In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.
Male ; Humans ; Autophagy/physiology* ; Apoptosis/physiology* ; Erectile Dysfunction/physiopathology* ; Fibrosis ; Penis/pathology* ; Animals ; Endothelial Cells/pathology* ; Myocytes, Smooth Muscle/pathology*

OBJECTIVES: To investigate the effect of Shenge powder (SGP) on myocardial fibrosis in rats with heart failure after myocardial infarction and its relation with lysyl oxidase like protein 2 (LOXL2)/transforming growth factor-β1 (TGF-β1)/IL-11 signaling pathway. METHODS: Seventy-two SPF male SD rats were divided into blank control group, model control group, SGP small dose group, SGP large dose group, positive control group, SGP large dose+LOXL2 activator group, with 12 rats in each group. Except for the blank control group, post-myocardial infarction heart failure was induced by coronary constriction. Corresponding treatments were given immediately after successful modeling, once a day for 4 weeks. Left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) in rats were detected by color Doppler ultrasound imaging. Levels of IL-1β and IL-6 in serum were analyzed by ELISA method. Myocardial collagen volume fraction (CVF) was evaluated by Masson staining. Expressions of collagen Ⅰ and α-smooth muscle actin (α-SMA) in myocardial tissue were detected by immunohistochemical staining. The mRNA expressions of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in myocardial tissue were detected by qRT-PCR. Expression of LOXL2, TGF-β1, and IL-11 proteins in myocardial tissue were detected by Western blotting. RESULTS: Compared with the blank control group, the LVFS and LVEF of the model control group decreased, the levels of serum IL-6 and IL-1β elevated, and the CVF value, the expressions of collagen Ⅰ and α-SMA in myocardial tissue, MMP-9 and TIMP-1 mRNA, and LOXL2, TGF-β1, IL-11 proteins increased (all P<0.05). Compared with the model control group, the LVFS and LVEF of SGP small dose group, SGP large dose group and positive control group increased, the levels of serum IL-6 and IL-1β decreased, and the CVF value, the expressions of collagen Ⅰ and α-SMA in myocardial tissue, MMP-9 and TIMP-1 mRNA, and LOXL2, TGF-β1, IL-11 proteins decreased (all P<0.05); while LOXL2 activator reversed the improvement effect of high-dose SGP on myocardial fibrosis in heart failure rats after myocardial infarction. CONCLUSIONS Shenge powder may inhibit myocardial fibrosis in heart failure rats after myocardial infarction by inhibiting the LOXL2/TGF-β1/IL-11 pathway.
Animals ; Male ; Rats, Sprague-Dawley ; Myocardial Infarction/complications* ; Transforming Growth Factor beta1/metabolism* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Rats ; Heart Failure/pathology* ; Myocardium/metabolism* ; Fibrosis ; Amino Acid Oxidoreductases/metabolism* ; Interleukin-11/metabolism* ; Tissue Inhibitor of Metalloproteinase-1/metabolism* ; Matrix Metalloproteinase 9/metabolism*

Skin fibrosis is primarily characterized by excessive fibroblasts proliferation and aberrant extracellular matrix accumulation, leading to pathological conditions such as hypertrophic scars, keloids, and systemic sclerosis. This dynamic and complex process involves intricate interactions among various resident skin cells and inflammatory cells, ultimately resulting in extracellular matrix deposition and even invasive growth. The maintenance of cellular phenotypes and functions relies on dynamic metabolic responses, and cellular signal transduction is closely coupled with metabolic processes. Given that the coupling of cell metabolism and signaling in the skin fibrosis microenvironment plays a critical role in inflammatory responses and fibrotic activation, modulation of these metabolic pathways may offer novel therapeutic strategies for inhibiting or even reversing the progression of skin fibrosis. This review systematically summarizes the metabolic characteristics of various cell types involved in skin fibrosis, with a focus on core metabolic reprogramming mechanisms such as hyperactive glycolysis, dysregulated fatty acid metabolism, cellular metabolic dysfunction and dysregulated mTOR/AMPK signaling. Furthermore, potential intervention strategies targeting these metabolic pathways are explored, thereby providing new research perspectives for the treatment of skin fibrosis.
Humans ; Fibrosis/metabolism* ; Skin/metabolism* ; Signal Transduction ; Fibroblasts/pathology* ; TOR Serine-Threonine Kinases/metabolism* ; Skin Diseases/pathology* ; Cellular Reprogramming ; Metabolic Reprogramming

BACKGROUND: Organic chemicals have been known to cause allergic diseases such as bronchial asthma and hypersensitivity pneumonitis; however, the possibility that they do not cause irreversible pulmonary fibrosis has not been considered. Polyacrylic acid (PAA), an organic chemical, has caused irreversible progressive pulmonary fibrosis in exposed workers, indicating its potential to induce pulmonary inflammation and fibrosis. Although intratracheal instillation studies are commonly used for evaluating lung pathology, traditional methods face challenges with chemical substances, particularly nanoparticles, which tend to aggregate in suspension and prevent uniform pulmonary distribution. Such aggregation alters the qualitative and quantitative responses to lung injury, limiting accurate assessment of lung pathology. To overcome this limitation, we developed a 'molecular dispersion method' that uses pH modification to negative charges to PAA particles, maintaining their dispersion. Using this method, we investigated the effects of PAA on pulmonary inflammation and fibrosis in a rat model. METHODS: F344 rats were intratracheally instilled with PAA using molecular dispersion (0.1 mg/rat, 1.0 mg/rat), PAA without molecular dispersion (1.0 mg/rat), and normal saline (control group). Rats were sacrificed at 3 days, 1 week, 1 month, 3 months, and 6 months after exposure to examine inflammatory and fibrotic responses. RESULTS: PAA caused persistent increases in neutrophil influx in the bronchoalveolar lavage fluid (BALF) from 3 days to 1 month following instillation. In histopathological findings, the group with molecular dispersion had almost no inflammatory masses in the lung tissue compared to the group without molecular dispersion, and exhibited relatively uniform dispersion. CONCLUSION Intratracheal instillation of dispersed PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA might have pulmonary inflammogenicity and fibrogenicity. Intrapulmonary dispersion of PAA particles following intratracheal instillation studies using the molecular dispersion method was similar to that following inhalation studies.
Animals ; Rats, Inbred F344 ; Acrylic Resins/adverse effects* ; Rats ; Inhalation Exposure/adverse effects* ; Male ; Pulmonary Fibrosis/pathology* ; Pneumonia/pathology* ; Lung/pathology* ; Bronchoalveolar Lavage Fluid/cytology*

Tubulointerstitial fibrosis (TIF) is one of the key indicators in evaluating the renal function of patients. Mild TIF can cause a vicious cycle of renal tubular glomerular injury and aggravate renal disease. Therefore, studying the mechanisms underlying TIF is essential to identify therapeutic targets, thereby protecting the renal function of patients with timely intervention. Astragaloside IV (AS-IV) is a Chinese medicine component that has been shown to inhibit the occurrence and progression of TIF via multiple pathways. Previous studies have reported that AS-IV protected against TIF by inhibiting inflammation, autophagy, endoplasmic reticulum stress, macrophages, and transforming growth factor-β1, which laid the foundation for the development of a new preventive and therapeutic option for TIF.
Saponins/pharmacology* ; Triterpenes/pharmacology* ; Humans ; Fibrosis ; Animals ; Kidney Tubules/drug effects* ; Kidney Diseases/pathology*

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

Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), leading to a high incidence of surgical interventions and significant disability. Despite its clinical relevance, no targeted pharmacological therapies are currently available. This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions, offering insights into potential future therapeutic strategies. We conducted a literature review using data from PubMed up to October 2024, focusing on studies related to IBD and fibrosis. Intestinal fibrosis results from a complex network involving stromal cells, immune cells, epithelial cells, and the gut microbiota. Chronic inflammation, driven by factors such as dysbiosis, epithelial injury, and immune activation, leads to the production of cytokines like interleukin (IL)-1β, IL-17, and transforming growth factor (TGF)-β. These mediators activate various stromal cell populations, including fibroblasts, pericytes, and smooth muscle cells. The activated stromal cells secrete excessive extracellular matrix components, thereby promoting fibrosis. Additionally, stromal cells influence the immune microenvironment through cytokine production. Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis. Additionally, investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells, particularly fibroblast activation protein (FAP) + fibroblasts, in the context of intestinal fibrosis. In conclusion, aberrant stromal cell activation, triggered by upstream immune signals, is a key mechanism underlying intestinal fibrosis. Further investigations into immune-stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent, alleviate, and potentially reverse fibrosis.
Humans ; Fibrosis/metabolism* ; Inflammatory Bowel Diseases/pathology* ; Animals ; Transforming Growth Factor beta/metabolism* ; Intestines/pathology*

OBJECTIVE: Peritoneal fibrosis (PF) is an adverse event that occurs during long-term peritoneal dialysis, significantly impairing treatment efficiency and adversely affecting patient outcomes. Astragaloside IV (AS-IV), a principal active component derived from Astragalus membranaceus (Fisch.) Bunge, has exhibited anti-inflammatory and antifibrotic effects in various settings. This study aims to investigate the potential therapeutic efficacy and mechanism of AS-IV in the treatment of PF. METHODS: The PF mouse model was established by intraperitoneal injection of 4.25% peritoneal dialysis fluid (100 mL/kg). The epithelial-mesenchymal transition (EMT) of HMrSV5 cells was induced by the addition of 10 ng/mL transforming growth factor β (TGF-β). The differentially expressed genes in HMrSV5 cells treated with AS-IV were screened using transcriptome sequencing analysis. The potential targets of AS-IV were screened using network pharmacology and analyzed using molecular docking and molecular dynamics simulations. RESULTS: Administration of AS-IV at doses of 20, 40, or 80 mg/kg effectively mitigated the increase in peritoneal thickness and the development of fibrosis in mice with PF. The expression of the fibrosis marker α-smooth muscle actin in the peritoneum was significantly decreased in AS-IV-treated mice. The treatment of AS-IV (10, 20, and 40 μmol/L) significantly delayed the EMT of HMrSV5 cells induced by TGF-β, as demonstrated by the decreased number of 5-ethynyl-2'-deoxyuridine-positive cells, reduced migrated area, and decreased expression of fibrosis markers. A total of 460 differentially expressed genes were detected in AS-IV-treated HMrSV5 cells through transcriptome sequencing, with notable enrichment in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase 1 (AKT) signaling pathway. The reduced levels of phosphorylated PI3K (p-PI3K) and p-AKT were detected in HMrSV5 cells with AS-IV treatment. Epidermal growth factor receptor (EGFR) was predicted as a direct target of AS-IV, exhibiting strong hydrogen bond interactions. The activation of the PI3K-AKT pathway by the compound 740Y-P, and the activation of the EGFR pathway by NSC 228155 each partially counteracted the inhibitory effect of AS-IV on the EMT of HMrSV5 cells. CONCLUSION AS-IV delayed the EMT process in peritoneal mesothelial cells and slowed the progression of PF, potentially serving as a therapeutic agent for the early prevention and treatment of PF. Please cite this article as: Huang Y, Chu CL, Qiu WH, Chen JY, Cao LX, Ji SY, Zhu B, Wang GK, Shen QQ. Astragaloside IV delayed the epithelial-mesenchymal transition in peritoneal fibrosis by inhibiting the activation of EGFR and PI3K-AKT pathways. J Integr Med. 2025; 23(6):694-705.
Epithelial-Mesenchymal Transition/drug effects* ; Animals ; Saponins/pharmacology* ; Triterpenes/pharmacology* ; Mice ; Peritoneal Fibrosis/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; ErbB Receptors/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction/drug effects* ; Male ; Humans ; Molecular Docking Simulation ; Cell Line ; Mice, Inbred C57BL

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*

As the field of oral pathology has evolved, the nomenclature and classification of oral mucosal diseases with a remarkable risk of malignant transformation have undergone several modifications. In 2005, the World Health Organization (WHO) introduced the concept of oral potentially malignant disorders (OPMDs) as an alternative to the terms for oral precancerous lesions and precancerous conditions. In the consensus report by the WHO Collaborating Center for Oral Cancer of 2021, OPMD is defined as "any oral mucosal abnormality that is associated with a statistically increased risk of developing oral cancer."This definition encompasses a range of conditions, in-cluding oral leukoplakia, oral submucous fibrosis, proliferative verrucous leukoplakia, oral lichen planus, and other lesions. In light of the complex etiology, unclear pathogenesis, and carcinogenesis of OPMDs, early and precise diagnosis and treatment can contribute to the secondary prevention of oral cancer. For this reason, this review, which aims to provide a basis for the precise clinical diagnosis of OPMDs, was performed. Its aim was achieved by reviewing the historical evolution and research progress of the nomenclature, classification, and histopathological diagnostic criteria of OPMDs.
Humans ; Mouth Neoplasms/diagnosis* ; Precancerous Conditions/diagnosis* ; Leukoplakia, Oral/diagnosis* ; Lichen Planus, Oral/pathology* ; Oral Submucous Fibrosis/pathology* ; Mouth Mucosa/pathology* ; World Health Organization