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.

Grounded in the theory of "all marrows dominated by brain", this study explored the therapeutic mechanism of Zuogui Pills in modulating the oxytocin(OXT)/oxytocin receptor(OXTR) feed-forward loop in the treatment of postmenopausal osteoporosis(PMOP). A PMOP rat model was established using ovariectomy, and 70 Sprague-Dawley female rats were randomly divided into the following groups: sham operation group, model group, estradiol group(17β-estradiol, 0.05 mg·kg~(-1)·d~(-1)), Zuogui Pills low, medium, and high dose groups(0.2, 0.4, 0.8 g·kg~(-1)·d~(-1), respectively), and an antagonist group(atosiban 0.9 mg·kg~(-1)·d~(-1) + 17β-estradiol 0.05 mg·kg~(-1)·d~(-1) + Zuogui Pills 0.4 g·kg~(-1)·d~(-1)). After 12 weeks of model establishment, treatment was administered by gavage once daily for another 12 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of estrogen(E_2), OXT, tartrate-resistant acid phosphatase(TRACP-5b), and bone alkaline phosphatase(BALP). Histopathological changes in the left distal femur were observed through hematoxylin and eosin(HE) staining. Micro-computed tomography(micro-CT) was used to analyze the microstructure of the right distal femur. Western blot was employed to detect the expression levels of OXTR, small GTP-binding protein Ras, Raf1 proto-oncogene(Raf1), mitogen-activated protein kinase kinase 1/2(MEK1/2), and extracellular signal-regulated kinase 1/2(ERK1/2), and their phosphorylated forms in tibial tissues. Compared with the model group, the Zuogui Pills medium and high dose groups showed significantly increased levels of E_2, OXT, and BALP, with a notable decrease in TRACP-5b levels. Morphologically, the trabeculae in the left distal femur were more tightly arranged. The fibrous structure in the right distal femur was significantly improved in the Zuogui Pills high dose group. Additionally, the expression of OXTR, Ras, p-Raf1, p-MEK1/2, and p-ERK1/2 proteins in tibial tissues was significantly increased. The therapeutic effect of the Zuogui Pills high dose group was partially inhibited when an OXTR antagonist was administered. These findings suggest that Zuogui Pills can regulate the OXT/OXTR feed-forward loop, activate the phosphorylation of the downstream Ras/Raf1/MEK/ERK signaling pathway, and ultimately improve bone mineral density, thereby exerting therapeutic effects in PMOP.
Animals ; Rats, Sprague-Dawley ; Rats ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Oxytocin/genetics* ; Receptors, Oxytocin/genetics* ; Humans ; Osteoporosis, Postmenopausal/genetics* ; Bone and Bones/drug effects* ; Brain/drug effects* ; Bone Marrow/drug effects*

ObjectiveTo use bioinformatics technology to screen the molecular patterns and diagnostic biomarkers of ferroptosis closely related to psoriasis， observe the therapeutic effect of Kaixuan Jiedu core prescription on psoriasis and explore its potential mechanism through animal experiments. MethodsPsoriasis microarray data from GEO were analyzed to identify differentially expressed genes （DEGs）. Intersection with a ferroptosis gene set yielded psoriasis ferroptosis-related genes （FRGs）， which underwent correlation， consensus clustering， enrichment， and immune infiltration analyses. Core diagnostic FRGs （Hub-FRGs） were identified using random forest （RF）， support vector machine （SVM）， LASSO regression， Nomogram， and ROC analyses. In vivo， imiquimod （5% cream） induced psoriasis in mice （except controls）. Drug treatment groups received respective doses， while control and model groups received saline via daily gavage for 7 days. Back skin changes were recorded and PASI scored. Hematoxylin-eosin （HE） staining assessed histopathology. The levels of ferrous ion （Fe²⁺）， malondialdehyde （MDA）， 4-hydroxynonenal （4-HNE） and free fatty acid （FFA） in skin tissue were detected. The level of reactive oxygen species （ROS） in skin tissue was detected by immunofluorescence. Immunohistochemistry was used to detect the expression of ChaC glutathione-specific γ-glutamyl transferase 1 （CHAC1）， arachidonic acid 12-lipoxygenase β （ALOX12B）， trimotif protein 21 （TRIM21）， proliferation marker （Ki67） and nuclear transcription factor-κB （NF-κB） protein. ResultsAnalysis of GSE30999 identified 2 100 DEGs and 24 FRGs. Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment revealed 1 000 biological functions and 75 pathways. After cluster analysis， combined with three machine learning algorithms， Nomogram and ROC curve analysis， the core Hub-FRGs （CHAC1， ALOX12 B， TRIM21） were obtained. Immunoinfiltration showed inactive memory CD4⁺T cells and activated dendritic cells abundance significantly correlated with Hub-FRGs. In vivo， model group vs. control showed significantly increased PASI/Baker scores （P<0.05）， epidermal hyperkeratosis， inflammatory infiltration， and elevated levels of Fe²⁺， MDA， 4-HNE， FFA， ROS， CHAC1， ALOX12B， TRIM21， Ki67， and NF-κB （P<0.05）. Drug groups vs. model group exhibited significantly reduced scores （P<0.05）， alleviated skin lesions， and decreased levels of Fe²⁺， MDA， 4-HNE， FFA， ROS， Hub-FRGs， Ki67， and NF-κB （P<0.05）. ConclusionKaixuan Jiedu core prescription can significantly improve the skin pathological injury of psoriasis mice， showing good therapeutic and repair effects， and its mechanism may be related to regulating the expression of ferroptosis genes CHAC1， ALOX12B and TRIM21， which are closely related to the pathogenesis of psoriasis.

ObjectiveTo use bioinformatics technology to screen the molecular patterns and diagnostic biomarkers of ferroptosis closely related to psoriasis， observe the therapeutic effect of Kaixuan Jiedu core prescription on psoriasis and explore its potential mechanism through animal experiments. MethodsPsoriasis microarray data from GEO were analyzed to identify differentially expressed genes （DEGs）. Intersection with a ferroptosis gene set yielded psoriasis ferroptosis-related genes （FRGs）， which underwent correlation， consensus clustering， enrichment， and immune infiltration analyses. Core diagnostic FRGs （Hub-FRGs） were identified using random forest （RF）， support vector machine （SVM）， LASSO regression， Nomogram， and ROC analyses. In vivo， imiquimod （5% cream） induced psoriasis in mice （except controls）. Drug treatment groups received respective doses， while control and model groups received saline via daily gavage for 7 days. Back skin changes were recorded and PASI scored. Hematoxylin-eosin （HE） staining assessed histopathology. The levels of ferrous ion （Fe²⁺）， malondialdehyde （MDA）， 4-hydroxynonenal （4-HNE） and free fatty acid （FFA） in skin tissue were detected. The level of reactive oxygen species （ROS） in skin tissue was detected by immunofluorescence. Immunohistochemistry was used to detect the expression of ChaC glutathione-specific γ-glutamyl transferase 1 （CHAC1）， arachidonic acid 12-lipoxygenase β （ALOX12B）， trimotif protein 21 （TRIM21）， proliferation marker （Ki67） and nuclear transcription factor-κB （NF-κB） protein. ResultsAnalysis of GSE30999 identified 2 100 DEGs and 24 FRGs. Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment revealed 1 000 biological functions and 75 pathways. After cluster analysis， combined with three machine learning algorithms， Nomogram and ROC curve analysis， the core Hub-FRGs （CHAC1， ALOX12 B， TRIM21） were obtained. Immunoinfiltration showed inactive memory CD4⁺T cells and activated dendritic cells abundance significantly correlated with Hub-FRGs. In vivo， model group vs. control showed significantly increased PASI/Baker scores （P<0.05）， epidermal hyperkeratosis， inflammatory infiltration， and elevated levels of Fe²⁺， MDA， 4-HNE， FFA， ROS， CHAC1， ALOX12B， TRIM21， Ki67， and NF-κB （P<0.05）. Drug groups vs. model group exhibited significantly reduced scores （P<0.05）， alleviated skin lesions， and decreased levels of Fe²⁺， MDA， 4-HNE， FFA， ROS， Hub-FRGs， Ki67， and NF-κB （P<0.05）. ConclusionKaixuan Jiedu core prescription can significantly improve the skin pathological injury of psoriasis mice， showing good therapeutic and repair effects， and its mechanism may be related to regulating the expression of ferroptosis genes CHAC1， ALOX12B and TRIM21， which are closely related to the pathogenesis of psoriasis.

OBJECTIVE: To observe the clinical symptoms and MRI outcomes of patients with ruptured lumbar disc herniation(LDH) through a multicenter randomized controlled study, and to evaluate the clinical efficacy and safety of Yiqi Huoxue formula() in the treatment of this disease. METHODS: A total of 160 outpatients and inpatients with ruptured LDH admitted to 4 medical centers from January 2023 to June 2023 were selected and randomly divided into the Yiqi Huoxue formula group and the control group, with 80 patients in each group. In the Yiqi Huoxue formula group, there were 43 males and 37 females, with an age of (41.03±9.56) years and a disease duration of (10.45±25.37) days, and the patients were treated with Yiqi Huoxue formula. In the control group, there were 34 males and 46 females, with an age of (42.14±8.73) years and a disease duration of (11.31±21.14) days;during the acute phase, patients in this group could take celecoxib capsules orally, and methylcobalamin orally at the same time. The Japanese Orthopaedic Association (JOA) score, Oswestry disability index (ODI), changes in the volume of herniated disc tissue on MRI, herniation rate, and absorption rate were recorded at the time of enrollment and during follow-ups at the 3rd, 6th, and 12th month after treatment. RESULTS: A total of 156 patients completed the clinical follow-up, and 4 patients withdrew midway. The clinical symptoms of all patients who completed the study were relieved to varying degrees, and reabsorption of herniated disc tissue was observed in all patients in the Yiqi Huoxue formula group after treatment. For the JOA score:in the Yiqi Huoxue formula group, it was (10.73±2.76) points before treatment and (24.65±2.19) points at the 12th month after treatment;in the control group, it was (11.01±1.20) points before treatment and (17.07±3.26) points at the 12th month after treatment. For the ODI score:in the Yiqi Huoxue formula group, it was (26.21±3.55) points before treatment and (5.65±2.19) points at the 12th month after treatment;in the control group, it was (27.92±2.51) points before treatment and (9.09±2.15) points at the 12th month after treatment. At the 12th month after treatment, the JOA and ODI scores of both groups were better than those before treatment, and the scores of the Yiqi Huoxue formula group were better than those of the control group, with statistically significant differences (P<0.05). In terms of the herniated disc volume and herniation rate on MRI, the Yiqi Huoxue formula group was superior to the control group, with statistically significant differences(P<0.05). Reabsorption occurred in 56.96%(45/79) of patients in the Yiqi Huoxue formula group, which was significantly higher than the 37.66%(29/77) in the control group. CONCLUSION After treatment with Yiqi Huoxue formula, patients with ruptured LDH show significant improvement in clinical symptoms and a marked reduction in the volume of herniated discs. During the follow-up period, no obvious adverse drug reactions are observed in patients, and no recurrence of symptoms is found at the last follow-up, indicating that the formula has safe and reliable efficacy.
Humans ; Male ; Female ; Intervertebral Disc Displacement/drug therapy* ; Adult ; Drugs, Chinese Herbal/adverse effects* ; Middle Aged ; Lumbar Vertebrae

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

OBJECTIVE: To examine the effectiveness of Chinese medicine (CM) Lianhua Qingwen Granule (LHQW) and Jingyin Gubiao Prescription (JYGB) in asymptomatic or mild patients with Omicron infection in the shelter hospital. METHODS: This single-center retrospective cohort study was conducted in the largest shelter hospital in Shanghai, China, from April 10, 2022 to May 30, 2022. A total of 56,244 asymptomatic and mild Omicron cases were included and divided into 4 groups, i.e., non-administration group (23,702 cases), LHQW group (11,576 cases), JYGB group (12,112 cases), and dual combination of LHQW and JYGB group (8,854 cases). The length of stay (LOS) in the hospital was used to assess the effectiveness of LHQW and JYGB treatment on Omicron infection. RESULTS: Patients aged 41-60 years, with nadir threshold cycle (C_T) value of N gene <25, or those fully vaccinated preferred to receive CM therapy. Before or after propensity score matching (PSM), the multiple linear regression showed that LHQW and JYGB treatment were independent influence factors of LOS (both P<0.001). After PSM, there were significant differences in LOS between the LHQW/JYGB combination and the other groups (P<0.01). The results of factorial design ANOVA proved that the LHQW/JYGB combination therapy synergistically shortened LOS (P=0.032). CONCLUSIONS Patients with a nadir C_T value <25 were more likely to accept CM. The LHQW/JYGB combination therapy could shorten the LOS of Omicron-infected individuals in an isolated environment.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; China/epidemiology* ; Hospitalization ; COVID-19 Drug Treatment ; COVID-19/epidemiology* ; SARS-CoV-2 ; Retrospective Studies ; Treatment Outcome ; Length of Stay ; Young Adult ; Aged

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.

OBJECTIVES: To explore the association between GPSM2 expression level and gastric cancer progression and analyze the functional pathways and action mechanism of GPSM2. METHODS: We analyzed GPSM2 expression levels in gastric cancer tumors based on data from the GEPIA database and the clinical data of 109 patients. Public databases enrichment analysis were used to assess the impact of GPSM2 expression level on survival outcomes and the functional pathways and action mechanism of GPSM2. We further observed the effects of GPSM2 knockdown and overexpression on proliferation, migration and apoptosis of MGC803 cells using CCK-8 assay, colony formation assay, flow cytometry and immunoblotting and on the growth of MGC803 cell xenografts in nude mice. RESULTS: Bioinformatic analysis and immunohistochemical staining of the clinical specimens both revealed high GPSM2 expressions in gastric cancer (P<0.01). A high GPSM2 expression was significantly correlated with T3-4 stages, N2-3 stages, a carcinoembryonic antigen (CEA) level ≥5 μg/L, and a carbohydrate antigen (CA) 19-9 level ≥37 kU/L (P<0.05). Cox regression analysis identified high GPSM2 expression as an independent risk factor affecting 5-year survival of the patients (P<0.05). Gene ontology (GO) analysis suggested that GPSM2 was involved in cell cycle regulation. In MGC803 cells, GPSM2 overexpression significantly promoted cell proliferation and G1/S transition and xenograft growth in nude mice. KEGG pathway enrichment analysis indicated that GPSM2 executed its biological functions by regulating the p53 signaling pathway, which was confirmed by the results of immunoblotting experiments showing suppression of p53 signaling pathway activity in GPSM2-over expressing MGC803 cells. CONCLUSIONS GPSM2 is highly expressed in gastric cancer to affect patient prognosis by promoting tumor cell proliferation and G1/S transition possibly via inhibiting the p53 pathway.
Stomach Neoplasms/metabolism* ; Humans ; Cell Proliferation ; Prognosis ; Animals ; Mice, Nude ; Cell Line, Tumor ; Mice ; Apoptosis ; Tumor Suppressor Protein p53/metabolism* ; Cell Movement

OBJECTIVES: To investigate the expression of apolipoprotein C1 (APOC1) in papillary thyroid carcinoma (PTC) and its effects on proliferation and apoptosis of PTC cells. METHODS: The expression level of APOC1 in PTC and its impact on prognosis were analyzed using GEPIA 2 and Kaplan-Meier databases. Immunohistochemistry (IHC) and Western blotting were used to detect the expression of APOC1 in PTC and adjacent tissues and in 3 PTC cell lines and normal thyroid Nthyori 3-1 cells. In TPC-1 and BCPAP cells, the effect of Lipofectamine 2000-mediated transfection with APOC1 siRNA or an APOC1-overexpressing plasmid on cell growth and colony formation ability were examined by observing the growth curves and using colony-forming assay. The changes in cell cycle and apoptosis of the transfected cells were analyzed with flow cytometry. RT-qPCR and Western blotting were used to detect the changes in expressions of P21, P27, CDK4, cyclin D1, Bcl-2, Bax, caspase-3 and caspase-9 and the key proteins in the JAK2/STAT3 signaling pathway. RESULTS: APOC1 expression was significantly higher in PTC tissues and the 3 PTC cell lines than in the adjacent tissues and Nthyori 3-1 cells, respectively. In TPC-1 and BCPAP cells, APOC1 knockdown obviously reduced cell proliferative activity, increased the percentage of G0/G1 phase cells, lowered the percentages of S and G2 phase cells, promoted cell apoptosis, and downregulated mRNA and protein expression levels of CDK4, cyclin D1 and Bcl-2 and the protein levels of p-JAK2 and p-STAT3. APOC1 overexpression in the cells produced the opposite effects on cell proliferation, apoptosis, cell cycle and the mRNA and protein expressions. The application of AG490, a JAK2 inhibitor, strongly attenuated APOC1 overexpression-induced activation of the JAK2/STAT3 signaling pathway in BCPAP cells. CONCLUSIONS APOC1 overexpression promotes proliferation and inhibits apoptosis of PTC cells possibly by activating the JAK2/STAT3 signaling pathway and accelerating cell cycle progression.
Humans ; Apoptosis ; Cell Proliferation ; STAT3 Transcription Factor/metabolism* ; Signal Transduction ; Janus Kinase 2/metabolism* ; Thyroid Neoplasms/pathology* ; Thyroid Cancer, Papillary ; Cell Line, Tumor ; Carcinoma, Papillary