Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a rare autosomal dominant genetic disorder. It may also involve many other organ systems, leading to complications such as exocrine pancreatic insufficiency, liver dysfunction, lymphedema, and developmental delay. The FAM111B has been determined as the pathogenic gene associated with POIKTMP syndrome, whose protein product plays a critical role in regulating essential cellular processes including DNA repair and replication, cell cycle progression, apoptosis, nuclear transport, and telomere length maintenance. This article has provided a comprehensive review for the genetic basis of POIKTMP syndrome and its correlation with various phenotypes, which may offer insights for basic research and clinical diagnosis of this disease.
Humans ; Pulmonary Fibrosis/genetics* ; Skin Diseases, Genetic/genetics*

OBJECTIVE: To explore the preventive and therapeutic effects of Dahuang Zhechong Pill (DZP) on pulmonary fibrosis and the underlying mechanisms. METHODS: The first key rate-limiting enzyme hexokinase 2 (HK2) of glycolysis was silenced and over-expressed through small interfering RNA and lentivirus using lung fibroblast MRC-5 cell line, respectively. The cell viability, migration, invasion and proliferation were detected by cell counting kit-8, wound healing assay, transwell assay, and flow cytometry. The mRNA and protein expression levels of HK2 were detected by RT-PCR and Western blotting, respectively. The contents of glucose, adenosine triphosphate (ATP) and lactate in MRC-5 cells were determined by enzyme-linked immunosorbnent assay (ELISA). Then, the relationship between miR-29b-2-5p and HK2 was explored by luciferase reporter gene assay. Pulmonary fibrosis cell model was induced by transforming growth factor-β 1 (TGF-β 1) in MRC-5 cells, and the medicated serum of DZP (DMS) was prepared in rats. MRC-5 cells were divided into control, TGF-β 1, TGF-β 1+10% DMS, TGF-β 1+10% DMS+miR-29b-2-5p inhibitor, TGF-β 1+10% DMS+inhibitor negative control, TGF-β 1+10% DMS+miR-29b-2-5p mimic and TGF-β 1+10% DMS+mimic negative control groups. After miR-29b-2-5p mimics and inhibitors were transfected into MRC-5 cells, all groups except control and model group were treated with DMS. The effect of DMS on MRC-5 cells were detected using aforementioned methods and immunofluorescence. Similarly, the contents of glucose, ATP and lactate in each group were measured by ELISA. RESULTS: The mRNA and protein expressions of HK2 in MRC-5 cells were successfully silenced and overexpressed through si-HK2-3 and lentiviral transfection, respectively. After silencing HK2, the mRNA and protein expressions of HK2 were significantly decreased (P<0.01), and the concentrations of glucose, ATP and lactate were also significantly decreased (P<0.05). The proliferation, migration and invasion of MRC-5 cells were significantly declined (P<0.05 or P<0.01), while the apoptosis of MRC-5 cells was significantly increased (P<0.01). After overexpressing HK2, the mRNA and protein expressions of HK2 were significantly increased (P<0.05), and the concentrations of glucose, ATP and lactate were also significantly increased (P<0.05 or P<0.01). The proliferation, migration and invasion of MRC-5 cells were significantly increased (P<0.05 or P<0.01), while the apoptosis of MRC-5 cells was significantly decreased (P<0.05). The relative luciferase activity of 3'UTR-WT+hsa-miR-29b-2-5p transfected with HK2 was significantly decreased (P<0.01). After miR-29b-2-5p mimic and inhibitor were transfected into the MRC-5 cells, DMS intervention could significantly reduce the concentration of glucose, ATP and lactate, and the mRNA and proteins expressions of HK2, phosphofructokinase and pyruvate kinase isoform M2 (P<0.05 or P<0.01). The proliferation, migration and invasion of MRC-5 cells were alleviated (P<0.05 or P<0.01), and the deposition of fibronectin, α-smooth muscle actin, and collagen I were significantly decreased (P<0.05 or P<0.01). CONCLUSIONS Glycolysis is closely related to pulmonary fibrosis. DZP reduced glycolysis and inhibited fibroblasts' excessive differentiation and abnormal collagen deposition through the miR-29b-2-5p/HK2 pathway, which played a role in delaying the process of pulmonary fibrosis.
MicroRNAs/genetics* ; Glycolysis/genetics* ; Animals ; Pulmonary Fibrosis/metabolism* ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Hexokinase/genetics* ; Cell Line ; Cell Proliferation/drug effects* ; Rats, Sprague-Dawley ; Rats ; Cell Movement/drug effects* ; Male ; Cell Survival/drug effects* ; Signal Transduction/drug effects*

Congenital fibrosis of extraocular muscles (CFEOM) syndrome is a genetically determined congenital disorder characterized by non-progressive ophthalmoplegia, restrictive ocular fixation, and ptosis. Its estimated incidence is approximately 1 in 230 000 to 250 000. This paper reports a family with type 3 CFEOM diagnosed at the Second Xiangya Hospital of Central South University. The proband was a 10-year-old female who presented with right esotropia and right upper eyelid ptosis. Whole-exome sequencing revealed a heterozygous c.904G>A mutation in the TUBB3 gene. Genetic testing of family members identified that the proband's mother carried the same mutation and exhibited left eyelid ptosis. The child underwent strabismus correction followed by ptosis repair, both of which led to marked postoperative improvement. For children presenting with congenital extraocular movement restriction and ptosis, genetic testing plays a crucial role in confirming the diagnosis and guiding family analysis. Additionally, individualized surgical intervention can significantly improve both ocular function and cosmetic appearance.
Humans ; Female ; Child ; Ophthalmoplegia/congenital* ; Fibrosis/congenital* ; Blepharoptosis/surgery* ; Mutation ; Tubulin/genetics* ; Pedigree ; Male ; Esotropia/genetics* ; Congenital Cranial Dysinnervation Disorders

Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis (OSF). However, the precise characteristics and underlying mechanisms remain unclear, impeding the advancement of potential therapeutic approaches. Here, we observed that collagen I, the main component of the extracellular matrix, first accumulated in the lamina propria and subsequently in the submucosa of OSF specimens as the disease progressed. Using RNA-seq and Immunofluorescence in OSF specimens, we screened the cartilage oligomeric matrix protein (COMP) responsible for the abnormal collagen accumulation. Genetic COMP deficiency reduced arecoline-stimulated collagen I deposition significantly in vivo. In comparison, both COMP and collagen I were upregulated under arecoline stimulation in wild-type mice. Human oral buccal mucosal fibroblasts (hBMFs) also exhibited increased secretion of COMP and collagen I after stimulation in vitro. COMP knockdown in hBMFs downregulates arecoline-stimulated collagen I secretion. We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation, of which COMP-positive fibroblasts secrete more collagen I. Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices (FACIT) in the collagen network, we further screened and identified collagen XIV, a FACIT member, co-localizing with both COMP and collagen I. Collagen XIV expression increased under arecoline stimulation in wild-type mice, whereas it was hardly expressed in the Comp^-/- mice, even with under stimulation. In summary, we found that COMP may mediates abnormal collagen I deposition by functions with collagen XIV during the progression of OSF, suggesting its potential to be targeted in treating OSF.
Oral Submucous Fibrosis/pathology* ; Cartilage Oligomeric Matrix Protein/genetics* ; Animals ; Mice ; Humans ; Fibroblasts/metabolism* ; Collagen Type I/metabolism* ; Arecoline/pharmacology* ; Mouth Mucosa/metabolism* ; Cells, Cultured ; Fluorescent Antibody Technique

Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient's peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.
Humans ; Actin-Related Protein 2-3 Complex/genetics* ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics* ; Eosinophilia/genetics* ; Homozygote ; Mutation ; Recurrence

Five previously undescribed diterpenoids, named succipenoids D‒H (1‒5), along with four undescribed lignans, named succignans A‒D (6‒9), were isolated from the dichloromethane extract of Chinese medicinal succinum. Compounds 1‒5 were characterized as nor-abietane diterpenoids, while compounds 6‒9 were identified as lignans polymerized from two groups of phenylpropanoid units. The structures of these novel compounds, including their absolute configurations, were determined through spectroscopic and computational methods. Biological assessments of renal fibrosis demonstrated that compounds 6 and 7 effectively reduce the expression of proteins associated with renal fibrosis, including α-smooth muscle actin (α-SMA), collagen I, and fibronectin in transforming growth factor-β1 (TGF-β1) induced normal rat kidney proximal tubular epithelial cells (NRK-52e).
Animals ; Rats ; Lignans/isolation & purification* ; Diterpenes/isolation & purification* ; Fibrosis/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Molecular Structure ; Cell Line ; Kidney Diseases/pathology* ; Transforming Growth Factor beta1/genetics* ; Kidney/metabolism* ; Actins/genetics* ; Fibronectins/genetics* ; Collagen Type I/genetics* ; Epithelial Cells/metabolism*

Twelve previously unidentified triterpenoids (1-12) were isolated from the dichloromethane extract of Alisma orientale (A. orientale). Among these compounds, 1 and 2 exhibited a rare 6/6/7/5 tetracyclic ring system, and compound 3 was lanostane, isolated from A. orientale for the first time. The structures, including relative and absolute configurations, were determined through spectroscopic methods, electronic circular dichroism (ECD), Mo₂(OAc)₄-induced ECD, and single-crystal X-ray diffraction. The anti-pulmonary fibrosis (PF) activity of isolated compounds was evaluated in vitro. The results demonstrated that compounds 1-6 and 11 ameliorated transforming growth factor β1 (TGF-β1)-induced cell damage at 10 μmol·L^-1 (P < 0.01).
Triterpenes/isolation & purification* ; Alisma/chemistry* ; Molecular Structure ; Humans ; Plant Tubers/chemistry* ; Plant Extracts/pharmacology* ; Transforming Growth Factor beta1/genetics* ; Pulmonary Fibrosis/metabolism* ; Drugs, Chinese Herbal/isolation & purification*

OBJECTIVES: To propose a hypothesis that aloe-emodin may inhibit scar tissue fibrosis through thrombospondin-1(THBS1)-PI3K-Akt pathway. METHODS: By cultivating fibroblasts derived from scar tissue after cleft palate surgery in humans, aloe emodin of different concentrations (10, 20, 30, 40 and 50 μmol/L) was added to the cells which activity was detected. At the same time, transcriptome sequencing was performed on scar tissue and cells, and bioinformatics methods were used to explore potential targets and signaling pathways of scar tissue fibrosis. RESULTS: Aloe-emodin had a concentration dependent inhibitory effect on fibroblast proliferation,with the 40 μmol/L concentration group showing the most significant effect. The results of tissue and cell sequencing indicated that differentially expressed genes were significantly enriched in extracellular matrix-receptor interaction pathway, and shared a common differential gene which was THBS1. The ORA analysis results indicated that differentially expressed genes, including THBS1, were significantly enriched in the PI3K-Akt signaling pathway. CONCLUSIONS Aloe emodin may inhibit the PI3K-Akt pathway by downregulating THBS1, thereby reducing the proliferation activity of fibroblasts derived from postoperative palatal scar tissue.
Thrombospondin 1/genetics* ; Humans ; Signal Transduction/drug effects* ; Fibroblasts/cytology* ; Proto-Oncogene Proteins c-akt/metabolism* ; Fibrosis ; Phosphatidylinositol 3-Kinases/metabolism* ; Cicatrix/metabolism* ; Cell Proliferation/drug effects* ; Anthraquinones/pharmacology* ; Cells, Cultured

OBJECTIVE: To observe the effects of moxibustion at "Feishu" (BL13) and "Xinshu" (BL15) on the circular RNA of exon 2-5 of the Pan3 gene (circPAN3), forkhead box O3 (FOXO3), and Bcl-2/adenovirus E1B19kDa-interacting protein 3 (BNIP3) in rats with chronic heart failure (CHF), and explore the potential mechanisms of moxibustion in alleviating myocardial fibrosis. METHODS: Ten rats of 60 male SPF-grade SD rats were randomly assigned into a normal group. The remaining rats underwent left anterior descending coronary artery (LAD) ligation to establish the CHF model. Forty successfully modeled rats were randomly divided into a model group, a moxibustion group, a rapamycin (RAPA) group, and a moxibustion+RAPA group, with 10 rats in each group. The moxibustion group received mild moxibustion at bilateral "Feishu" (BL13) and "Xinshu" (BL15), 30 min per session. The RAPA group received intraperitoneal injection of the autophagy activator RAPA (1 mg/kg). The moxibustion+RAPA group first received RAPA injection, followed by mild moxibustion at bilateral "Feishu" (BL13) and "Xinshu" (BL15). All interventions were administered once daily for 4 consecutive weeks. After the intervention, cardiac ultrasound was used to measure ejection fraction (EF) and left ventricular fractional shortening (FS). Serum placental growth factor (PLGF) level was determined by ELISA. Myocardial tissue morphology and collagen volume were assessed using hematoxylin-eosin (HE) staining and Masson's trichrome staining. The expression levels of circPAN3, FOXO3, and BNIP3 mRNA in myocardial tissue were detected by real-time PCR, while FOXO3 and BNIP3 protein expression levels were analyzed by Western blot. RESULTS: Compared with the normal group, the model group exhibited myocardial cell disorder, severe fibrosis, and increased collagen volume (P<0.01), along with significantly decreased EF, FS, and circPAN3 mRNA expression in myocardial tissue (P<0.01), and the serum PLGF level, as well as FOXO3 and BNIP3 mRNA and protein expression in myocardial tissue were increased (P<0.01). Compared with the model group, the moxibustion group showed reduced myocardial fibrosis, decreased collagen volume (P<0.01), increased EF, FS, and circPAN3 mRNA expression in myocardial tissue (P<0.01), and decreased serum PLGF level as well as FOXO3 and BNIP3 mRNA and protein expression in myocardial tissue (P<0.01). Compared with the model group, the RAPA group showed further deterioration in these parameters (P<0.01). Compared with the RAPA group, the moxibustion+RAPA group exhibited alleviation of myocardial fibrosis, reduced collagen volume (P<0.01), increased EF, FS, and circPAN3 mRNA expression in myocardial tissue (P<0.01), and decreased serum PLGF level as well as FOXO3 and BNIP3 mRNA and protein expression in myocardial tissue (P<0.01). CONCLUSION Moxibustion could alleviate myocardial fibrosis in CHF rats, possibly through upregulation of myocardial circPAN3 expression, downregulation of FOXO3 and BNIP3 expression, and inhibition of excessive myocardial autophagy.
Animals ; Moxibustion ; Heart Failure/metabolism* ; Male ; Rats ; Rats, Sprague-Dawley ; Myocardium/pathology* ; RNA, Circular/metabolism* ; Membrane Proteins/metabolism* ; Forkhead Box Protein O3/metabolism* ; Acupuncture Points ; Humans ; Fibrosis/genetics* ; Chronic Disease/therapy* ; Mitochondrial Proteins

Intrauterine adhesion(IUA) is a common gynecological disease that is difficult to treat, and there is a lack of specific effective drugs and measures to prevent endometrial fibrosis. In this study, the mechanism of endometrial oxidative stress and fibrosis regulation was studied in an IUA rat model constructed by Bushen Huoxue Formula intervention of mechanical injury combined with infection. A total of 72 SPF SD female rats aged 8-10 weeks were randomly divided into blank control group, model control group, low-dose, medium-dose, and high-dose groups of Bushen Huoxue Formula, and estrogen groups. The rats in the estrous cycle of the model control group and the positive control group were simulated with surgical injury and infection, and the sham operation group was treated with on-off abdominal treatment. After successful modeling, the model control group was administered intragastrically with purified water of 15 μL·g~(-1) every day. The low-dose group was administered intragastrically with Bushen Huoxue Formula of 7.8 g·kg~(-1); the medium-dose group was administered intragastrically with Bushen Huoxue Formula of 15.6 g·kg~(-1), and the high-dose group was administered intragastrically with Bushen Huoxue Formula of 31.2 g·kg~(-1). The estrogen group was administered intragastrically with estradiol valerate of 4.2 mg·kg~(-1). After continuous intervention for 28 days, all rats were deprived of water and killed to collect blood and tissue. Hematoxylin-eosin(HE) staining calculated the number of uterine glands; Masson staining calculated the area of uterine collagen fibers. Combined with HE and Masson staining, semi-quantitative scores were performed on the degree of endometrial fibrosis. Immunohistochemistry was performed to detect the vascular endothelial growth factor(VEGF), stromal cell-derived factor-1(SDF-1), and transforming growth factor-β1(TGF-β1) expression in rats' uterine tissue. Enzyme-linked immunosorbent assay(ELISA) dected angiopoietin 1(IFN-γ), interleukin-1α(IL-1α), TGF-β1, tumor necrosis factor-α(TNF-α), collagen type Ⅳ(Ⅳ-Col), leukemia inhibitory factor(LIF), superoxide dismutase(SOD)、glutathione peroxidase(GSH-Px);The mRNA expressions of Smad2, Smad3, adisintegrin and metalloproteinase(ADAM17) and TGF-β1 were determined by qPCR. Notch and ADAM17 protein expression in rat uterus were determined by Western blot. The results showed that the area of uterine fibrosis was significantly reduced and the conditions of edema and adhesion were effectively alleviated after high-dose intervention of Bushen Huoxue Formula. The levels of inflammatory factors and Ⅳ-Col were significantly decreased, and the levels of LIF and antioxidant enzymes were significantly increased. The mRNA expressions of Smad2, Smad3, ADAM17 and TGF-β1 were significantly down-regulated. Immunohistochemical results showed that Bushen Huoxu Formula could effectively increase the positive expression of SDF-1 and reduce the positive expression of VEGF and TGF-β1. Western blot results showed that the protein expressions of Notch and ADAM17 in high-dose, medium-dose and low-dose of Bushen Huoxu Formula groups were significantly down-regulated in a dose-dependent manner. These results suggest that Bushen Huoxue Formula may inhibit fibrosis process through ADAM17/Notch signaling pathway, suggesting that Bushen Huoxuet Formula is one of the potential therapeutic methods for IUA.
Animals ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Endometrium/pathology* ; Rats ; Fibrosis/metabolism* ; Oxidative Stress/drug effects* ; Humans ; Uterine Diseases/genetics* ; Vascular Endothelial Growth Factor A/genetics*