Chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) are both chronic progressive respiratory diseases that cannot be completely cured. COPD is characterized by irreversible airflow limitation, chronic airway inflammation, and gradual decline in lung function, whereas PH is characterized by pulmonary vasoconstriction, remodeling, and infiltration of inflammatory cells. These diseases have similar pathological features, such as vascular hyperplasia, arteriolar contraction, and inflammatory infiltration. Despite these well-documented observations, the exact mechanisms underlying the occurrence and development of COPD and PH remain unclear. Evidence that mitochondrial dynamics imbalance is one major factor in the development of COPD and PH. Mitochondrial dynamics is precisely regulated by mitochondrial fusion proteins and fission proteins. When mitochondrial dynamics equilibrium is disrupted, it causes mitochondrial and even cell morphological dysfunction. Mitochondrial dynamics participates in various pathological processes for heart and lung disease. Mitochondrial dynamics may be different in the early and late stages of COPD and PH. In the early stages of the disease, mitochondrial fusion increases, inhibiting fission, and thereby compensatorily increasing adenosine triphosphate (ATP) production. With the development of the disease, mitochondria decompensation causes excessive fission. Mitochondrial dynamics is involved in the development of COPD and PH in a spatiotemporal manner. Based on this understanding, treatment strategies for mitochondrial dynamics abnormalities may be different at different stages of COPD and PH disease. This article will provide new ideas for the potential treatment of related diseases.
Humans ; Mitochondrial Dynamics/physiology* ; Pulmonary Disease, Chronic Obstructive/metabolism* ; Hypertension, Pulmonary/metabolism* ; Mitochondria/metabolism* ; Animals

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

The proband was a 32-year-old female patient who sought medical attention for over 9 months of pregnancy, reduced fetal movement, and discomfort in the lower abdomen. The proband and her father had normal activated partial thromboplastin time and prothrombin time, decreased fibrinogen activity and antigen levels, and prolonged thrombin time, whereas the test results of her mother were normal. Ultrasonography showed intermuscular vein thrombosis in the left calf of the proband. Peripheral blood DNA was extracted from the proband and her parents, and Sanger sequencing was performed to detect the base sequences of the FGA, FGB, and FGG genes. The proband and her father had heterozygous missense mutations in exon 6 c.615A > C (p. Leu205Phe) and exon 8 c.1121A > C (p. Tyr374Ser) of the FGG gene. Bioinformatics analysis suggested that the two gene mutations may be the pathogenic mechanism of this congenital hypodysfibrinogenemia family.

Objective:Given the insufficiency of current clinical biomarkers for early diagnosis of esophageal adenocarcinoma(EAC),this study developed a panel of serum protein biomarker assays using liquid-phase chip technology and preliminarily validated the detection capabilities of these markers for EAC.Methods:Collected serum samples from 48 patients with EAC and 33 age-matched healthy controls(HC).The levels of squamous cell carcinoma antigen(SCCA),human cytokeratin 19 fragment(Cyfra21-1),hepatocyte growth factor(HGF)and IL-8 in serum were analyzed by liquid chip technology.The diagnostic efficacy of a single indicator and a combination of four indicators were evaluated by receiver operation characteristic(ROC)curve.Results:The detection ranges of SCCA,Cyfra21-1,HGF and IL-8 were 0.24～1 000 ng/ml,45.72～100 000 pg/ml,21.95～16 000 pg/ml,and 0.61～10 000 pg/ml,respectively.The liquid chip technology shows a strong correlation with clinical chemiluminescence immunoassay(r=0.949 4,P<0.000 1)and ELISA technology(r=0.955 1,P<0.000 1).Compared to the HC group,serum levels of SCCA and HGF were signifi-cantly elevated in the EAC group(P<0.01),IL-8 was significantly decreased(P<0.05),while Cyfra21-1 shows no significant difference(P>0.05).In the early EAC group,serum HGF was significantly higher than in the HC group(P<0.01).ROC curve analysis shows that among individual markers,HGF exhibits the best diagnostic efficacy for early EAC with an area under the curve(AUC)of 0.761,while the AUC for the combination of the four biomarkers was 0.857,both superior to the clinical biomarkers SCCA(AUC=0.604)and Cyfra21-1(AUC=0.515).Conclusion:Liquid chip technology is used to jointly detect SCCA,Cyfra21-1,HGF,and IL-8 in human serum.In the early diagnosis of EAC,the diagnostic efficacy of the combined use of these four biomarkers is superior to that of the commonly used clinical tumor markers SCCA and Cyfra21-1.This advantage stems from the high throughput and high sensitivity characteristics of liquid-phase chip technology.Consequently,this combined detection method holds significant clinical application and is expected to provide a more accurate and reliable tool for the early diagnosis of EAC.

The proband was a 32-year-old female patient who sought medical attention for over 9 months of pregnancy, reduced fetal movement, and discomfort in the lower abdomen. The proband and her father had normal activated partial thromboplastin time and prothrombin time, decreased fibrinogen activity and antigen levels, and prolonged thrombin time, whereas the test results of her mother were normal. Ultrasonography showed intermuscular vein thrombosis in the left calf of the proband. Peripheral blood DNA was extracted from the proband and her parents, and Sanger sequencing was performed to detect the base sequences of the FGA, FGB, and FGG genes. The proband and her father had heterozygous missense mutations in exon 6 c.615A > C (p. Leu205Phe) and exon 8 c.1121A > C (p. Tyr374Ser) of the FGG gene. Bioinformatics analysis suggested that the two gene mutations may be the pathogenic mechanism of this congenital hypodysfibrinogenemia family.

Objective·To identify and evaluate novel and reliable non-invasive serological biomarkers for detecting pancreatic ductal adenocarcinoma(PDAC).Methods·Sixty-seven PDAC patients(Ruijin cohort Ⅰ)were recruited at Pancreatic Center,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,from May 2018 to December 2019.Global proteome profiling of 67 PDAC tumor tissues and 67 matched adjacent normal tissues was performed using mass spectrum.Bioinformatics analysis on the proteomics data was conducted to identify new biomarkers,and receiver operating characteristic(ROC)curves and the area under the curve(AUC)were used to evaluate their value of detecting PDAC.The proteomic and mRNA sequencing data were further downloaded and analysed from the Clinical Proteomic Tumor Analysis Consortium(CPTAC)cohort for validation.In addition,the Ruijin Cohort Ⅱ,consisting of 47 PDAC patients and 75 healthy individuals,was recruited for a case-control study from June 2021 to June 2022.Enzyme-linked immunosorbent assay(ELISA)was used to detect the expression level of new biomarkers in the serum of patients and healthy individuals to evaluate the serological diagnostic values of them.Results·Collagen type Ⅻ α1 chain(COL12A1)was identified as a candidate biomarker for PDAC diagnosis based on differential expression analysis on the proteomic data and was validated to be higher in tumor tissues than in adjacent normal tissues in the CPTAC cohort.In addition,COL12A1 protein levels were significantly higher in the sera of PDAC patients than in those of healthy controls,showing good diagnostic performance with an AUC of 0.82,a sensitivity of 81%,and a specificity of 83%.ROC analysis revealed that COL12A1 improved the performance of carbohydrate antigen 199(CA199)in distinguishing PDAC patients from healthy individuals(AUCCA199=0.91 vs AUCCA199+COL12A1=0.95,P<0.05).Furthermore,COL12A1 also showed excellent ability to distinguish early-stage PDAC patients(stage Ⅰ?Ⅱ)from healthy individuals(AUCCOL12A1=0.83),and significantly improved the AUC of CA199 in early-stage PDAC patients(AUCCA199=0.92 vs AUCCA199+COL12A1=0.97,P<0.05).Conclusion·COL12A1 is a potential serological diagnostic marker that complements CA199 in detecting early-stage PDAC.

Objective·To identify and evaluate novel and reliable non-invasive serological biomarkers for detecting pancreatic ductal adenocarcinoma(PDAC).Methods·Sixty-seven PDAC patients(Ruijin cohort Ⅰ)were recruited at Pancreatic Center,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,from May 2018 to December 2019.Global proteome profiling of 67 PDAC tumor tissues and 67 matched adjacent normal tissues was performed using mass spectrum.Bioinformatics analysis on the proteomics data was conducted to identify new biomarkers,and receiver operating characteristic(ROC)curves and the area under the curve(AUC)were used to evaluate their value of detecting PDAC.The proteomic and mRNA sequencing data were further downloaded and analysed from the Clinical Proteomic Tumor Analysis Consortium(CPTAC)cohort for validation.In addition,the Ruijin Cohort Ⅱ,consisting of 47 PDAC patients and 75 healthy individuals,was recruited for a case-control study from June 2021 to June 2022.Enzyme-linked immunosorbent assay(ELISA)was used to detect the expression level of new biomarkers in the serum of patients and healthy individuals to evaluate the serological diagnostic values of them.Results·Collagen type Ⅻ α1 chain(COL12A1)was identified as a candidate biomarker for PDAC diagnosis based on differential expression analysis on the proteomic data and was validated to be higher in tumor tissues than in adjacent normal tissues in the CPTAC cohort.In addition,COL12A1 protein levels were significantly higher in the sera of PDAC patients than in those of healthy controls,showing good diagnostic performance with an AUC of 0.82,a sensitivity of 81%,and a specificity of 83%.ROC analysis revealed that COL12A1 improved the performance of carbohydrate antigen 199(CA199)in distinguishing PDAC patients from healthy individuals(AUCCA199=0.91 vs AUCCA199+COL12A1=0.95,P<0.05).Furthermore,COL12A1 also showed excellent ability to distinguish early-stage PDAC patients(stage Ⅰ?Ⅱ)from healthy individuals(AUCCOL12A1=0.83),and significantly improved the AUC of CA199 in early-stage PDAC patients(AUCCA199=0.92 vs AUCCA199+COL12A1=0.97,P<0.05).Conclusion·COL12A1 is a potential serological diagnostic marker that complements CA199 in detecting early-stage PDAC.

Objective:Given the insufficiency of current clinical biomarkers for early diagnosis of esophageal adenocarcinoma(EAC),this study developed a panel of serum protein biomarker assays using liquid-phase chip technology and preliminarily validated the detection capabilities of these markers for EAC.Methods:Collected serum samples from 48 patients with EAC and 33 age-matched healthy controls(HC).The levels of squamous cell carcinoma antigen(SCCA),human cytokeratin 19 fragment(Cyfra21-1),hepatocyte growth factor(HGF)and IL-8 in serum were analyzed by liquid chip technology.The diagnostic efficacy of a single indicator and a combination of four indicators were evaluated by receiver operation characteristic(ROC)curve.Results:The detection ranges of SCCA,Cyfra21-1,HGF and IL-8 were 0.24～1 000 ng/ml,45.72～100 000 pg/ml,21.95～16 000 pg/ml,and 0.61～10 000 pg/ml,respectively.The liquid chip technology shows a strong correlation with clinical chemiluminescence immunoassay(r=0.949 4,P<0.000 1)and ELISA technology(r=0.955 1,P<0.000 1).Compared to the HC group,serum levels of SCCA and HGF were signifi-cantly elevated in the EAC group(P<0.01),IL-8 was significantly decreased(P<0.05),while Cyfra21-1 shows no significant difference(P>0.05).In the early EAC group,serum HGF was significantly higher than in the HC group(P<0.01).ROC curve analysis shows that among individual markers,HGF exhibits the best diagnostic efficacy for early EAC with an area under the curve(AUC)of 0.761,while the AUC for the combination of the four biomarkers was 0.857,both superior to the clinical biomarkers SCCA(AUC=0.604)and Cyfra21-1(AUC=0.515).Conclusion:Liquid chip technology is used to jointly detect SCCA,Cyfra21-1,HGF,and IL-8 in human serum.In the early diagnosis of EAC,the diagnostic efficacy of the combined use of these four biomarkers is superior to that of the commonly used clinical tumor markers SCCA and Cyfra21-1.This advantage stems from the high throughput and high sensitivity characteristics of liquid-phase chip technology.Consequently,this combined detection method holds significant clinical application and is expected to provide a more accurate and reliable tool for the early diagnosis of EAC.

Objective:To explore the value of coronary artery plaque progression parameters based on coronary CT angiography (CCTA) in predicting the occurrence of major adverse cardiovascular events (MACE) in patients with non-obstructive coronary artery disease.Methods:The study included clinical, imaging, and prognosis (MACE) parameters of non-obstructive coronary artery disease patients who underwent CCTA at the First Affiliated Hospital of Nanjing Medical University from September 2010 to December 2022. Patients were grouped based on the occurrence of MACE, and differences in clinical data, plaque baseline, and progression parameters between the two groups were compared. Univariate and multivariate Cox regression analyses were employed to identify factors that could effectively predict the occurrence of MACE in patients. Models were constructed using plaque baseline parameters, plaque progression parameters, and a combination of both. The concordance index-time curve, net reclassification improvement and integrated discrimination improvement were used to evaluate the risk stratification ability of the models.Results:A total of 258 patients were included, of whom 62 cases experienced MACE during the follow-up period. In comparison to the MACE(-) group, patients in the MACE(+) group exhibited longer lesion length, greater degree of stenosis, larger plaque total volume, calcified plaque volume, non-calcified plaque volume, fibrous plaque volume, total plaque burden, lipid-rich plaque burden, higher peri-coronary adipose tissue attenuation index (FAI), and annual change of diameter stenosis(ΔDS/y). There were also more cases of coronary artery disease reporting and data system upgrades and non-obstructive progression to obstructive status ( P<0.05). Multivariate Cox analysis revealed that FAI, ΔDS/y, and non-obstructive progression to obstructive status were independent predictors of MACE occurrence. Concordance index-time curve results indicated that the combined model had a better predictive efficacy for MACE in patients with non-obstructive coronary artery disease compared to models based on plaque baseline parameters and plaque progression parameters. Conclusion:The plaque progression parameters and FAI based on CCTA have the potential to predict the high-risk population for MACE in patients with non-obstructive coronary artery disease, demonstrating good risk stratification value.

Objective:The phenotype and genotype of a pedigree with Glanzmann thrombasthenia caused by compound heterozygous mutation in the ITGA2B gene and its molecular pathogenesis were explored.Methods:The platelet aggregation rate of the proband and his family was detected by using a platelet aggregation test with adenosine diphosphate, collagen, epinephrine, arachidonic acid, and ristocetin. The expression levels of CD41 (αⅡb), CD61 (β3), and CD42b (GPⅠb) on the platelet surface was detected by flow cytometry. Gene sequencing technology was used for the genetic identification of the family. RT-PCR was used in the detection of mRNA splicing, and qRT-PCR was used in detecting the relative mRNA level of the ITGA2B gene. Bioinformatics analysis was used to evaluate the pathogenicity of mutation sites and their effects on protein structure and function. The expressions of total αⅡb and β3 in platelets were analyzed by Western blot.Results:Except ristocetin, the other four inducers could not induce platelet aggregation in the proband. Flow cytometry showed that the expression levels of αⅡb and β3 were only 0.25% and 9.76%, respectively, on the platelet surface of the proband, whereas GPⅠb expression was relatively normal. The expression levels of glycoproteins in the other family members were almost normal. c.480C>G and c.2929C>T mutations were detected in the proband through gene sequencing. The c.480C>G mutation was inherited from his mother, and the c.2929C>T mutation was inherited from his father. The RT-PCR and sequencing results showed that the c.480C>G mutation caused mRNA splicing in the proband and his mother, resulting in the deletion of 99 bases in c.476G-574A (p.S160-S192). qRT-PCR showed that the c.2929C>T variant reduced the mRNA level of the ITGA2B gene in the proband and his father. Bioinformatics analysis suggested that the c.480C>G mutation might form a binding sequence with hnRNP A1 protein and generate the 5′SS splice site. The three-dimensional structural model of the αⅡb subunit showed that the β-propeller domain of the p.S160-S192 deletion lost two β-strands and one α-helix in blade 2. The c.2929C>T nonsense mutation caused premature translation termination and produced a truncated protein with the deletion of p.R977-E1039, including the cytoplasmic domain, transmembrane domain, and a β chain of the extracellular Calf-2 domain. The total αⅡb expression of the proband was absent, and the relative expression of β3 was 11.36% of the normal level.Conclusion:The compound heterozygous mutation c.480C>G in exon 4 and c.2929C>T in exon 28 of the ITGA2B gene probably underlies Glanzmann thrombasthenia in this pedigree.