Fibrosis, the pathological scarring of vital organs, is a severe and often irreversible condition that leads to progressive organ dysfunction. It is particularly pronounced in organs like the liver, kidneys, lungs, and heart. Despite its clinical significance, the full understanding of its etiology and complex pathogenesis remains incomplete, posing substantial challenges to diagnosing, treating, and preventing the progression of fibrosis. Among the various molecular players involved, platelet-derived growth factor-C (PDGF-C) has emerged as a crucial factor in fibrotic diseases, contributing to the pathological transformation of tissues in several key organs. PDGF-C is a member of the PDGFs family of growth factors and is synthesized and secreted by various cell types, including fibroblasts, smooth muscle cells, and endothelial cells. It acts through both autocrine and paracrine mechanisms, exerting its biological effects by binding to and activating the PDGF receptors (PDGFRs), specifically PDGFRα and PDGFRβ. This binding triggers multiple intracellular signaling pathways, such as JAK/STAT, PI3K/AKT and Ras-MAPK pathways. which are integral to the regulation of cell proliferation, survival, migration, and fibrosis. Notably, PDGF-C has been shown to promote the proliferation and migration of fibroblasts, key effector cells in the fibrotic process, thus accelerating the accumulation of extracellular matrix components and the formation of fibrotic tissue. Numerous studies have documented an upregulation of PDGF-C expression in various fibrotic diseases, suggesting its significant role in the initiation and progression of fibrosis. For instance, in liver fibrosis, PDGF-C stimulates hepatic stellate cell activation, contributing to the excessive deposition of collagen and other extracellular matrix proteins. Similarly, in pulmonary fibrosis, PDGF-C enhances the migration of fibroblasts into the damaged areas of lungs, thereby worsening the pathological process. Such findings highlight the pivotal role of PDGF-C in fibrotic diseases and underscore its potential as a therapeutic target for these conditions. Given its central role in the pathogenesis of fibrosis, PDGF-C has become an attractive target for therapeutic intervention. Several studies have focused on developing inhibitors that block the PDGF-C/PDGFR signaling pathway. These inhibitors aim to reduce fibroblast activation, prevent the excessive accumulation of extracellular matrix components, and halt the progression of fibrosis. Preclinical studies have demonstrated the efficacy of such inhibitors in animal models of liver, kidney, and lung fibrosis, with promising results in reducing fibrotic lesions and improving organ function. Furthermore, several clinical inhibitors, such as Olaratumab and Seralutinib, are ongoing to assess the safety and efficacy of these inhibitors in human patients, offering hope for novel therapeutic options in the treatment of fibrotic diseases. In conclusion, PDGF-C plays a critical role in the development and progression of fibrosis in vital organs. Its ability to regulate fibroblast activity and influence key signaling pathways makes it a promising target for therapeutic strategies aiming at combating fibrosis. Ongoing research into the regulation of PDGF-C expression and the development of PDGF-C/PDGFR inhibitors holds the potential to offer new insights and approaches for the diagnosis, treatment, and prevention of fibrotic diseases. Ultimately, these efforts may lead to the development of more effective and targeted therapies that can mitigate the impact of fibrosis and improve patient outcomes.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Humans ; Vascular Stiffness ; Coal Mining ; Occupational Diseases/epidemiology* ; Risk Factors ; Coal ; Miners

ObjectiveThrough the correlation analysis between intestinal absorption profile and inhibition of macrophage foaming， the pharmacodynamic components of Zhuriheng dripping pills（ZRH） were explored to provide a basis for establishing its quality standard. MethodIntestinal absorption fluids with 0， 5， 10， 15， 20 times clinical equivalent doses were prepared by a rat everted gut sac（EGS）， and the oxidized low density lipoprotein（ox-LDL）-induced RAW264.7 macrophage foaming model was used to investigate the effect of intestinal absorption fluid with different doses on the accumulation of lipids in RAW264.7 cells by oil red O staining and cholesterol content determination， and to screen for the optimal dose. Ultra performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry（UPLC-Q-Exactive Orbitrap MS） was used to analyze and identify intestinal absorption fractions of ZRH intestinal absorption fluids， and partial least squares-discriminant analysis（PLS-DA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were performed on different doses of ZRH intestinal absorption fluids using SIMCA 13.0 with peak area as the independent variable and the pharmacodynamic indicators as the dependent variables to screen the compounds with variable importance in the projection（VIP） value>1.0 as contributing components， and Pearson correlation analysis was used to determine the spectral effect relationship， determined the compounds and positive correlation with pharmacodynamic were as active ingredients. Molecular docking was used to verify the binding energy of peroxisome proliferator-activated receptor α（PPARα）， PPARγ， PPARβ， human retinoid X receptor α（RXRA） and nuclear transcription factor-κB（NF-κB） with the active ingredients in ZRH intestinal absorption fluids. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） was performed to detect the mRNA levels of PPARγ， scavenger receptor A1（SRA1） and adenosine triphosphate-binding cassette transporter A1（ABCA1） in RAW264.7 cells， Westen blot was used to detect the expression level of PPARγ protein in RAW264.7 cells， and enzyme-linked immunosorbent assay（ELISA） was used to detect the levels of interleukin（IL）-1β and NF-κB in RAW264.7 cells. ResultAccording to the results of oil red O staining and cholesterol content determination， the ZRH intestinal absorption fluids could significantly reduce macrophage foaming， and intestinal absorption fluids with 15， 20 times clinical equivalent doses had the best effect， the 15-fold ZRH intestinal absorption fluid was finally determined as the study subject. Spectral effect relationship showed that 52 corresponding peaks in the ZRH-containing intestinal fluid were positively correlated with the efficacy， including organic acids， phenylpropanoids， iridoids， flavonoids， bile acids， coumarins and chromones. Target validation results showed that 86.9%-96.2% of the total components processed good binding activities with the key targets of PPARα， PPARγ， PPARβ， RXRA and NF-κB， and the docking energy values were all less than -6.0 kcal·mol^-1（1 cal≈4.19 J）. The results of validation showed that， compared with the normal group， the model group showed a significant increase in the levels of SRA1 and PPARγ mRNA expression， a significant decrease in ABCA1 mRNA expression， a significant increase in the level of PPARγ protein expression， and a significant increase in the levels of IL-1β and NF-κB（P<0.01）， compared with the model group， the 15-fold intestinal absorption fluid group showed a significant decrease in the levels of SRA1 and PPARγ mRNA expression（P<0.05， P<0.01）， ABCA1 mRNA expression level was significantly up-regulated， the levels of IL-1β and NF-κB were significantly reduced（P<0.01）， and PPARγ protein expression level was significantly reduced（P<0.05）. ConclusionThis study identifies 52 components and their metabolites in ZRH intestinal absorption fluid that are positively correlated with the inhibition of macrophage foaming， which may be related to the regulation of the PPARs pathway in cells and the reduction of the levels of inflammatory factors， and can provide a reference for the quality control and clinical application of ZRH.

Objective To explore the value of dynamic nomogram constructed by multi spiral computed tomography(MSCT)features combined with inflammatory indicators in predicting the status of microvascular invasion(MVI)of hepatocellular carcinoma(HCC)before surgery.Methods The clinical and imaging data of 137 patients with postoperative pathologically confirmed HCC were analyzed retrospectively.According to the status of the MVI,they were divided into positive group(44 cases)and negative group(93 cases).Multivariate logistic regression analysis was used to screen independent risk factors for predicting the MVI status of HCC patients,and a joint prediction model was constructed,which was displayed in the form of a dynamic nomogram.The receiver operating characteristic(ROC)curve,calibration curve and Hosmer-Lemeshow test were used to evaluate the diagnostic efficiency,calibration and goodness of fit of the model,Akaike information criterion(AIC)and Bayesian information criterion(BIC)were used for comparison between the models,and a 5-fold cross-validation and decision curve analysis(DCA)were also used to evaluate the stability and clinical applicability of the model.Results Multivariate logistic regression analysis showed that necrosis and delayed-phase enhancement(DEd),and alkaline phosphatase to lymphocyte ratio(ALR)were independent risk factors for predicting MVI status in HCC patients.The area under the curve(AUC)of the dynamic nomogram was 0.721,with the sensitivity of 0.705 and the specificity of 0.656.The AIC and BIC values were 152.372 and 158.212,respectively.The calibration curve and the Hosmer-Lemeshow test showed that the model had a high degree of calibration and goodness of fit(χ2=2.372,P=0.967),the average AUC of the 5-fold cross-validation was 0.787,and the DCA showed that the nomogram model had a good clinical applicability.Conclusion The dynamic nomogram model constructed by MSCT features combined with inflammatory indicators is feasible to predict the MVI status of HCC patients before surgery,and the dynamic nomogram can directly generate the prediction results of different individuals.

BACKGROUND:Graphene is the thinnest,strongest,and toughest type of two-dimensional new crystal material,demonstrating significant advantages in biomedical applications.Angiogenesis and vascularization of bone are key factors in tissue repair and regeneration,and are effective ways to address vascular and osteogenic issues. OBJECTIVE:To review the characteristics and mechanisms of graphene and its derivatives in promoting angiogenesis activity and vascularizing bone,in order to provide a reference for their clinical application in vascular tissue repair and regeneration. METHODS:Using a computer to search for relevant literature included in PubMed,ScienceDirect,CNKI,and Wanfang databases,the Chinese search terms were"grapheme","angiogenesis,vascularization","vascularized bone",and"endothelial cells",while the English search terms were"graphene""angiogenesis OR vascularization""vascularized bone""endothelial cells".After excluding literature unrelated to the topic of the article,according to the inclusion and exclusion criteria,62 articles were ultimately included for result analysis. RESULTS AND CONCLUSION:(1)At present,graphene oxide has been studied more and is the most widely used in graphene and its derivatives.(2)Graphene and its derivatives are suitable for heart,bone,nerve,and wound healing related diseases.(3)Graphene and its derivatives have excellent physical and chemical properties and biological properties,but they have potential cytotoxicity.We should pay attention to its biological safety in application.(4)The application of graphene and its derivatives requires further research to demonstrate the optimal size and concentration and measures to reduce toxicity.(5)On the cellular level,graphene and its derivatives can promote angiogenic activity by tip endothelial cell phenotype,mesenchymal stem cell adhesion and proliferation, and vascular smooth muscle cell growth.(6)On the molecular level,graphene and its derivatives can increase the expression of vascular endothelial growth factor,basic fibroblast growth factor,hepatocyte growth factor and activate reactive oxygen species/nitric oxide synthase/nitric oxide signaling pathway,lysophosphatilate R6/Hippo-YAP pathway,stromal cell-derived factor-1/vascular endothelial growth factor and ZEB 1/Notch1 pathway.(7)Grapheme oxide and graphene oxide-copper phosphorylated extracellular regulatory protein kinase and activated hypoxia-inducible factor-1,thereby promoting the up-regulation of vascular endothelial growth factor and bone morphogenetic protein-2 expression,and promoting angiogenesis and vascularized bone.(8)In summary,graphene and its derivatives,especially graphene oxide,have great application prospects in the repair and regeneration of vascularized tissues due to their excellent biological properties,good angiogenesis and vascularized bone ability.

Objective:To analyze the efficacy and safety of daratumumab plus dexamethasone in the treatment of renal injury patients with light chain amyloidosis, and to provide clinical reference.Methods:It was a single center retrospective observational study. The clinical data before and after daratumumab treatment of renal injury patients with light chain amyloidosis treated with daratumumab plus dexamethasone from December 2021 to August 2022 were retrospectively collected. The hematologic response, kidney response, prognosis, and adverse events were analyzed. The treatment regimen was 16 mg/kg intravenous infusion of daratumumab on day 1 + 20 mg intravenous push of dexamethasone on day 1-2, once every 2 weeks. The follow-up was up to February 28, 2023.Results:The study included 18 patients, with age of (58.4±7.7) years old, and a male to female ratio of 11∶7. Eleven patients were newly diagnosed and 7 patients were retreated. There were 7, 5, 5 and 1 patients, respectively at the stage Ⅰ, Ⅱ, Ⅲ and Ⅳ of light chain amyloidosis according to 2012 Mayo stage criteria. The median course of disease before onset was 2.5 (1.0, 8.0) months and the follow-up time was (8.7±2.8) months. The patients received (10±3) times of treatment. The overall hematologic response rates were 9/13, 11/13 and 13/13 at 1 month, 3 months, and 6 months respectively after treatment, meanwhile 8/13, 10/13 and 12/13 achieved at least very good partial response at 1 month, 3 months, and 6 months respectively (the other 5 patients did not undergo detailed evaluation due to baseline difference of serum free κ and λ light chain <20 mg/L). The median duration of hematologic response was 16 (13, 40) days. At 3 months, 6 months and the end of follow-up, 10, 13 and 13 of 18 patients respectively achieved renal response, and the median duration of response was 66 (26, 182) days. During follow-up, the median difference of serum free κ and λ light chain decreased by 93% (72%, 97%). Until the last follow-up, one patient died of organ hemorrhage. Other infusion reactions, leukopenia, neutropenia and infection all improved after symptomatic treatments.Conclusion:Daratumumab plus dexamethasone treatment is effective for light chain amyloidosis nephropathy in inducing hematologic remission and kidney remission, with good safety.

Objective To investigate the expression,synergistic relationship and clinical significance of alcohol de-hydrogenase(ADH1A)and vascular endothelial growth factor-A(VEGFA)in hepatocellular carcinoma(HCC).Methods The expression and correlation of ADH1A and VEGFA in HCC and adjacent normal tissues were ana-lyzed by GEPIA.TCGA and GSEA were used to analyze the pathway of ADH1A in HCC.The clinical and patho-logical data of 84 patients with HCC were collected,and 54 patients with paracancer normal tissue samples were se-lected as controls to analyze the correlation between ADH1A and VEGFA and clinicopathological parameters of HCC.Immunohistochemistry was used to detect the protein expression of ADH1A and VEGFA in cases and con-trols,and the correlation between the expression of ADH1A and VEGFA and the clinical progression and prognosis of patients with HCC was analyzed based on clinical pathological parameters and Kaplan-Meier.Results Bioinfor-matics analysis found that ADH1A was low-expressed in HCC and VEGFA was highly expressed in HCC,and there was a negative correlation between the two(P<0.001);immunohistochemical detection results showed that the expression of ADH1A in HCC tissue was lower than that in normal tissue adjacent to cancer(P<0.01)while the expression rate of VEGFA in HCC tissue was significantly higher than that of normal tissue adjacent to cancer(P<0.01);The recurrence rate of vascular thrombus and HCC patients in HCC group with high expression of ADH1A was lower(P<0.05).The proportion of tumor diameter>5 cm,high TNM stage,microsatellite and G2-G3 dif-ferentiation in HCC tissues in VEGFA high expression group was higher(P<0.05).Kaplan-Meier survival analy-sis showed that patients with high ADH1A expression and low VEGFA expression had a higher five-year survival rate.Conclusion Low expression of ADH1A and high expression of VEGFA in tumor tissues of patients with HCC indicate tumor progression and can be used as one of the prognostic evaluation indicators for patients with HCC.

Objective To investigate the balance control abilities and cortical activation characteristics of elderly individuals under different sensory strategies. Methods From January to May,2023,19 healthy young adults and 20 elderly individuals were recruited in Changzhou as control group and experimental group,respectively.Both groups wore functional near-infrared spectroscopy(fNIRS)caps and performed balance control tasks on a balance platform under three different sensory strategies.Test A was 40 seconds of standing on a stable surface with eyes closed,Test B was 40 seconds of standing on an unstable surface with eyes open,and Test C was 40 seconds of standing on an unstable surface with eyes closed.Before and after the tests,both groups performed 40 seconds of standing on a stable surface with eyes open.The overall stability index(OSI)and cortical activation β values of the regions of interest(ROI)were measured and compared between two groups.The ROIs included the left premotor cortex(LPMC),right premotor cortex(RPMC),left sensorimotor cortex(LSMC),right sensorimotor cortex(RSMC),left prefrontal cortex(LPFC)and right prefrontal cortex(RPFC). Results There was no significant difference in OSI and β values of each ROI in Tests A and B between two groups(P>0.05).In Test C,there was a lower OSI in the experimental group(Z=-2.056,P<0.05),and there were signifi-cant differences in the β values of RSMC(t=2.623,PFDR<0.05),LPMC(Z=-2.360,PFDR<0.05)and LPFC(t=3.202,PFDR<0.05)between two groups. Conclusion Elderly individuals experience a decline in balance control abilities,accompanied by increased activation in related brain regions,when both vision and proprioception are restricted.

Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.