered after 5 d ofrefeeding. Hepatic ANGPTL3 gene expression was significantly down-regulated concomitantly with decreased serum glucose concentration, elevated serum β-hydroxybutyrate and free fatty acid levels in pregnant toxemic goats, and these changes were reversed after refeeding. These results suggest ANGPTL3 may play a certain role in the development of pregnancy toxemia in goats.展开更多
BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and e...BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality.To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration.Recombinant human angiopoietin-like protein 4(rhANGPTL4)is reported to protect the blood-brain barrier when administered exogenously,and endogenous ANGPTL4 deficiency deteriorates radiationinduced intestinal injury.AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion.Intestinal epithelial(Caco-2)cells and human umbilical vein endothelial cells were challenged by hypoxia/reoxygenation to mimic I/R in vitro.RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran(4 kilodaltons;FD-4)clearance,ratio of phosphorylated myosin light chain/total myosin light chain,myosin light chain kinase and loss of zonula occludens-1,claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation.rhANGPTL4 treatment significantly reversed these indicators,which were associated with inhibiting the inflammatory and oxidative cascade,excessive activation of cellular autophagy and apoptosis and improvement of survival rate.Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation,whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.展开更多
Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such pept...Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis.In total,1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry(nano LC-MS/MS)and 4 novel COX-2 inhibitory peptides(AGFP,FPGA,LFPD,and VGFP)were identified.Enzyme kinetic data indicated that AGFP,FPGA,and LFPD displayed mixed-type COX-2 inhibition,whereas VGFP was a non-competitive inhibitor.This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site.These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.展开更多
BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untran...BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndr...Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.展开更多
In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2...In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2 diabetes mellitus(T2DM)is a chronic disorder characterized by dysregulated glucose homeostasis.The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications,including cardiovascular disease,re-tinopathy,neuropathy,and nephropathy.T2DM arises from a complex interplay between genetic,epigenetic,and environmental factors.Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM.Specifically,variations within the glucokinase regulatory protein(GCKR)gene have been linked to heightened susceptibility to T2DM and its associated complications.The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development.Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype.These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.展开更多
This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore t...This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.展开更多
Fibroids, also called leiomyomas or myomas, are communal tumors of the muscle or uterine wall that affect about 20% of females who are of reproductive age. They can look as if singly or in clusters, and they often cea...Fibroids, also called leiomyomas or myomas, are communal tumors of the muscle or uterine wall that affect about 20% of females who are of reproductive age. They can look as if singly or in clusters, and they often cease to grow after menopause. Fibroids can be classified as intramural, sub serosal, pedunculated, or submucosal based on where they are positioned in the uterus. Although fibroids are benign, they can grow quickly and cause a range of symptoms, such as pelvic pressure, heavy menstrual flow, and infertility. As a result, fibroids are a main reason behind hysterectomy surgeries. The majority of cases of breast cancer are ductal and lobular cancers, making it the second utmost common cancer in women international. Gene mutations like those in BRCA1 or BRCA2 knowingly raise the risk of breast and other cancers, typically with an earlier cancer onset. Cancer risk is influenced by a complex interplay of genetic abnormalities, environmental factors, and lifestyle selections. Further research into these relations is domineering. Although they are common in uterine leiomyomas, especially multiple leiomyomas, MED12 mutations do not significantly correlate with tumor size. These mutations have also been noticed in smooth muscle tumors and leiomyosarcomas, two other types of uterine cancer. The identification of MED12 mutations as the sole genetic abnormality originates in leiomyomas raises the opportunity of a role in the genesis of cancer. 10% - 15% of women who are of reproductive age have endometriosis, which grants serious difficulties because of its chronic nature and range of clinical symptoms. Even after effective surgeries, issues reoccur often, adding to the enormous financial burden. The effects of MED12 mutations have been experiential in recent studies examining the molecular causes of endometriosis-associated infertility, which have shown anomalies in cellular connections and signaling cascades. Computational techniques were used in this study to investigate LifeGreenTM’s potential to prevent uterine fibroids and breast cancer. The efficacy of LifeGreenTM as a preventive measure or a treatment for common gynecological matters was examined and modeled. We investigated the mechanisms underlying LifeGreenTM’s benefits in the treatment of uterine fibroids and breast cancer using computational techniques. Our research contributes to our understanding of its potential therapeutic benefits for women’s health.展开更多
Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PT...Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.展开更多
基金This study was supported by the grant of the National Natural Science Foundation of China (No. 81471427).
文摘Background:A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population.However,the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus (GDM) has not been reported to date.The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development.Methods:We conducted a prospective,nested case-control study in a pregnancy cohort.First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy.Median ANGPTL2 levels were compared using Mann-Whitney U-test.Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles.Results:The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM (3.06 [2.59,3.65] ng/ml vs.2.46 [2.05,2.96] ng/ml,P =0.003).Fasting blood glucose was higher in women with GDM than that in women without GDM (5.0 ± 0.9 mmol/L vs.4.4 ± 0.6 mmol/L,P 〈 0.001).Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM (9.1 ± 3.5 mmol/L vs.6.2 ± 1.2 mmol/L,P 〈 0.001).A multivariate model adjusted for baseline characteristics,medical complications,and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy.Conclusions:At 1 1-13 weeks in pregnancies that develop GDM,the serum concentration of ANGPTL2 is increased,and it can be combined with maternal factors to provide effective early screening for GDM.
基金Supported by Youth Talents Project of Joint Fund of Hubei Health Commission,No.WJ2019H170and Xiaogan Natural Science Project,No.XGKJ2020010033。
文摘BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in the development of MAFLD,with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma.Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers.However,imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints.Consequently,it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis.AIM To investigate the predictive value of angiopoietin-like protein 8(ANGPTL8)in MAFLD and its progression.METHODS We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department,Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology,during September 2021-July 2022.Using abdominal ultrasonography and MAFLD diagnostic criteria,among the 160 patients,80 patients(50%)were diagnosed with MAFLD.The MAFLD group was divided into the liver fibrosis group(n=23)and non-liver fibrosis group(n=57)by using a cut-off fibrosis-4 index≥1.45.Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression.Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression.RESULTS Compared with non-MAFLD patients,MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose(TyG)index(both P<0.05).Serum ANGPTL8(r=0.576,P<0.001)and TyG index(r=0.473,P<0.001)were positively correlated with MAFLD.Serum ANGPTL8 was a risk factor for MAFLD[odds ratio(OR):1.123,95%confidence interval(CI):1.066-1.184,P<0.001).Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD[area under the curve(AUC):0.832 and 0.886,respectively;both P<0.05].Compared with MAFLD patients without fibrosis,those with fibrosis had higher serum ANGPTL8 and TyG index(both P<0.05),and both parameters were positively correlated with MAFLD-associated fibrosis.Elevated serum ANGPTL8(OR:1.093,95%CI:1.044-1.144,P<0.001)and TyG index(OR:2.383,95%CI:1.199-4.736,P<0.013)were risk factors for MAFLD-associated fibrosis.Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD-associated fibrosis(AUC:0.812 and 0.835,respectively;both P<0.05).CONCLUSION The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD.They can serve as predictors for the risk of MAFLD and liver fibrosis,with the ANGPTL8+TyG index potentially exhibiting even higher predictive value.
基金supported by the National Key R&D Program of China (2022YFE0196200)the National Natural Science Foundation of China–Deutsche Forschungsgemeinschaft of Germany (31761133021)+3 种基金the National Natural Science Foundation of China (31970469 and 31701794)the earmarked fund for Modern Agro-industry Technology Research System, China (2023CYJSTX01-20)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi, China (2017104)the Fund for Shanxi “1331 Project”, China
文摘Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis.However,little is known about the role of LRP2 in lipid homeostasis in insects.In the present study,we investigated the function of LRP2 in the migratory locust Locusta migratoria(LmLRP2).The mRNA of LmLRP2 is widely distributed in various tissues,including integument,wing pads,foregut,midgut,hindgut,Malpighian tubules and fat body,and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage.Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut.Using RNAi to silence LmLRP2 caused molting defects in nymphs(more than 60%),and the neutral lipid was found to accumulate in the midgut and surface of the integument,but not in the fat body,of dsLmLRP2-treated nymphs.The results of a lipidomics analysis showed that the main components of lipids(diglyceride and triglyceride)were significantly increased in the midgut,but decreased in the fat body and hemolymph.Furthermore,the content of total triglyceride was significantly increased in the midgut,but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs.Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells,and is required for lipid export from the midgut to the hemolymphand fat body in locusts.
基金Supported by the National Natural Science Foundation of China,No.81471094 and No.82202743.
文摘BACKGROUND Recently,type 2 diabetic osteoporosis(T2DOP)has become a research hotspot for the complications of diabetes,but the specific mechanism of its occurrence and development remains unknown.Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP.Polycytosine RNA-binding protein 1(PCBP1),an iron ion chaperone,is considered a protector of ferroptosis.AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes.METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose(HG)and/or ferroptosis inhibitors at different concentrations and times.Transmission electron microscopy was used to examine the morpho-logical changes in the mitochondria of osteoblasts under HG,and western blotting was used to detect the expression levels of PCBP1,ferritin,and the ferroptosis-related protein glutathione peroxidase 4(GPX4).A lentivirus silenced and overex-pressed PCBP1.Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin(OPG)and osteocalcin(OCN),whereas flow cytometry was used to detect changes in reactive oxygen species(ROS)levels in each group.RESULTS Under HG,the viability of osteoblasts was considerably decreased,the number of mitochondria undergoing atrophy was considerably increased,PCBP1 and ferritin expression levels were increased,and GPX4 expression was decreased.Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1,increased the expression levels of ferritin,GPX4,OPG,and OCN,compared with the HG group.Flow cytometry results showed a reduction in ROS,and an opposite result was obtained after silencing PCBP1.CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment.Moreover,PCBP1 may be a potential therapeutic target for T2DOP.
文摘AIM:To confirm the role of angiopoietin-like protein 8(Angptl 8) in proliferative diabetic retinopathy(PDR).METHODS:The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy(NDR) patients(idiopathic macular hole patients) were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay(ELISA).Experimental diabetes mice model was induced with streptozotocin.The expression of glycosylated hemoglobin and Angptl 8 in sera was detected.Recombinant Angptl 8 was re-infused into wild type(WT) diabetic mice and spatial frequency threshold and contrast sensitivity were measured.In vitro retinal pigment epithelium(RPE) were stimulated by recombinant Angptl 8 for 24 h.MMT assay were used to detect cell proliferation.At the same time,q RT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells.RESULTS:The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients(F=99.02,P〈0.0001 in sera;t=10.42,P〈0.0001 in aqueous).After successfully establishing the diabetic mice model,we found that glycosylated hemoglobin and Angptl 8 expression levels were increased.Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity(P〈0.01).In vitro,RPE cells stimulated by recombinant Angptl 8could increase the relative absorbance of MMT assay(1.486±0.042 vs 1.000±0.104,P〈0.05) and proliferating cell nuclear antigen(PCNA) expression(0.55±0.01 vs 0.29±0.03,P〈0.05).The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1(4.973±0.205 vs 2.720±0.197,P〈0.05),cyclin F(5.690±0.219 vs 4.297±0.292,P〈0.05) and E2 F2(2.297±0.102 vs 1.750±0.146,P〈0.05),and reducing the expression of proliferation-inhibiting factors cdkn1(2.370±0.074 vs 3.317±0.135,P〈0.05) and cdkn2(4.793±0.065 vs 5.387±0.149,P〈0.05).CONCLUSION:The expression of Angptl 8 is increased in PDR,and the increased Angptl 8 can promote proliferation and increase proliferation-related factors.
文摘Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
基金the National Natural Science Foundation of China (31072167)the Key Project of Hunan Provincial Science & Technology Department, China(2009FJ1005)Innovation Project of Hunan Provincial Education Department (CX2009B153), China
文摘Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 (ANGPTL3) can contribute to disorder of carbohydrate and lipid metabolism. The present study was conducted to investigate the change of ANGPTL3 expression during pregnancy toxemia, We firstly cloned the full-length cDNA of ANGPTL3 in Liuyang Black goats, revealing that goat ANGPTL3 had the typical structure of the angiopoietin-like family, and its mRNA was exclusively expressed in liver. Pregnancy toxemia of pregnant goat does with twins during late gestation was induced by being fasted for 72 h, and then they were recovered after 5 d ofrefeeding. Hepatic ANGPTL3 gene expression was significantly down-regulated concomitantly with decreased serum glucose concentration, elevated serum β-hydroxybutyrate and free fatty acid levels in pregnant toxemic goats, and these changes were reversed after refeeding. These results suggest ANGPTL3 may play a certain role in the development of pregnancy toxemia in goats.
基金the National Natural Science Foundation of China,No.81600446the Science and Technology of Traditional Chinese Medicine Foundation in Qingdao,No.2021-zyyz03the Science and technology development of Medicine and health Foundation in Shandong Province,China,No.202004010508.
文摘BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality.To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration.Recombinant human angiopoietin-like protein 4(rhANGPTL4)is reported to protect the blood-brain barrier when administered exogenously,and endogenous ANGPTL4 deficiency deteriorates radiationinduced intestinal injury.AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion.Intestinal epithelial(Caco-2)cells and human umbilical vein endothelial cells were challenged by hypoxia/reoxygenation to mimic I/R in vitro.RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran(4 kilodaltons;FD-4)clearance,ratio of phosphorylated myosin light chain/total myosin light chain,myosin light chain kinase and loss of zonula occludens-1,claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation.rhANGPTL4 treatment significantly reversed these indicators,which were associated with inhibiting the inflammatory and oxidative cascade,excessive activation of cellular autophagy and apoptosis and improvement of survival rate.Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation,whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.
基金supported by the Major Project of Science and Technology Department of Yunnan Province (202002AA100005 and 202102AE090027-2)the Project of Yunnan Province Food and Drug Homologous Resources Functional Food Innovation Team (A3032023057)+2 种基金the YEFICRC project of Yunnan provincial key programs (2019ZG009)Yunnan Province Ten Thousand Plan Industrial Technology Talents project (YNWR-CYJS-2020-010)the Yunnan Provincial Department of Science and Technology Agricultural Joint Special Project (202101BD070001-120)。
文摘Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis.In total,1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry(nano LC-MS/MS)and 4 novel COX-2 inhibitory peptides(AGFP,FPGA,LFPD,and VGFP)were identified.Enzyme kinetic data indicated that AGFP,FPGA,and LFPD displayed mixed-type COX-2 inhibition,whereas VGFP was a non-competitive inhibitor.This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site.These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.
基金Supported by General Program of National Natural Science Foundation of China,No.81770197Scientific and Technological Research Major Program of Chongqing Municipal Education Commission,No.KJZD-M202312802+1 种基金Chongqing Natural Science Foundation of China,No.CSTB2022NSCQ-MSX0190,No.CSTB2022NSCQ-MSX0176,and No.cstc2020jcyj-msxmX0051Xinqiao Young Postdoc Talent Incubation Program,No.2022YQB098.
文摘BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean Government,Ministry of Science and ICT(MSIT)(2016R1C1B102207,2022R1A2C1004141 and 2022R1A2C-1091712)the National R&D Program for Cancer Control through the National Cancer Center(NCC)funded by the Ministry of Health&Welfare,Republic of Korea(HA22C0053000022).
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.
基金Supported by the Kuwait Foundation for the Advancement of Sciences(KFAS)and Dasman Diabetes Institute,No.RACB-2021-007.
文摘In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2 diabetes mellitus(T2DM)is a chronic disorder characterized by dysregulated glucose homeostasis.The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications,including cardiovascular disease,re-tinopathy,neuropathy,and nephropathy.T2DM arises from a complex interplay between genetic,epigenetic,and environmental factors.Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM.Specifically,variations within the glucokinase regulatory protein(GCKR)gene have been linked to heightened susceptibility to T2DM and its associated complications.The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development.Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype.These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.
文摘This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.
文摘Fibroids, also called leiomyomas or myomas, are communal tumors of the muscle or uterine wall that affect about 20% of females who are of reproductive age. They can look as if singly or in clusters, and they often cease to grow after menopause. Fibroids can be classified as intramural, sub serosal, pedunculated, or submucosal based on where they are positioned in the uterus. Although fibroids are benign, they can grow quickly and cause a range of symptoms, such as pelvic pressure, heavy menstrual flow, and infertility. As a result, fibroids are a main reason behind hysterectomy surgeries. The majority of cases of breast cancer are ductal and lobular cancers, making it the second utmost common cancer in women international. Gene mutations like those in BRCA1 or BRCA2 knowingly raise the risk of breast and other cancers, typically with an earlier cancer onset. Cancer risk is influenced by a complex interplay of genetic abnormalities, environmental factors, and lifestyle selections. Further research into these relations is domineering. Although they are common in uterine leiomyomas, especially multiple leiomyomas, MED12 mutations do not significantly correlate with tumor size. These mutations have also been noticed in smooth muscle tumors and leiomyosarcomas, two other types of uterine cancer. The identification of MED12 mutations as the sole genetic abnormality originates in leiomyomas raises the opportunity of a role in the genesis of cancer. 10% - 15% of women who are of reproductive age have endometriosis, which grants serious difficulties because of its chronic nature and range of clinical symptoms. Even after effective surgeries, issues reoccur often, adding to the enormous financial burden. The effects of MED12 mutations have been experiential in recent studies examining the molecular causes of endometriosis-associated infertility, which have shown anomalies in cellular connections and signaling cascades. Computational techniques were used in this study to investigate LifeGreenTM’s potential to prevent uterine fibroids and breast cancer. The efficacy of LifeGreenTM as a preventive measure or a treatment for common gynecological matters was examined and modeled. We investigated the mechanisms underlying LifeGreenTM’s benefits in the treatment of uterine fibroids and breast cancer using computational techniques. Our research contributes to our understanding of its potential therapeutic benefits for women’s health.
基金supported by the Natural Science Research Project of Anhui Province University, No.2023AH040394 (to TY)Hefei Comprehensive National Science Center Leading Medicine and Frontier Technology Research Institute Project, No.2023IHM01073 (to TY)the Natural Science Foundation of Anhui Province, Nos.2308085QH258 (to JW), 2008085MH246 (to TY)。
文摘Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.