Etoposide-induced protein 2.4 (EI24), an essential component of autophagy, is lowly expressed in pulmonary fibrosis. Hesperidin (Hes), a flavonoid, can regulate autophagy in various diseases. However, whether Hes can inhibit pulmonary fibrosis by mechanically regulating EI24-mediated autophagy has not been uncovered.

RLE-6TN cells were treated with transforming growth factor β1 (TGF-β1) and rats were injected with bleomycin (BLM) to construct the pulmonary fibrosis model. The effect of Hes on pulmonary fibrosis was evaluated by cell counting kit-8, immunofluorescence, hematoxylin and eosin, masson trichome staining and western blotting.

Hes reduced cell viability of TGF-β1-induced RLE-6TN cells. Administration of Hes restored the decrease in autophagy marker levels in TGF-β1-induced RLE-6TN cells. Hes inhibited the transcriptional and translational levels of α-SMA, collagen I and fibronectin that were increased by TGF-β1 in RLE-6TN cells. Mechanically, Hes restored EI24 expression, and EI24 knockdown reversed the effect of Hes on the expressions of autophagy and fibrosis-related proteins. Additionally, Hes enhanced autophagy and fibrosis markers, which were worsened by EI24 knockdown in BLM-induced rats.

Hes activated autophagy by upregulating EI24, which improved pulmonary fibrosis both in vitro and in vivo.

Asthma is a chronic respiratory disorder affecting individuals across all age groups. It is characterized by airway inflammation and remodeling and leads to progressive airflow restriction. While corticosteroids remain a mainstay therapy, their efficacy is limited in severe asthma due to genetic and epigenetic alterations, as well as elevated pro-inflammatory cytokines interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-5 (IL-5), which drive structural airway changes including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. This underscores the critical need for biologically targeted therapies. This review systematically examines the roles of IL-4 and IL-13, key drivers of type-2 inflammation, in airway remodeling and their potential as therapeutic targets. IL-4 orchestrates eosinophil recruitment, immunoglobulin class switching, and Th2 differentiation, whereas IL-13 directly modulates structural cells, including fibroblasts and epithelial cells, to promote mucus hypersecretion and extracellular matrix (ECM) deposition. Despite shared signaling pathways, IL-13 emerges as the dominant cytokine in remodeling processes including mucus hypersecretion, fibrosis and smooth muscle hypertrophy. While IL-4 primarily amplifies inflammatory cascades by driving IgE switching, promoting Th2 cell polarization that sustain cytokine release, and inducing chemokines to recruit eosinophils. In steroid-resistant severe asthma, biologics targeting IL-4/IL-13 show promise in reducing exacerbations and eosinophilic inflammation. However, their capacity to reverse established remodeling remains inconsistent, as clinical trials prioritize inflammatory biomarkers over long-term structural outcomes. This synthesis highlights critical gaps in understanding the durability of IL-4/IL-13 inhibition on airway structure and advocates for therapies combining biologics with remodeling-specific strategies. Through the integration of mechanistic insights and clinical evidence, this review emphasizes the need for long-term studies utilizing advanced imaging, histopathological techniques, and patient-reported outcomes to evaluate how IL-4/IL-13-targeted therapies alter airway remodeling and symptom burden, thereby informing more effective treatment approaches for severe, steroid-resistant asthma.

Hypertrophic scars (HS) affect up to 70 % of individuals following deep dermal injuries, burns, or surgical procedures, leading to significant functional impairments and psychological distress. Despite their high prevalence, effective therapeutic options remain limited, and the underlying pathophysiology is not fully elucidated. This study integrates network pharmacology, molecular docking, and in vivo experimentation to investigate the therapeutic potential of total salvianolic acid (TSA) from Salvia miltiorrhiza in HS treatment. A systematic pharmacology approach identified 186 target proteins, highlighting TGF-β1, Smad3, IL-2, and IL-4 as key modulators of fibrosis and inflammation. Molecular docking confirmed high-affinity interactions between TSA's active components and these targets. TSA significantly reduced scar elevation, fibrosis, and collagen deposition in a rabbit ear hypertrophic scar model, restoring tissue architecture and improving hemorheological parameters. Histological and immunohistochemical analyses confirmed TSA's ability to suppress TGF-β/Smad signaling, downregulate inflammatory cytokines and normalize collagen dynamics. These findings provide compelling evidence that TSA is a multi-targeted, pharmacologically active compound with promising anti-fibrotic and microcirculatory benefits, paving the way for novel therapeutic strategies in HS management. This study establishes a scientific foundation for TSA-based interventions, with potential clinical implications in regenerative medicine and scar therapy.

Systemic sclerosis (SSc) is a prototypic fibrosing disorder characterized by widespread fibrosis and immune dysregulation. Current evidence highlights the intricate cross-talk between the canonical Wnt/β-catenin signaling pathway and transforming growth factor-beta (TGF-β) signaling, both of which play fundamental roles in the pathogenesis of fibrosis. This review aims to elucidate the central role of the Wnt/β-catenin-TGF-β pathway and TGF-β signal transduction pathway in fibrotic diseases, focusing on SSc. We summarized evidence from cellular biology studies, animal model investigations, and clinical observations to provide a comprehensive view of the mechanisms by which these pathways cause pathological fibrosis. In addition, we explore the possibilities of antifibrotic therapeutic strategies against Wnt/β-catenin-TGF-β signaling to counteract fibrosis. We aim to delineate approaches towards effectively treating fibrosis in SSc by targeting these interconnected signaling pathways.

An Mg-based alloy device manufactured via a superplastic forming process (Mg-AZ31+SPF) and coated using a hydrothermal method (Mg AZ31+SPF+HT) was investigated as a method to increase mechanical and osteointegration capability. The cell viability and osteointegrative properties of alloy-derived Mg AZ31+SPF and Mg AZ31+SPF+HT extracts were investigated regarding their effect on human mesenchymal stem cells (hMSCs) (maintained in basal (BM) and osteogenic medium (OM)) after 7 and 14 days of treatment. The viability was analyzed through metabolic activity and double-strand DNA quantification, while the osteoinductive effects were evaluated through qRT-PCR, osteoimage, and BioPlex investigations. Finally, a preliminary liquid mass spectrometry analysis was conducted on the secretome of hMSCs. Biocompatibility analysis revealed no toxic effect on cells' viability or proliferation during the experimental period. A modulation effect was observed on the osteoblast pre-commitment genes of hMSCs treated with Mg-AZ31+SPF+HT in OM, which was supported by mineralization nodule analysis. A preliminary mass spectrometry investigation highlighted the modulation of protein clusters involved in extracellular exosomes, Hippo, and the lipid metabolism process. In conclusion, our results revealed that the Mg AZ31+SPF+HT extracts can modulate the canonical and non-canonical osteogenic process in vitro, suggesting their possible application in bone tissue engineering.

Prostate cancer is the second most common cancer globally, with radiation therapy (RT) being a key treatment for clinically localized and locally advanced cases. Given high survival rates, addressing long-term side effects of RT is crucial for preserving quality-of-life. Radiogenomics, the study of genetic variations affecting response to radiation, has primarily focussed on genomic biomarkers, while DNA methylation studies offer insights into RT responses. Although most research has centred on tumours, no epigenome-wide association studies have explored peripheral blood biomarkers of RT-induced toxicities in prostate cancer patients. Identifying such biomarkers could reveal molecular mechanisms underlying RT response and enable personalized treatment.

We analysed 105 prostate cancer patients (52 cases and 53 controls). Cases developed grade ≥ 2 genitourinary and/or gastrointestinal late toxicity after 12 months of starting RT, whereas controls did not. An epigenome-wide association study of post-RT toxicities was performed using the Illumina MethylationEPIC BeadChip, adjusting for age and cell type composition. We constructed two methylation risk scores-one using differentially methylated positions (MRSsites) and another using differentially methylated regions (MRSregions)-as well as a Support Vector Machine-based methylation signature (SVMsites). We evaluated RT effects on biological age and stochastic epigenetic mutations within established radiation response pathways. Gene Ontology and pathway enrichment analyses were also performed.

Pre-RT methylation analysis identified 56 differentially methylated positions (adjusted p-value ≤ 0.05), and 6 differentially methylated regions (p-value ≤ 0.05) associated with the genes NTM, ACAP1, IL1RL2, VOOP1, AKR1E2, and an intergenic region on chromosome 13 related to Short/Long Interspersed Nuclear Elements. Both Methylation Risk Scores (MRSsites AUC = 0.87; MRSregions AUC = 0.89) and the 8-CpG Support Vector Machine signature (SVMsites AUC = 0.98) exhibited strong discriminatory accuracy in classifying patients in the discovery cohort. Gene ontology analysis revealed significant enrichment (adjusted p-value ≤ 0.05) of genes involved in DNA repair, inflammatory response, tissue repair, and oxidative stress response pathways.

Epigenetic biomarkers show potential for predicting severe long-term adverse effects of RT in prostate cancer patients. The identified methylation patterns provide valuable insights into toxicity mechanisms and may aid personalized treatment strategies. However, validation in independent cohorts is essential to confirm their predictive value and clinical applicability.

Adhesive arachnoiditis (AA) is a rare form of chronic degenerative pathology associated with persistent inflammation in the arachnoid matter of the spinal cord. Despite the existing knowledge, the detailed pathological mechanisms underlying AA are not fully understood. This study aimed to elucidate through comprehensive single nuclei RNA sequencing (snRNA-seq) to delineate the transcriptomic landscape of AA. From six arachnoid membrane samples, a total of 52,886 cells met the quality control standards for analysis. The main cell populations identified with specific gene markers were as follows: fibroblasts, glial cells, microglial cells, endothelial cells, mural cells, plasma cells, and T cells. Downstream analysis of fibroblasts, glial cells, and microglial cells was performed. Notably, fibroblast subsets 1 and 3 demonstrated a strong association with AA. Among them, subcluster 3 demonstrated elevated expression of genes COL1A1, COL3A1, and FN1, indicative of enhanced Wnt/β-catenin and extracellular matrix (ECM) synthesis pathways. Subcluster 3 was predicted to progressively transform into subcluster 1. In subcluster 1, there was a significant upregulation of genes such as BMP and ALPL, signaling enhanced activation of calcification-related pathways. This was highly relevant to end-stage arachnoid ossification formation. After being activated, microglial cells transformed into inflammatory disease-associated microglial cells and continued to express high levels of chemokines CCL2, CCL4, IL-1β, and other inflammatory factors NAMPT, INPP5D and NLRP3. This might be the main reason why AA recurrence is frequently observed in patients. These insights enhance our understanding of the pathological progression of AA and may contribute to the identification of novel therapeutic targets.

Hepatic fibrosis is a wound healing response that leads to excessive deposition of extracellular matrix (ECM) due to sustained liver injury. Hepatic stellate cells (HSCs) are key players in ECM synthesis, with the TGF-β/Smad signaling pathway being central to their activation. Despite advances in understanding the pathogenesis of hepatic fibrosis, effective anti-fibrotic therapies are still lacking.

This treatise conducts a comprehensive review of the literature on the hepatoprotective effects of natural products, including natural medicine compounds, herbal extracts, and polysaccharides. The focus is on their ability to modulate the TGF-β pathway, which is critical in the activation of HSCs and ECM synthesis in hepatic fibrosis.

The review identifies a variety of natural products that have shown promise in inhibiting the TGF-β/Smad signaling cascade, thereby reducing the activation of HSCs and ECM accumulation. These findings highlight the potential of these natural products as therapeutic agents in the treatment of hepatic fibrosis.

The exploration of natural products as modulators of the TGF-β pathway presents a novel avenue for both clinical and preclinical research into hepatic fibrosis. Further investigation is warranted to fully understand the mechanisms of action and to develop these compounds into effective anti-fibrotic pharmaceuticals.

The zig-zag eel exhibits both sexual dimorphism and sex reversal, making it crucial to understand the mechanisms of sex determination and differentiation. Additionally, the wild populations of the zig-zag eel are significantly declining, emphasizing the need for urgent conservation efforts. In this study, we identified 7 Dmrt, 62 HMG-box, and 73 TGF-β family members in the zig-zag eel genome. Evolutionary analysis revealed that the HMG-box and TGF-β families in the zig-zag eel are primarily characterized by purifying selection. Furthermore, we identified 52 differentially expressed genes between males and females, with more male-biased genes than female-biased genes within these three gene families. ZzDmrt2a was highly expressed in the ovary, while ZzDmrt2b was highly expressed in the testis. Interestingly, Zzgdf9, located on the Y chromosome, was significantly expressed in the ovary. Our results highlight the complexity of sex differentiation mechanisms and underscores the importance of further research to elucidate the specific functions and regulatory networks of these sex-biased genes. Such insights could inform breeding strategies in aquaculture, contributing to the conservation and management of the zig-zag eel.

Fibrotic responses in the gingiva are characterized by their hyperproliferative nature instead of scar tissue formation. Clinically, these conditions appear as "gingival overgrowth" (GO), which can be of drug-induced or genetic origin. Despite surgical removal, GO can recur. Therefore, non-invasive methods of treating GO are required. In other fibrotic systems, the matricellular protein CCN2 represents a potential therapeutic target. However, CCN2 has been relatively understudied in the context of GO.

Herein, we describe what is known regarding CCN2 expression in GO and gingival fibroblasts. Specifically, CCN2 is induced by agents that promote fibrogenesis in the oral cavity, such as transforming growth factor-β, and drugs that promote GO, such as cyclosporine, nifedipine, and phenytoin.

Although little is known regarding the possible function of CCN2 in GO, given the correlation between CCN2 expression and GO recurrence, we hope that this review will inspire further research on this topic.

The most common form of priapism is ischaemic and its prevalence in men has increased in recent years as a result of intracavernosal drug use. Currently, there is no approved specific treatment for ischaemic priapism other than cavernosal aspiration, which can only provide detumescence. This study aims to evaluate the efficacy of intracavernosal mesenchymal stem cell (MSC) therapy in an ischaemic priapism model.

Thirty male Wistar albino rats were divided into three groups: sham (n = 6), priapism (n = 12) and priapism + MSC treatment (n = 12). The experimental groups were also divided into 1 and 12 h subgroups of ischaemic priapism. The experimental model was created using a vacuum erection device and constrictive tape technique, and intracavernosal MSC were applied immediately after the tape was removed. After 4 weeks, intracavernosal pressures (ICPs) and systemic mean arterial pressure (MAP) were measured. Penectomy was then performed to assess histopathological and molecular changes in the rats' penile tissues.

In the ischaemic priapism model, MSC therapy showed significant improvements in peak and mean ICPs and mean ICP/MAP ratio. Histopathological analysis showed significant increases in smooth-muscle/collagen ratio and e-NOS and n-NOS expression. Although there was a decrease in fibrosis, it was not significant. At the molecular level, there were significant decreases in TGF-beta and VEGF mRNA expression, whilst NGF and BDNF mRNA-expression levels showed significant increases with MSC therapy. In terms of ICPs, the therapy showed more significant improvements in short-term priapism. However, when looking at histopathological and molecular parameters, the therapy had positive effects on a wider range of parameters in the long-term priapism.

MSC treatment improved cavernosal physiology and had positive effects at the histopathological and molecular level in the ischaemic priapism model.

Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is responsible for the development of fibrotic cataracts, which contribute to severe visual impairment. Recent evidence has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) can attenuate EMT in several tissues. However, the effect of MSC-Exo on EMT in LECs (LECs-EMT) has not been determined. In this study, we isolated exosomes from human umbilical cord MSCs (hucMSC-Exo) and evaluated their effect on LECs-EMT both in vitro and in vivo. HucMSC-Exo application significantly suppressed the expression of mesenchymal cell-associated genes while increasing the expression of epithelial cell-associated genes. Cell proliferation and migration of LECs undergoing EMT were inhibited after hucMSC-Exo treatment. The volume of EMT plaques in mice with injury-induced anterior subcapsular cataract (ASC) was significantly reduced in the hucMSC-Exo-treated group. Furthermore, miR-148a-3p was abundant in hucMSC-Exo. After transfection with miR-148a-3p inhibitor, the anti-fibrotic effect of hucMSC-Exo was attenuated in LECs-EMT. A dual-luciferase reporter assay identified PRNP as a direct target gene of miR-148a-3p. Furthermore, we verified that hucMSC-Exo inhibited LECs-EMT through the miR-148a-3p/PRNP axis and the potential downstream ERK signaling pathway. Taken together, our work reveals the inhibitory effect of hucMSC-Exo on LECs-EMT and the underlying mechanism involved, which may provide potential therapeutic options for fibrotic cataracts.

Fibrosis is the leading cause of many lethal diseases. It is characterized by the accumulation of extracellular matrix (ECM) components, which leads to damaged tissue functioning in the influenced organs. Essential oils are concentrated hydrophobic liquid having volatile compounds extracted from plant or plant parts while antioxidants are the compounds that help in scavenging free radicals and prevent reducing the oxidation processes. In this review, challenges that come during the treatment of fibrosis have been covered, mechanism of action of both essential oil and antioxidants is also outlined in this article. This review aimed to provide scientific fundamental and knowledge, ideas for the development and application of essential oils and antioxidants in the treatment of fibrosis.

The structural similarity between aristolactams (ALs) and aristolochic acids (AAs) raises constant concerns about the safety of ALs-containing plants. Natural ALs are distributed more extensively than AAs, leading to a higher risk of ALs exposure in daily consumption. This study aimed to evaluate and compare the in vitro nephrotoxicity on human renal tubular epithelial cells (HK-2 cells) of eight natural ALs with different substituents on the phenanthrene ring and amide ring, including aristolactam Ⅰ (AL Ⅰ), AL BⅡ, velutinam, AL AⅡ, sauristolactam, AL AⅠa, AL FⅠ and N-methyl piperolactam A. Their IC50 values of cell viability were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of kidney injury molecule-1 (KIM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN). The reactive oxygen species (ROS) assay was used to detect the intracellular oxidative stress level. The results showed that the eight ALs all had specific nephrotoxicity on HK-2 cells. Particularly, AL Ⅰ, AL BⅡ and velutinam exhibited more potent cytotoxicity on HK-2 cells (IC50 = 2.49-2.78 μM) than the other five ALs (IC50 = 12.33-43.84 μM). The structure-toxicity relationships indicated that both methylenedioxy (-OCH2O-) and methoxy (-OCH3) were positively contributing functional groups of ALs on nephrotoxicity, while the hydroxy group (-OH) and methyl substitution on nitrogen (N-CH3) accounted for a detrimental effect conversely. Consistent with this structure-toxicity relationship, the eight ALs increased KIM-1 levels in the same trend as their cytotoxicity at the same concentration of 2.5 μg/mL, associating with different levels of ROS generation. And the four most toxic ALs, AL Ⅰ, AL BⅡ, velutinam and AL AⅡ, could also induce fibrosis by increasing TGF-β1 and FN levels.

Metabolic disorders in polycystic ovary syndrome (PCOS) patients have attracted increasing attention, and nonalcoholic fatty liver disease (NAFLD) in particular has been the focus of much research due to its high incidence and potential harm in patients with PCOS. However, little is known about whether PCOS is associated with more severe NAFLD histopathology. Although Jiawei Qi Gong Wan (JQGW) is widely used clinically, its specific effects and mechanisms on the liver remain unclear.

The aim of this study was to explore the mechanism of JQGW in improving metabolic abnormalities in the liver in PCOS mice in order to support the development of therapies to prevent PCOS complications.

A mouse model of PCOS was established by subcutaneously implanting letrozole tubes. The effect of JQGW on liver metabolism in mice was observed by measuring biochemical indicators in serum. Liver morphological changes were observed using hematoxylin and eosin staining along with Sirius red staining, while Western blotting and qRT-PCR were used to quantify the expression of genes and proteins related to liver fibrosis and inflammation processes. Network pharmacology was used to analyze the key factors that JQGW may target in improving liver fibrosis in PCOS mice, and the results were verified by Western blotting of liver tissue from PCOS mice.

PCOS mice had obvious liver metabolic dysfunction, inflammation, and fibrosis, all of which could be reversed by JQGW. Network pharmacology functional enrichment revealed that the overlapping targeted genes were enriched mainly in insulin resistance-related pathways and androgen-related pathways. We verified related proteins and found that JQGW improved liver fibrosis and inflammation in PCOS mice mainly by regulating the Akt2-FoxO1 and YAP/TAZ signaling pathways.

JQGW can improve liver metabolic function in a letrozole-induced PCOS mouse model by inhibiting liver fibrosis and inflammation, and it acts mechanistically by regulating the Akt2-FoxO1 and YAP/TAZ signaling pathways. Our findings thus provide a valuable reference for the advancement of therapeutic strategies aimed at addressing PCOS patients with abnormal liver metabolism.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo pathway that regulate organ size, tissue homeostasis, and cancer development. YAP/TAZ play crucial regulatory roles in organ growth, cell proliferation, cell renewal, and regeneration. Mechanistically, YAP/TAZ influence the occurrence and progression of liver regeneration (LR) through various signaling pathways, including Notch, Wnt/β-catenin, TGF-β/Smad. While the activation of YAP/TAZ can promote the regeneration of damaged liver tissue, their mechanisms of action may differ under various LR conditions. Furthermore, excessive activation of YAP/TAZ may also lead to severe liver damage, manifesting as alcoholic hepatitis, liver fibrosis, and even liver cancer. Here, we review the role and mechanisms of YAP/TAZ in LR and liver disease, highlighting the potential for advancements in clinical diagnosis and treatment targeting YAP/TAZ in these contexts.

Anterior Cruciate Ligament (ACL) injuries rank among the most prevalent and severe types of injuries, significantly impacting both athletes and non-athletes alike. These injuries not only result in immediate physical impairment, such as intense pain, substantial swelling, and a marked loss of mobility, but also carry long-term health consequences that can alter a person's quality of life. Chronic pain, persistent instability, and an increased risk of developing osteoarthritis are among the lasting effects that can follow an ACL injury. An in-depth understanding of the biophysics behind ACL injuries is paramount for devising effective prevention and treatment protocols. Biophysics, which combines principles from physics with biological systems, provides crucial insights into the mechanical and structural integrity of the ACL and its susceptibility to injury under various conditions. This systematic review aims to collate and synthesize the current knowledge surrounding the biophysical mechanisms that underlie ACL injuries.

The foreign body reaction (FBR) to biomaterials results in fibrous encapsulation. Excessive capsule fibrosis (capsular contracture) is a major challenge to the long-term stability of implants. Clinical data suggests that the tissue type in contact with silicone breast implants alters susceptibility to developing capsular contracture; however, the tissue-specific inflammatory and fibrotic characteristics of capsule have not been well characterized at the cellular and molecular level. In this study, 60 breast implant capsule samples are collected from patients and stratified by the adjacent tissue type including subcutaneous tissue, glandular breast tissue, or muscle tissue. Capsule thickness, collagen organization, immune and fibrotic cellular populations, and expression of inflammatory and fibrotic markers is quantified with histological staining, immunohistochemistry, and real-time PCR. The findings suggest there are significant differences in M1-like macrophages, CD4+ T cells, CD26+ fibroblasts, and expression of IL-1β, IL-6, TGF-β, and collagen type 1 depending on the tissue type abutting the implant. Subglandular breast implant capsule displays a significant increase in inflammatory and fibrotic markers. These findings suggest that the tissue microenvironment contributes uniquely to the FBR. This data could provide new avenues for research and clinical applications to improve the site-specific biocompatibility and longevity of implantable devices.

The aryl hydrocarbon receptor (AHR) is a pivotal nuclear receptor involved in mediating cellular responses to a wide range of environmental pollutants and endogenous ligands. AHR plays a central role in regulating essential physiological processes, including xenobiotic metabolism, immune response modulation, cell cycle control, tumorigenesis, and developmental events. Recent studies have identified AHR as a critical mediator and a potential therapeutic target in the pathogenesis of ocular diseases. This review provides a thorough analysis of the various functions of AHR signalling in the ocular environment, with a specific emphasis on its effects on the retina, retinal pigment epithelium (RPE), choroid, and cornea. We provide a detailed discussion on the molecular mechanisms through which AHR integrates environmental and endogenous signals, influencing the development and progression of age-related macular degeneration (AMD), retinitis pigmentosa, uveitis, and other major ocular disorders. Furthermore, we evaluate the therapeutic potential of modulating AHR activity through novel ligands and agonists as a strategy for treating eye diseases. Understanding the molecular mechanisms of AHR in ocular tissues may facilitate the development of AHR-targeted therapies, which is crucial for addressing the pressing clinical demand for novel treatment strategies in ocular diseases.

Methyltransferase-like 3 (METTL3) is extensively reported to be involved in organ fibrosis. Ovarian fibrosis is a main characteristic of polycystic ovary syndrome (PCOS). However, the reaction mechanism of METTL3 in PCOS is poorly investigated. This paper was intended to reveal the role and the mechanism of METTL3 in PCOS. Animal and cell models of PCOS were induced by dehydroepiandrosterone (DHEA). H&E staining was performed to detect the pathological alterations in ovary tissues. Masson staining, immunofluorescence, along with western blot measured fibrosis both in vitro and in vivo. To evaluate estrous cycle, vaginal smear was performed. Lipid peroxidation and ferroptosis were evaluated by MDA assay kits, GSH assay kits, immunohistochemistry, Prussian blue staining and western blot. qRT-PCR and western blot were adopted to estimate METTL3 and GPX4 expression. The m6A and hormone secretion levels were respectively assessed by m6A RNA Methylation Quantitative Kit and corresponding kits. The interaction between METTL3 and GPX4 was testified by immunoprecipitation. The fibrosis and ferroptosis were aggravated and m6A and METTL3 expression were increased in ovarian tissues of DHEA-induced PCOS mice. METTL3 silencing alleviated pathological changes, affected hormone secretion level, and repressed fibrosis, lipid peroxidation and ferroptosis in the ovarian tissues of PCOS mice. In vitro, DHEA stimulation increased m6A and METTL3 expression and induced ferroptosis and fibrosis. METTL3 knockdown promoted GPX4 expression in DHEA-induced granulosa cells by m6A modification and restrained DHEA-induced fibrosis, lipid peroxidation and ferroptosis in granulosa cells via elevating GPX4. METTL3 silence inhibited ovarian fibrosis in PCOS, which was mediated through suppressing ferroptosis by upregulating GPX4 in m6A-dependent manner.

Idiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility.

An inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration.

We found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts.

These insights into the molecular mechanisms underlying ITR's therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.

Over 60% of End Stage Renal Disease (ESRD) patients are relying on hemodialysis (HD) to survive, and the arteriovenous fistula (AVF) is the preferred vascular access method for HD. However approximately half of all newly created AVF fail to mature and cannot be used without a salvage procedure. We have recently demonstrated an association between AVF maturation failure and post-operative fibrosis, while our RNA-seq study also revealed that veins that ultimately failed during AVF maturation had elevated levels of platelet factor 4 (PF4/CXCL4). However, a link between these two findings was yet to be established.

In this study, we investigated potential mechanisms between PF4 levels and fibrotic remodeling in veins. We compared the local expression of PF4 and fibrosis marker integrin β6 (ITGB6) in veins that successfully underwent maturation with that in veins that ultimately failed to mature. We also measured the changes of expression level of α-smooth muscle actin (αSMA/ACTA2) and collagen (Col1/COL1A1) in venous fibroblasts upon various treatments, such as PF4 pharmacological treatment, alteration of PF4 expression, and blocking of PF4 receptors.

We found that PF4 is expressed in veins and co-localizes with αSMA. In venous fibroblasts, PF4 stimulates expression of αSMA and Col1 via different pathways. The former requires integrins αvβ5 and α5β1, while chemokine receptor CXCR3 is needed for the latter. Interestingly, we also discovered that the expression of PF4 is associated with that of ITGB6, the β subunit of integrin αvβ6. This integrin is critical for the activation of the major fibrosis factor TGFβ, and overexpression of PF4 promotes activation of the TGFβ pathway.

These results indicate that upregulation of PF4 may cause venous fibrosis both directly by stimulating fibroblast differentiation and expression of extracellular matrix (ECM) molecules and indirectly by facilitating the activation of the TGFβ pathway.

Continuous artificial aqueous humor drainage in the eyes of patients with glaucoma undergoing trabeculectomy likely exerts abnormal shear stress. However, it remains unknown how changes in intraocular pressure (IOP) can affect aqueous humor outflow (AHO).

Here, we induced and maintained low intraocular pressure (L-IOP) in healthy Sprague Dawley (SD) rats by puncturing their eyes using a tube (200-µm diameter) for 2 weeks. After the rats were euthanized, their eyes were removed, fixed, embedded, stained, and scanned to analyze the physiological and pathological changes in the trabecular meshwork (TM) and Schlemm's canal (SC). We measured SC parameters using ImageJ software and assessed the expression of various markers related to flow shear stress (KLF4), fibrosis (TGF-β1, TGF-β2, α-SMA, pSmad1/5, pSmad2/3, and fibronectin), cytoskeleton (integrin β1 and F-actin), diastolic function (nitric oxide synthase and endothelial nitric oxide synthase [eNOS]), apoptosis (cleaved caspase-3), and proliferation (Ki-67) using immunofluorescence or immunohistochemistry.

L-IOP eyes showed a larger SC area, higher eNOS expression, and lower KLF4 and F-actin expression in the TM and SC (both P < 0.05) than control eyes. The aqueous humor of L-IOP eyes had a higher abundance of fibrotic proteins and apoptotic cells than that of control eyes, with significantly higher TGF-β1, α-SMA, fibronectin, and cleaved caspase-3 expression (all P < 0.05).

In conclusion, a persistence of L-IOP for 2 weeks may contribute to fibrosis in the TM and SC and might be detrimental to conventional AHO in SD rat eyes.

Clinicians should consider that aberrant shear force induced by aqueous humor fluctuation may damage AHO outflow channel when treating patients.

Methamphetamine (METH) chronic exposure is an important risk factor for hypertension development. However, the mechanisms behind METH-induced hypertension remain unclear. Therefore, we aimed to reveal the potential mechanisms underlying METH-induced hypertension.

We structured the mouse hypertension model by METH, and observed that METH-treated mice have presented vascular remodeling (large-and small-size arteries) with collagen deposit around the vessel and increasing blood pressure (BP) and Sigma1 receptor (Sigmar1) in vascular tissue. We hypothesized that Sigmar1 is crucial in METH-induced hypertension and vascular remodeling. Sigmar1 knockout (KO) mice and antagonist (BD1047) pretreated mice exposed to METH for six-week showed higher BP and more collagen deposited around vessels than wild-type (WT) mice exposed to METH for six-week, in contrast, mice pretreated with Sigmar1 agonist (PRE-084) had unchanged BP and perivascular collagen despite the six-week METH exposure. Furthermore, we found that METH exposure induced vascular smooth muscle cells (VSMCs) and mesenchymal stem cells to differentiate into the myofibroblast-like cell and secrete collagen into surrounding vessels. Mechanically, Sigmar1 can suppress the COL1A1 expression by blocking the classical fibrotic TGF-β/Smad2/3 signaling pathway in METH-exposed VSMCs and mesenchymal stem cells.

Our results suggest that Sigmar1 is involved in METH-induced hypertension and vascular fibrosis by blocking the activation of the TGF-β/Smad2/3 signaling pathway. Accordingly, Sigmar1 may be a novel therapeutic target for METH-induced hypertension and vascular fibrosis.

Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor β1 (TGF-β1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.

Postoperative Intestinal Adhesions (PIAs) remain a significant complication of abdominal surgery that can cause pain, infertility, and a potentially lethal bowel obstruction. Kangnian (KN) decoction, a Traditional Chinese Medicine prescription, has been shown to be effective in treating PIAs. Nevertheless, its underlying mechanisms remain unclear.

This study aims to explore the therapeutic effects of KN decoction in a PIA rat model, as well as its potential mechanisms via metabolomics and proteomics analyses.

60 rats were randomly assigned to six groups: Normal Control (NC), PIA model, Dexamethasone, KN-Low, KN-Medium, and KN-High. The PIA model was created by abdominal surgery under anesthesia. Pathological damage was evaluated through H&E staining and adhesion grading of affected tissues. The levels of serum cytokines (IL-1β, IL-6, TNF-α, and TGF-1), Connective Tissue Growth Factor (CTGF), and Motilin (MTL) in adherent intestinal tissues were detected using ELISA kits. Untargeted metabolomics was used to investigate potential metabolic pathways of the KN decoction intervention in intestinal adhesions and to screen for differential biomarkers. The label-free quantitative proteomics technique was employed to detect Differentially Expressed Proteins and for biological function and pathway enrichment analyses.

In PIA rats, KN decoction significantly improved the pathological injury associated with intestinal adhesions and effectively regulated the blood inflammation indicators. Furthermore, KN presented a favorable anti-fibrotic and protective effect against abdominal adhesions, effectively modifying gastrointestinal motility disorders in PIA rats. We identified 58 variables as potential biomarkers and discovered seven main pathological pathways that may be associated with PIAs. Proteomics analysis revealed 75 DEPs that were primarily involved in Valine, leucine, and isoleucine degradation, the MAPK signaling pathway, and retrograde endocannabinoid signaling.

This study proved that KN reduces intestinal mucosal injury, downregulates inflammatory factors, and alleviates intestinal adhesions, thus protecting the intestinal barrier function in PIA rats. The combination of proteomics and metabolomics provided a feasible approach for unraveling the therapeutic mechanism of KN decoction in PIAs.

Osteoarthritis (OA) is a prevalent, chronic joint disorder affecting millions of people worldwide, characterized by articular cartilage degradation, subchondral bone remodeling, synovial cytokine secretion, and osteophyte formation. OA primarily affects the hips, knees, hands, and spine. Patients with OA exhibit a higher prevalence of cardiovascular comorbidities and potentially important associations between OA and cardiovascular diseases have prompted investigations into potentially similar pathophysiological associations. This review explores the coexistence of atherosclerotic peripheral vascular disease (ASPVD) in OA patients, including evidence from a contemporary study suggesting associations between OA and arterial wall thickness and blood flow changes which are characteristic of early atherosclerosis, and which stimulate reactive pathology in endothelial cells. Observations from this study demonstrate elevated arterial flow volume and increased intima-media thickness in arteries ipsilateral to OA knees, suggesting a potential link between OA and arterial wall disease. We further explore the intricate relationship between the vascular system and skeletal health, highlighting bidirectional interactions among endothelial cells, inflammatory cells, and various bone cells. Mechanical endothelial cell dysfunction is discussed, emphasizing the impact of vessel wall material changes and endothelial cell responses to alterations in fluid shear stress. Inflammatory changes in OA and ASPVD are also explored, showcasing shared pathophysiological processes involving immune cell infiltration and pro-inflammatory cytokines. Additionally, the role of hypofibrinolysis in OA and ASPVD is discussed, highlighting similarities in elevations of the hypercoagulative and hypofibrinolytic factor, plasminogen activator inhibitor (PAI-1). The review suggests a provocative relationship among low-grade chronic inflammation, endothelial dysfunction, and hypofibrinolytic states in OA and ASPVD, warranting further investigation. In conclusion, this review provides an exploration of the possible associations between OA and ASPVD. While the ongoing study's findings and other reports are observational, they suggest shared pathophysiological processes and emphasize the need for further research to elucidate additional potentially correlative linkages between these conditions. Understanding common molecular pathways may pave a way for targeted interventions that address both OA and ASPVD.

TGFβ1 is a powerful regulator of fibrosis; secreted in a latent form, it becomes active after release from the latent complex. During tissue fibrosis, the EDA + isoform of cellular fibronectin is overexpressed. In pulmonary fibrosis it has been proposed that the fibronectin splice variant including an EDA domain (FN EDA+) activates latent TGFβ. Our work investigates the potential of blocking the 'splicing in' of EDA with antisense oligonucleotides to inhibit TGFβ1-induced EDA + fibronectin and to prevent the cascade of events initiated by TGFβ1 in human renal proximal tubule cells (PTEC). Human primary PTEC were treated with TGFβ1 for 48 h, medium removed and the cells transfected with RNase H-independent antisense oligonucleotides (ASO) designed to block EDA exon inclusion (ASO5). The efficacy of ASO to block EDA exon inclusion was assessed by EDA + fibronectin RNA and protein expression; the expression of TGFβ, αSMA (α smooth muscle actin), MMP2 (matrix metalloproteinse-2), MMP9 (matrix metalloproteinse-9), Collagen I, K Cadherin and connexin 43 was analysed. Targeting antisense oligonucleotides designed to block EDA exon inclusion in fibronectin pre mRNA were effective in reducing the amount of TGFβ1 -induced cellular EDA + fibronectin RNA and secreted EDA + fibronectin protein (assessed by western immunoblotting and immunocytochemistry) in human proximal tubule cells in an in vitro cell culture model. The effect was selective for EDA + exon with no effect on EDB + fibronectin RNA and total fibronectin mRNA. Exogenous TGFβ1 induced endogenous TGFβ, αSMA, MMP2, MMP9 and Col I mRNA. TGFβ1 treatment for 48h reduced the expression of K-Cadherin and increased the expression of connexin-43. These TGFβ1-induced pro-fibrotic changes were attenuated by ASO5 treatment. 48 h after the removal of exogenous TGFβ, further increases in αSMA, MMP2, MMP9 was observed; ASO5 significantly inhibited this subsequent increase. ASO5 treatment also significantly inhibited ability of the cell culture medium harvested at the end of the experiment (96h) to stimulate SMAD3 reporter cells. The role of endogenous TGFβ1 was confirmed by the use of a TGFβ receptor inhibitor. Our results demonstrate a critical role of FN EDA+ in a cycle of TGFβ driven pro-fibrotic responses in human PTEC and blocking its production with ASO technology offers a potential therapy to interrupt this vicious circle and hence limit the progression of renal fibrosis.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease resulting from inadequate type VII collagen (C7). Although recurrent skin blisters and wounds are the most apparent disease features, the impact of C7 loss is not confined to the skin and mucous membranes. RDEB is a systemic disease marred by chronic inflammation, fibrotic changes, pain, itch, and anemia, significantly impacting QOL and survival. In this narrative review, we summarize these systemic features of RDEB and promising research avenues to address them.

The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-β1 (TGF-β1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-β1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-β1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.

Fibrosis is a complex pathological process that can lead to the permanent loss of biological function, with P2ry2 playing a crucial role in this process. Long non-coding RNAs (lncRNAs) have been reported to play an critically important role in the fibrotic process. However, it remains unclear whether lncRNAs can regulate fibrosis through P2ry2. In this study, we detected the expression of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1). We investigated the expression patterns of lnc-MALAT1 and P2ry2 in denervated skeletal muscle, a classical model of fibrosis. Additionally, we utilized a TGF-β-mediated fibrosis model in NIH/3T3 cells to examine the effects of lnc-MALAT1 and P2ry2 on fibroblast activation and the underlying regulatory mechanisms in vitro. Our results demonstrated that the expression levels of lnc-MALAT1 and P2ry2 were consistently elevated in denervated skeletal muscle, correlating with the degree of fibrosis. In vitro experiments confirmed the regulatory effect of lnc-MALAT1 on P2ry2. Furthermore, we identified miR-335-3p as a potential key molecule in the regulatory relationship of lnc-MALAT1/P2ry2. Dual luciferase reporter assays and AGO2-RIP verified the molecular sponging effect of lnc-MALAT1 on miR-335-3p. Additionally, we validated the regulation of the lnc-MALAT1/miR-335-3p/P2ry2 axis through experimental approaches. In conclusion, our study identified a crucial role of lnc-MALAT1/miR-335-3p/P2ry2 axis in fibroblast activation, providing a promising treatment option against the fibrosis.

Bladder outlet obstruction (BOO) is the primary clinical manifestation of benign prostatic hyperplasia, the most common urinary system disease in elderly men, and leads to associated lower urinary tract symptoms. Although BOO is reportedly associated with increased systemic oxidative stress (OS), the underlying mechanism remains unclear. The elucidation of this mechanism is the primary aim of this study. A Sprague-Dawley rat model of BOO was constructed and used for urodynamic monitoring. The bladder tissue of rats was collected and subjected to real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), histological examination, and immunohistochemical staining. Through bioinformatics prediction, we found that transforming growth factor β2 (TGFβ2) expression was upregulated in rats with BOO compared with normal bladder tissue. In vitro analyses using primary bladder smooth muscle cells (BSMCs) revealed that hydrogen peroxide (H2O2) induced TGFβ2 expression. Moreover, H2O2 induced epithelial-to-mesenchymal transition (EMT) by reducing E-cadherin, an endothelial marker and CK-18, a cytokeratin maker, and increasing mesenchymal markers, including N-cadherin, vimentin, and α-smooth muscle actin (α-SMA) levels. The downregulation of TGFβ2 expression in BSMCs using siRNA technology alleviated H2O2-induced changes in EMT marker expression. The findings of the study indicate that TGFβ2 plays a crucial role in BOO by participating in OS-induced EMT in BSMCs.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-β1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFβ pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFβ1 and p-Smad2/3. Furthermore, TGFβ1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFβ1/Smad2/3 pathway via Nbl1.

Fibrosis is a pathological change mainly characterized by an increase of fibrous connective tissue and decrease of parenchymal cells. Its continuous progress may lead to the destruction of organ structure and function decline. An excess of alternatively activated M2 macrophages have been considered crucial candidates in the progression of fibrosis. Bone morphogenetic proteins (BMPs), a group of multifunctional growth factors, are essential for organ development and pathophysiological process, however, the roles that BMPs play in innate immune homeostasis in the development of fibrosis and the downstream signals have not been fully explored. In the current study, we firstly found that the expression of BMP4 was significantly down-regulated in human and mouse fibrosis samples. Then we investigated the effects of BMP4 on macrophage polarization in IL-4 environment and related molecular mechanisms, and found that BMP4 caused a decrease in polarized response towards M2, reflected in the expression of the markers Fizz1, Ym1 and Arg1, together with an inhibition in Stat6 phosphorylation. This relied on the Smad1/5/8 signaling, which had a crosstalk with Stat6. Moreover, the in vivo study showed that BMP4 treatment can reduce collagen deposition and delay the development of experimental pulmonary fibrosis in mice by inhibiting M2 macrophages through adoptive transfer experiment. These findings revealed a novel role of BMP4 in regulating macrophages, offering potential strategies for treating pulmonary fibrosis.

Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-β1 (TGF-β1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-β1 (MsiTGF-β1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-β1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-β1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-β1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-β1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-β1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.

Colostrum is a nutritious milk synthesized by mammals during the postpartum period, and its rich bioactive components has led to a global increase in the consumption of bovine colostrum as a supplement. Bovine colostrum contains key components such as immunoglobulins, oligosaccharides, lactoferrin and lysozyme. It is a special supplement source due to its natural, high bioavailability and high concentrations of growth factors. Growth factors are critical to many physiological functions, and considering its presence in the colostrum, further research must be conducted on its safe application in many bodily disorders. Growth factors contribute to wound healing, muscle and bone development, and supporting growth in children. Additionally, the molecular mechanisms have been explored, highlighting the growth factors roles in cell proliferation, tissue regeneration, and the regulation of immune responses. These findings are crucial for understanding the potential health effects of bovine colostrum, ensuring its safe use, and forming a basis for future clinical applications. This review article examines the growth factors concentration in bovine colostrum, their benefits, clinical studies, and molecular mechanisms.

Acute coronary artery blockage leads to acute myocardial infarction (AMI). Cardiomyocytes are terminally differentiated cells that rarely divide. Treatments preventing cardiomyocyte loss during AMI have a high therapeutic benefit. Accumulating evidence shows that microRNAs (miRNAs) may play an essential role in cardiovascular diseases. This study aims to explore the biological function and underlying regulatory molecular mechanism of miR-322-5p on myocardial infarction (MI). This study's miR-322-5p is downregulated in MI-injured hearts according to integrative bioinformatics and experimental analyses. In the MI rat model, miR-322-5p overexpression partially eliminated MI-induced changes in myocardial enzymes and oxidative stress markers, improved MI-caused impairment on cardiac functions, inhibited myocardial apoptosis, attenuated MI-caused alterations in TGF-β, p-Smad2, p-Smad4, and Smad7 protein levels. In oxygen-glucose deprivation (OGD)-injured H9c2 cells, miR-322-5p overexpression partially rescued OGD-inhibited cell viability and attenuated OGD-caused alterations in the TGF-β/Smad signaling. miR-322-5p directly targeted Smurf2 and inhibited Smurf2 expression. In OGD-injured H9c2 cells, Smurf2 knockdown exerted similar effects to miR-322-5p overexpression upon cell viability and TGF-β/Smad signaling; moreover, Smurf2 knockdown partially attenuated miR-322-5p inhibition effects on OGD-injured H9c2 cells. In conclusion, miR-322-5p is downregulated in MI rat heart and OGD-stimulated rat cardiomyocytes; the miR-322-5p/Smurf2 axis improves OGD-inhibited cardiomyocyte cell viability and MI-induced cardiac injuries and dysfunction through the TGF-β/Smad signaling.