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.

OBJECTIVE: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification. METHODS: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. RESULTS: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G₁-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway. CONCLUSION Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.
Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation ; Matrix Metalloproteinase 9 ; Molecular Docking Simulation ; Cell Cycle ; ErbB Receptors ; Apoptosis ; Colorectal Neoplasms/pathology* ; Cell Line, Tumor

Objective To construct and identify a patient-derived organoid model,and to investigate the sensitivity of chemotherapy drugs using this model.Methods Pancreatic cancer cells were obtained from the surgical specimens of two female patients with a confirmed diagnosis of pancreatic cancer after tumor tissue digestion,and then the cells were inoculated into a culture dish using matrigel for three-dimensional culture.Paraffin sections were prepared for HE staining and immunohistochemical staining and were compared with the parent tumor tissue to determine whether the histopathological features of the tumor in vivo were preserved.The pancreatic cancer organoids were treated with seven chemotherapy drugs at different concentrations;Cell Titer-Glo?3D reagent was used to measure cell viability,and the results of drug sensitivity were analyzed.Results Two patient-derived pancreatic cancer organoids were successfully constructed,and HE staining and immunohistochemical staining showed that the pancreatic cancer organoids had consistent histopathological features with the tumors of the corresponding patient.Both pancreatic cancer organoids were more sensitive to gemcitabine monotherapy and the combination of oxaliplatin+SN38+fluorouracil,and patient 1 was more sensitive than patient 2.There were individual differences in the response to drugs between the organoids from different patients.Conclusion The pancreatic cancer organoid model successfully constructed in this study can reflect the histological classification of parent pancreatic tumors and can be used for in vitro chemotherapy drug sensitivity test,which is expected to provide a reference for clinical medication.

Objective:To construct a remote screening network for breast cancer based on automated breast ultrasound (ABUS) and explore the value of ABUS with remote reading for breast cancer screening.Methods:We constructed a remote breast cancer screening network including one remote reading center and 48 image-acquisition centers. We recruited women to participate in breast cancer screening at one of these image-acquisition centers from January 2021 to January 2023. The technicians collected the whole breast images using the ABUS. The images were then sent to the reading center through the PVBUS System and interpreted independently by two radiologists using the Breast Imaging Reporting and Data System (BI-RADS). BI-RADS categories 1 and 2 indicate negative screening results, and women diagnosed with these categories were recommended for annual breast ultrasound screening. BI-RADS categories 3, 4, and 5 indicate positive results. Women with BI-RADS category 3 lesions were recommended for follow-up examinations every 6 months using ABUS or handheld ultrasound, while those with BI-RADS 4 and 5 lesions were suggested to undergo pathological examinations.Results:In our study, we enrolled 10 344 women who completed the ABUS screening and were followed up for more than 12 months. After remote reading, 6 164 women were diagnosed with BI-RADS category 1 and 2 626 woman were within BI-RADS category 2. In contrast, 1 404 women were within BI-RADS category 3, a total of 135 women were within BI-RADS category 4, and 15 women were within BI-RADS category 5. The positive screening rate of ABUS was 15.0% (1 554/10 344). The ABUS with remote reading had a detection rate of 3.7/1 000 (38/10 344) for breast cancer screening, with a sensitivity of 97.4% (38/39) and a specificity of 85.3% (8 789/10 305). Among the 38 breast cancer cases detected, 92.1% (35/38) were invasive carcinomas, and 63.2% (24/38) were stage 0 or Ⅰ breast cancers.Conclusions:Breast cancer screening based on ABUS with remote reading provided an efficient and feasible solution to the problem of unevenly distributed medical resources and medical staff levels in various regions of China, enabling the decentralization of high-quality medical resources and improving the accessibility of high-quality screening services. It has provided an alternative for breast cancer screening in China.

The toad, known for its various medicinal properties including parotid gland secretion (toad venom), dried skin, and gallbladder (toad bile), holds considerable medicinal applications as a valuable traditional Chinese animal medicine. Currently, in-depth attentions have been paid to the chemical composition and pharmacological properties of toad venom and skin; however, a lesser number of detailed analyses were concentrated on the toad bile. This review provides an overview of the chemical constituents in the bile of the Bufo genus, with a special focus on the cholestane and bufadienolides, and highlights the progress in their biosynthetic pathway and pharmacological activities. The analysis uncovers a distinct category of unsaturated Δ²² or Δ²³-C₂₇/C₂₈ bile acids in the toad gallbladder, potentially acting as key intermediaries in forming C-17 α-pyrone of bufadienolides. Furthermore, the high presence of 3α-OH configured bufadienolides in toad bile, in contrast to the common 3β-OH configured found in toad venom or skin, indicates a possible link between their minimal toxicity and the toad's self-defensive or physiological control. This review provides scientific basis for the development and utilization of toad bile resources, and provides useful reference for the discovery of lead compounds, analysis of the biosynthetic pathway of bufadienolides, and research on toad physiology.

Objective:To construct a remote screening network for breast cancer based on automated breast ultrasound (ABUS) and explore the value of ABUS with remote reading for breast cancer screening.Methods:We constructed a remote breast cancer screening network including one remote reading center and 48 image-acquisition centers. We recruited women to participate in breast cancer screening at one of these image-acquisition centers from January 2021 to January 2023. The technicians collected the whole breast images using the ABUS. The images were then sent to the reading center through the PVBUS System and interpreted independently by two radiologists using the Breast Imaging Reporting and Data System (BI-RADS). BI-RADS categories 1 and 2 indicate negative screening results, and women diagnosed with these categories were recommended for annual breast ultrasound screening. BI-RADS categories 3, 4, and 5 indicate positive results. Women with BI-RADS category 3 lesions were recommended for follow-up examinations every 6 months using ABUS or handheld ultrasound, while those with BI-RADS 4 and 5 lesions were suggested to undergo pathological examinations.Results:In our study, we enrolled 10 344 women who completed the ABUS screening and were followed up for more than 12 months. After remote reading, 6 164 women were diagnosed with BI-RADS category 1 and 2 626 woman were within BI-RADS category 2. In contrast, 1 404 women were within BI-RADS category 3, a total of 135 women were within BI-RADS category 4, and 15 women were within BI-RADS category 5. The positive screening rate of ABUS was 15.0% (1 554/10 344). The ABUS with remote reading had a detection rate of 3.7/1 000 (38/10 344) for breast cancer screening, with a sensitivity of 97.4% (38/39) and a specificity of 85.3% (8 789/10 305). Among the 38 breast cancer cases detected, 92.1% (35/38) were invasive carcinomas, and 63.2% (24/38) were stage 0 or Ⅰ breast cancers.Conclusions:Breast cancer screening based on ABUS with remote reading provided an efficient and feasible solution to the problem of unevenly distributed medical resources and medical staff levels in various regions of China, enabling the decentralization of high-quality medical resources and improving the accessibility of high-quality screening services. It has provided an alternative for breast cancer screening in China.

Objective:To investigate the value of systemic inflammatory response syndrome (SIRS), pediatric sequential organ failure assessment (pSOFA) and pediatric critical illness score (PCIS) in predicting mortality of pediatric sepsis in pediatric intensive care units (PICU) from Southwest China.Methods:This was a prospective multicenter observational study. A total of 447 children with sepsis admitted to 12 PICU in Southwest China from April 2022 to March 2023 were enrolled. Based on the prognosis, the patients were divided into survival group and non-survival group. The physiological parameters of SIRS, pSOFA and PCIS were recorded and scored within 24 h after PICU admission. The general clinical data and some laboratory results were recorded. The area under the curve (AUC) of the receiver operating characteristic curve was used to compare the predictive value of SIRS, pSOFA and PCIS in mortality of pediatric sepsis.Results:Amongst 447 children with sepsis, 260 patients were male and 187 patients were female, aged 2.5 (0.8, 7.0) years, 405 patients were in the survival group and 42 patients were in the non-survival group. 418 patients (93.5%) met the criteria of SIRS, and 440 patients (98.4%) met the criteria of pSOFA≥2. There was no significant difference in the number of items meeting the SIRS criteria between the survival group and the non-survival group (3(2, 4) vs. 3(3, 4) points, Z=1.30, P=0.192). The pSOFA score of the non-survival group was significantly higher than that of the survival group (9(6, 12) vs. 4(3, 7) points, Z=6.56, P<0.001), and the PCIS score was significantly lower than that of the survival group (72(68, 81) vs. 82(76, 88) points, Z=5.90, P<0.001). The predictive value of pSOFA (AUC=0.82) and PCIS (AUC=0.78) for sepsis mortality was significantly higher than that of SIRS (AUC=0.56) ( Z=6.59, 4.23, both P<0.001). There was no significant difference between pSOFA and PCIS ( Z=1.35, P=0.176). Platelet count, procalcitonin, lactic acid, albumin, creatinine, total bilirubin, activated partial thromboplastin time, prothrombin time and international normalized ratio were all able to predict mortality of sepsis to a certain degree (AUC=0.64, 0.68, 0.80, 0.64, 0.68, 0.60, 0.77, 0.75, 0.76, all P<0.05). Conclusion:Compared with SIRS, both pSOFA and PCIS had better predictive value in the mortality of pediatric sepsis in PICU.

Objective:To establish a brain metastasis (BM) prediction model for limited-stage small cell lung cancer (LS-SCLC) patients who achieved complete response (CR) or partial response (PR) after thoracic chemoradiotherapy, and to explore the value of prophylactic cranial irradiation (PCI) in different risk groups.Methods:Clinical data of 274 patients with LS-SCLC who achieved CR/PR after thoracic chemoradiotherapy in Tianjin Medical University Cancer Institute & Hospital from January 2010 to December 2021 were retrospectively analyzed, including 144 cases in the PCI group and 130 in the non-PCI group. The nomogram was developed based on variables determined by univariate and multivariate analyses in the non-PCI group. The bootstrap method, receiver operating characteristics (ROC) curve, calibration curve and decision curve analysis (DCA) were employed to evaluate the predictive power and clinical benefits of the model. Patients were stratified into high- and low-risk groups based on risk scores. The brain metastases-free survival (BMFS), progression-free survival (PFS), extracranial progression-free survival (ePFS) and overall survival (OS) were compared between patients with and without PCI in different risk-stratified populations using the log-rank test.Results:The nomogram included five variables: systemic immune inflammation index (SII), lymphocyte-to-monocyte ratio (LMR), pro-gastrin-releasing peptide precursor (ProGRP), neuron-specific enolase (NSE), and blood calcium. The area under the ROC curve (AUC) of the nomogram in predicting 1- and 2-year BMFS was 0.761 and 0.822. In the low-risk group, there was no significant difference in the BMFS ( P=0.374), PFS ( P=0.551), ePFS ( P=0.508) and OS ( P=0.767) between the PCI and non-PCI groups. In the high-risk group, PCI could significantly increase the BMFS ( P<0.001) and PFS ( P=0.022), while there was no significant difference in the ePFS ( P=0.963) and OS ( P=0.632). And propensity score-matching (PSM) analysis showed similar results. Conclusions:PCI does not improve OS in LS-SCLC patients regardless of high or low risk of BM. However, PCI significantly prolong the BMFS and PFS in patients at a high risk of BM.

Aim To study the effect of G protein-coupled estrogen receptor(GPER)inhibitor G15 on the sensitivity of breast cancer tamoxifen-resistant cells to T-47DTR. Methods Experiments were carried out with 4-hydroxytamoxifen(4-OHT),the active form of tamoxifen in vivo. The sensitivity of tamoxifen-resistant breast cancer cell line T-47DTR and its parental cell line T-47D to tamoxifen was detected by MTT assay; the expression of GPER protein was analyzed by plasma separation of inhibitor G15; the effect of 4-OHT combined with G15 on the apoptosis of T-47DTR cells was analyzed by flow cytometry AnnexinV-FITC/PI double staining; the expression levels of apoptosis-related proteins Bax,Bcl-2,caspase-3,cleaved caspase-3,caspase-9,cleaved caspase-9 were analysed by Western blot. Results(1)Compared with the parental cell T-47D,the resistance of T-47DTR-resistant cells to 4-OHT was significantly enhanced.(2)When 4-OHT(2 μmol·L-1)was administered,the membrane distribution of GPER increased,indicating that GPER was activated in T-47DTR-resistant cells compared with the control group; Compared with OHT,the use of G15(5 μmol·L-1)and OHT significantly reduced the expression of GPER.(3)GPER inhibitor G15 could increase the apoptotic rate of T-47DTR-resistant cells while down-regulating the anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic proteins Bax,cleaved caspase-3,cleaved caspase-9. Conclusions The GPER inhibitor G15 increases the apoptosis of T-47DTR cells and restores the sensitivity of drug-resistant cells to tamoxifen.

The present study aimed to explore the underlying mechanism of Wuling Capsules in the treatment of hepatic fibrosis(HF) through network pharmacology, molecular docking, and animal experiments. Firstly, the chemical components and targets of Wuling Capsules against HF were searched from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Traditional Chinese Medicines Integrated Database(TCMID), GeneCards, and literature retrieval. The protein-protein interaction(PPI) network analysis was carried out on the common targets by STRING database and Cytoscape 3.9.1 software, and the core targets were screened, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. Enrichment analysis was conducted on the core targets and the "drug-core component-target-pathway-disease" network was further constructed. Subsequently, molecular docking between core components and core targets was conducted using AutoDock Vina software to predict the underlying mechanism of action against HF. Finally, an HF model induced by CCl_4 was constructed in rats, and the general signs and liver tissue morphology were observed. HE and Masson staining were used to analyze the liver tissue sections. The effects of Wuling Capsules on the levels of inflammatory factors, hydroxyproline(HYP) levels, and core targets were analyzed by ELISA, RT-PCR, etc. A total of 445 chemical components of Wuling Capsules were screened, corresponding to 3 882 potential targets, intersecting with 1 240 targets of HF, and 47 core targets such as TNF, IL6, INS, and PIK3CA were screened. GO and KEGG enrichment analysis showed that the core targets mainly affected the process of cell stimulation response and metabolic regulation, involving cancer, PI3K-Akt, MAPK, and other signaling pathways. Molecular docking showed that the core components of Wuling Capsules, such as lucidenic acid K, ganoderic acid B, lucidenic acid N, saikosaponin Q2, and neocryptotanshinone, had high affinities with the core targets, such as TNF, IL6 and PIK3CA. Animal experiments showed that Wuling Capsules could reduce fat vacuole, inflammatory infiltration, and collagen deposition in rat liver, decrease the levels of inflammatory cytokines TNF-α, IL-6, and HYP, and downregulated the expressions of PI3K and Akt mRNA. This study suggests that the anti-HF effect of Wuling Capsules may be achieved by regulating the PI3K-Akt signaling pathway, reducing the levels of TNF-α and IL-6 inflammatory factors, and inhibiting the excessive deposition of collagen.
Animals ; Rats ; Interleukin-6 ; Network Pharmacology ; Animal Experimentation ; Tumor Necrosis Factor-alpha ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Liver Cirrhosis/genetics* ; Medicine, Chinese Traditional ; Capsules ; Class I Phosphatidylinositol 3-Kinases ; Collagen ; Drugs, Chinese Herbal/pharmacology*