BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patien...BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.AIM To explore the molecular mechanism of NAFLD.METHODS Whole genome sequencing(WGS)analysis was performed on liver tissues from patients with NAFLD(n=6)and patients with normal metabolic conditions(n=6)to identify the target genes.A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2(FBXO2)overexpression mouse model were used for in vivo studies.Plasmid transfection,co-immunoprecipitation-based mass spectrometry assays,and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.RESULTS A total of 30982 genes were detected in WGS analysis,with 649 up-regulated and 178 down-regulated.Expression of FBXO2,an E3 ligase,was upregulated in the liver tissues of patients with NAFLD.Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice.Overexpression of FBXO2 aggravated odium oleate(OA)-induced lipid accumulation in HepG2 cells,resulting in an abnormal expression of genes related to lipid metabolism,such as fatty acid synthase,peroxisome proliferator-activated receptor alpha,and so on.In contrast,knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes.The hydroxyl CoA dehydrogenase alpha subunit(HADHA),a protein involved in oxidative stress,was a target of FBXO2-mediated ubiquitination.FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells.Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD。展开更多
DNA polymerase Ⅲ is one of the five eubacterial DNA polymerases that is responsible for the replication of DNA duplex. Among the ten subunits of the DNA polymerase Ⅲ core enzyme, the alpha subunit catalyzes the reac...DNA polymerase Ⅲ is one of the five eubacterial DNA polymerases that is responsible for the replication of DNA duplex. Among the ten subunits of the DNA polymerase Ⅲ core enzyme, the alpha subunit catalyzes the reaction for polymerizing both DNA strands. In this study, we extracted genomic sequences of the alpha subunit from 159 sequenced eubacterial genomes, and carried out sequence- based phylogenetic and structural analyses. We found that all eubacterial genomes have one or more alpha subunits, which form either homodimers or heterodimers. Phylogenetic and domain structural analyses as well as copy number variations of the alpha subunit in each bacterium indicate the classification of alpha subunit into four basic groups: polC, dnaE1, dnaE2, and dnaE3. This classification is of essence in genome composition analysis. We also consolidated the naming convention to avoid further confusion in gene annotations.展开更多
Abstract Objecitve To explore whether phosphoinositide specific phospholipase C (PLC) activation via G protein in vascular smooth muscle cells (VSMCs) is altered in spontaneously hypertensive rats (SHR). Met...Abstract Objecitve To explore whether phosphoinositide specific phospholipase C (PLC) activation via G protein in vascular smooth muscle cells (VSMCs) is altered in spontaneously hypertensive rats (SHR). Methods The VSMCs derived from aortae of SHR and Wistar Kyoto (WKY) rats were loaded for 48 hours with myo inositol. Inositol phosphate release was initiated by the addition of 10 5 mol/L norepinephrine in intact cells or by guanosine 5' 0 (3 thio tri sphosphate) (GTP gamma S) in permeabilized cells. In the meantime, growth arrested VSMCs were stimulated by 10% calf serum for 0, 30, 45, or 60 min, then gene expressions of Gq alpha subunit (G alph a q) were observed. Results There were no significant differences in inositol 1, 4,5 triphosphate (IP 3) level and expression of G alpha q mRNA between quiescent VSMCs from SHR and that from WKY. When stimulated by norepinephrine, IP 3 production increased transiently with a peak level at 10 s in VSMCs from WKY, and a rapid biphasic IP 3 response, which was significantly higher than that of WKY, in VSMCs from SHR had been observed. G proteins activated by GTP gamma S significantly raised IP 3 production in VSMCs from SHR compared to WKY (SHR vs WKY: 234.8%±29.2% vs 142.4%±12.0% of basal IP 3, P<0.05). In addition, the serum effect showed an significant increase in expression of G alpha q mRNA in VSMCs from SHR. Conclusions The hereditary factors are not the only variable regulating IP 3 metabolism and G alpha q gene expression. Influences of multi environmental factors such as vasoactive compounds, together with genetic predisposition, palys an important role in the highly sensitive response of IP 3 production and G alpha q gene over expression in SHR.展开更多
BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its ro...BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its role in hepatocellular carcinoma(HCC)has not been fully deciphered.AIM To decipher the role of CDKN2B-AS1 in the progression of HCC.METHODS CDKN2B-AS1 expression in HCC was detected by quantitative real-time polymerase chain reaction.The malignant phenotypes of Li-7 and SNU-182 cells were detected by the CCK-8 method,EdU method,and flow cytometry,respectively.RNA immunoprecipitation was executed to confirm the interaction between CDKN2B-AS1 and E2F transcription factor 1(E2F1).Luciferase reporter assay and chromatin immunoprecipitation were performed to verify the binding of E2F1 to the promoter of G protein subunit alpha Z(GNAZ).E2F1 and GNAZ were detected by western blot in HCC cells.RESULTS In HCC tissues,CDKN2B-AS1 was upregulated.Depletion of CDKN2B-AS1 inhibited the proliferation of HCC cells,and the depletion of CDKN2B-AS1 also induced cell cycle arrest and apoptosis.CDKN2B-AS1 could interact with E2F1.Depletion of CDKN2B-AS1 inhibited the binding of E2F1 to the GNAZ promoter region.Overexpression of E2F1 reversed the biological effects of depletion of CDKN2B-AS1 on the malignant behaviors of HCC cells.CONCLUSION CDKN2B-AS1 recruits E2F1 to facilitate GNAZ transcription to promote HCC progression.展开更多
OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen a...OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.展开更多
目的探讨颅内动脉瘤患者血清缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)、半胱氨酸天冬氨酸蛋白水解酶-3(cysteine aspartate protein hydrolase-3,Caspase-3)、微小RNA-143(microRNA-143,miR-143)水平与动脉瘤破裂的关...目的探讨颅内动脉瘤患者血清缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)、半胱氨酸天冬氨酸蛋白水解酶-3(cysteine aspartate protein hydrolase-3,Caspase-3)、微小RNA-143(microRNA-143,miR-143)水平与动脉瘤破裂的关系。方法143例颅内动脉瘤患者作为病例组,根据颅内动脉瘤破裂与否分为未破裂组(n=95)和破裂组(n=48),另选取同期健康体检人群138例作为对照组,收集各组受检者的一般资料(年龄、性别及体质量指标);抽取病例组患者入院日、对照组体检者体检日空腹肘静脉血离心,采用酶联免疫吸附试验和实时荧光定量PCR检测各组受检者血清HIF-1α、Caspase-3及miR-143水平;随访病例组患者术后3个月,采用CT血管造影检查患者的动脉瘤影像特征(动脉瘤标准化表面最大压力、瘤体宽径、形状不规则占比、载瘤动脉宽度、低剪切力面积比值、动脉瘤标准化表面平均压力、瘤体长径、瘤径宽度、瘤体最长径、平均壁面剪切力及动脉瘤位置)并判断颅内动脉瘤破裂与否,采用多因素logistic分析病例组患者颅内动脉瘤破裂的影响因素,采用Spearman相关分析和ROC曲线分析病例组患者血清HIF-1α、Caspase-3、miR-143水平与颅内动脉瘤破裂的相关性及预警价值。结果病例组患者血清Caspase-3、HIF-1α高于对照组,miR-143水平低于对照组(P<0.05);破裂组颅内动脉瘤患者血清miR-143水平和瘤体宽径低于未破裂组,血清HIF-1α、Caspase-3及低剪切力面积比值、瘤体最长径、形状不规则占比、瘤体长径、平均壁面剪切力水平高于未破裂组(P<0.05);logistic分析结果显示,血清Caspase-3、miR-143、HIF-1α及低剪切力面积比值、瘤体宽径、瘤体长径、平均壁面剪切力、瘤体最长径、形状不规则是颅内动脉瘤破裂的影响因素(P<0.05);Spearman相关分析结果显示,血清miR-143与患者颅内动脉瘤破裂呈负相关(P<0.05),血清Caspase-3、HIF-1α与患者颅内动脉瘤破裂呈正相关(P<0.05);血清miR-143、Caspase-3及HIF-1α预测颅内动脉瘤破裂的曲线下面积(AUC)分别为0.716、0.689及0.702,3者联合预测颅内动脉瘤破裂的AUC为0.802大于单独指标预测。结论血清高HIF-1α、Caspase-3水平及低miR-143水平是颅内动脉瘤破裂的影响因素,且3者联合预测价值更高。展开更多
Hypoxic-ischemic(HI)brain damage poses a high risk of death or lifelong disability,yet effective treatments remain elusive.Here,we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult i...Hypoxic-ischemic(HI)brain damage poses a high risk of death or lifelong disability,yet effective treatments remain elusive.Here,we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice.Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery,through inhibiting the cleaved-caspase-3 level,microglia activation,and the release of proinflammation cytokines following HI injury.Engineered extracellular vesicles(EVs)containing neuron-targeting rabies virus glycoprotein(RVG)and miR-100-5p antagonists(RVG-EVs-Antagomir)selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery.Both pre-and post-HI administration showed therapeutic benefits.Mechanistically,we identified protein phosphatase 3 catalytic subunit alpha(Ppp3ca)as a novel candidate target gene of miR-100-5p,inhibiting c-Fos expression and neuronal apoptosis following HI insult.In conclusion,our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.展开更多
基金the National Natural Science Foundation of China,No.81741103.
文摘BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.
基金the National Natural Science Foundation of China,No.82070869 and 82270914.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.AIM To explore the molecular mechanism of NAFLD.METHODS Whole genome sequencing(WGS)analysis was performed on liver tissues from patients with NAFLD(n=6)and patients with normal metabolic conditions(n=6)to identify the target genes.A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2(FBXO2)overexpression mouse model were used for in vivo studies.Plasmid transfection,co-immunoprecipitation-based mass spectrometry assays,and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.RESULTS A total of 30982 genes were detected in WGS analysis,with 649 up-regulated and 178 down-regulated.Expression of FBXO2,an E3 ligase,was upregulated in the liver tissues of patients with NAFLD.Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice.Overexpression of FBXO2 aggravated odium oleate(OA)-induced lipid accumulation in HepG2 cells,resulting in an abnormal expression of genes related to lipid metabolism,such as fatty acid synthase,peroxisome proliferator-activated receptor alpha,and so on.In contrast,knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes.The hydroxyl CoA dehydrogenase alpha subunit(HADHA),a protein involved in oxidative stress,was a target of FBXO2-mediated ubiquitination.FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells.Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD。
文摘DNA polymerase Ⅲ is one of the five eubacterial DNA polymerases that is responsible for the replication of DNA duplex. Among the ten subunits of the DNA polymerase Ⅲ core enzyme, the alpha subunit catalyzes the reaction for polymerizing both DNA strands. In this study, we extracted genomic sequences of the alpha subunit from 159 sequenced eubacterial genomes, and carried out sequence- based phylogenetic and structural analyses. We found that all eubacterial genomes have one or more alpha subunits, which form either homodimers or heterodimers. Phylogenetic and domain structural analyses as well as copy number variations of the alpha subunit in each bacterium indicate the classification of alpha subunit into four basic groups: polC, dnaE1, dnaE2, and dnaE3. This classification is of essence in genome composition analysis. We also consolidated the naming convention to avoid further confusion in gene annotations.
文摘Abstract Objecitve To explore whether phosphoinositide specific phospholipase C (PLC) activation via G protein in vascular smooth muscle cells (VSMCs) is altered in spontaneously hypertensive rats (SHR). Methods The VSMCs derived from aortae of SHR and Wistar Kyoto (WKY) rats were loaded for 48 hours with myo inositol. Inositol phosphate release was initiated by the addition of 10 5 mol/L norepinephrine in intact cells or by guanosine 5' 0 (3 thio tri sphosphate) (GTP gamma S) in permeabilized cells. In the meantime, growth arrested VSMCs were stimulated by 10% calf serum for 0, 30, 45, or 60 min, then gene expressions of Gq alpha subunit (G alph a q) were observed. Results There were no significant differences in inositol 1, 4,5 triphosphate (IP 3) level and expression of G alpha q mRNA between quiescent VSMCs from SHR and that from WKY. When stimulated by norepinephrine, IP 3 production increased transiently with a peak level at 10 s in VSMCs from WKY, and a rapid biphasic IP 3 response, which was significantly higher than that of WKY, in VSMCs from SHR had been observed. G proteins activated by GTP gamma S significantly raised IP 3 production in VSMCs from SHR compared to WKY (SHR vs WKY: 234.8%±29.2% vs 142.4%±12.0% of basal IP 3, P<0.05). In addition, the serum effect showed an significant increase in expression of G alpha q mRNA in VSMCs from SHR. Conclusions The hereditary factors are not the only variable regulating IP 3 metabolism and G alpha q gene expression. Influences of multi environmental factors such as vasoactive compounds, together with genetic predisposition, palys an important role in the highly sensitive response of IP 3 production and G alpha q gene over expression in SHR.
文摘BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its role in hepatocellular carcinoma(HCC)has not been fully deciphered.AIM To decipher the role of CDKN2B-AS1 in the progression of HCC.METHODS CDKN2B-AS1 expression in HCC was detected by quantitative real-time polymerase chain reaction.The malignant phenotypes of Li-7 and SNU-182 cells were detected by the CCK-8 method,EdU method,and flow cytometry,respectively.RNA immunoprecipitation was executed to confirm the interaction between CDKN2B-AS1 and E2F transcription factor 1(E2F1).Luciferase reporter assay and chromatin immunoprecipitation were performed to verify the binding of E2F1 to the promoter of G protein subunit alpha Z(GNAZ).E2F1 and GNAZ were detected by western blot in HCC cells.RESULTS In HCC tissues,CDKN2B-AS1 was upregulated.Depletion of CDKN2B-AS1 inhibited the proliferation of HCC cells,and the depletion of CDKN2B-AS1 also induced cell cycle arrest and apoptosis.CDKN2B-AS1 could interact with E2F1.Depletion of CDKN2B-AS1 inhibited the binding of E2F1 to the GNAZ promoter region.Overexpression of E2F1 reversed the biological effects of depletion of CDKN2B-AS1 on the malignant behaviors of HCC cells.CONCLUSION CDKN2B-AS1 recruits E2F1 to facilitate GNAZ transcription to promote HCC progression.
基金Supported by the Guangxi Natural Science Foundation“Controllable Synthesis of Ordered Mesoporous Seafoam-Loaded g-C3N4 Gomposites and Their Mechanism of Adsorption-Photocatalytic Degradation of Antidepressants in Water Bodies”(2017GXNSFBA198216)the Open Fund for the Director of Guangxi Key Laboratory of Spatial Information and Geographic Information“Geographic Spatial Analysis of Regional Urinary Tract Stone Disease”(19-185-10-04)。
文摘OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.
文摘目的探讨颅内动脉瘤患者血清缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)、半胱氨酸天冬氨酸蛋白水解酶-3(cysteine aspartate protein hydrolase-3,Caspase-3)、微小RNA-143(microRNA-143,miR-143)水平与动脉瘤破裂的关系。方法143例颅内动脉瘤患者作为病例组,根据颅内动脉瘤破裂与否分为未破裂组(n=95)和破裂组(n=48),另选取同期健康体检人群138例作为对照组,收集各组受检者的一般资料(年龄、性别及体质量指标);抽取病例组患者入院日、对照组体检者体检日空腹肘静脉血离心,采用酶联免疫吸附试验和实时荧光定量PCR检测各组受检者血清HIF-1α、Caspase-3及miR-143水平;随访病例组患者术后3个月,采用CT血管造影检查患者的动脉瘤影像特征(动脉瘤标准化表面最大压力、瘤体宽径、形状不规则占比、载瘤动脉宽度、低剪切力面积比值、动脉瘤标准化表面平均压力、瘤体长径、瘤径宽度、瘤体最长径、平均壁面剪切力及动脉瘤位置)并判断颅内动脉瘤破裂与否,采用多因素logistic分析病例组患者颅内动脉瘤破裂的影响因素,采用Spearman相关分析和ROC曲线分析病例组患者血清HIF-1α、Caspase-3、miR-143水平与颅内动脉瘤破裂的相关性及预警价值。结果病例组患者血清Caspase-3、HIF-1α高于对照组,miR-143水平低于对照组(P<0.05);破裂组颅内动脉瘤患者血清miR-143水平和瘤体宽径低于未破裂组,血清HIF-1α、Caspase-3及低剪切力面积比值、瘤体最长径、形状不规则占比、瘤体长径、平均壁面剪切力水平高于未破裂组(P<0.05);logistic分析结果显示,血清Caspase-3、miR-143、HIF-1α及低剪切力面积比值、瘤体宽径、瘤体长径、平均壁面剪切力、瘤体最长径、形状不规则是颅内动脉瘤破裂的影响因素(P<0.05);Spearman相关分析结果显示,血清miR-143与患者颅内动脉瘤破裂呈负相关(P<0.05),血清Caspase-3、HIF-1α与患者颅内动脉瘤破裂呈正相关(P<0.05);血清miR-143、Caspase-3及HIF-1α预测颅内动脉瘤破裂的曲线下面积(AUC)分别为0.716、0.689及0.702,3者联合预测颅内动脉瘤破裂的AUC为0.802大于单独指标预测。结论血清高HIF-1α、Caspase-3水平及低miR-143水平是颅内动脉瘤破裂的影响因素,且3者联合预测价值更高。
基金supported by the National Natural Science Foundation of China(82271327,82072535,and U23A6011)the Natural Science Foundation of Shandong Province(ZR2024MH038).
文摘Hypoxic-ischemic(HI)brain damage poses a high risk of death or lifelong disability,yet effective treatments remain elusive.Here,we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice.Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery,through inhibiting the cleaved-caspase-3 level,microglia activation,and the release of proinflammation cytokines following HI injury.Engineered extracellular vesicles(EVs)containing neuron-targeting rabies virus glycoprotein(RVG)and miR-100-5p antagonists(RVG-EVs-Antagomir)selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery.Both pre-and post-HI administration showed therapeutic benefits.Mechanistically,we identified protein phosphatase 3 catalytic subunit alpha(Ppp3ca)as a novel candidate target gene of miR-100-5p,inhibiting c-Fos expression and neuronal apoptosis following HI insult.In conclusion,our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
