Expression Of Growth Factor Research Articles

Specific molecular imaging of BALB/c model mice with Graves' ophthalmopathy based on high expression of insulin-like growth factor 1 receptor.

At present, most of the targeted imaging based on insulin-like growth factor 1 receptor (IGF-1R) is for tumor research, and there is no IGF-1R-targeted imaging for Graves' ophthalmopathy(GO). This study aims to develop a peptide probe, 99mTc-ZIGF1R:4551-GGGC, targeting the IGF-1R, and to achieve specific imaging in Graves' disease (GD) animal models exhibiting GO. 99mTc-ZIGF1R:4551-GGGC probe was synthesized using a direct labeling method and its labeling efficiency assessed via instant thin-layer chromatography (ITLC). Western blot analysis confirmed the overexpression of IGF-1R in malignant melanoma B16F10 cells. Subsequent SPECT/CT whole-body imaging of B16F10 tumor-bearing mice evaluated the probe's targeting accuracy. In addition, a GO model was established using an electroporation immunoassay, followed by serological and histopathological examinations. The GO models then underwent 99mTc-ZIGF1R:4551-GGGC SPECT/CT imaging to assess eye-targeted imaging capabilities. The peptide probe exhibited a labeling efficiency exceeding 90%. Both GD and GO models were effectively created via electroporation immunoassay. Imaging results indicated significant accumulation and retention of the peptide probes in the tumors of B16F10 tumor-bearing mice. In the GO models, probe uptake was predominantly observed in retrobulbar tissues, contrasting with primary accumulation in the lungs and gastrointestinal tract in normal mice, where only minimal tracer was observed in retrobulbar tissues. Notably, GO mice demonstrated higher probe uptake and prolonged retention. This study successfully established GD and GO models, reducing the duration of the immune cycle. Moreover, a peptide probe targeting IGF-1R was synthesized, enabling specific imaging of retrobulbar tissues in GO models.

Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates FGR-associated fetal sex dependent effects on liver metabolism-related signaling pathways.

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic fatty liver diseases and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency and fetal weight was significantly improved following three administrations of a non-viral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex specific differences in liver gene and protein expression of pro-fibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, an indirect measure of hepatic activity, was also demonstrated with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing Control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later-life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.

Probiotic-Derived Metabolites from Lactiplantibacillus plantarum OC01 Reprogram Tumor-Associated Macrophages to an Inflammatory Anti-Tumoral Phenotype: Impact on Colorectal Cancer Cell Proliferation and Migration

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the polarization into the pro-tumoral M2-like TAM phenotype promotes the extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and therapy resistance. Probiotic metabolites can disrupt this crosstalk, possibly reverting the TAM polarization toward a pro-inflammatory anti-tumoral phenotype, thus potentially benefiting the intestinal mucosa and opposing CRC progression. Previously, we showed that Lactiplantibacillus plantarum OC01 metabolites counter interleukin (IL)-6-induced CRC proliferation and migration. Methods: Here, we explore how probiotics affect CRC secretome and how this influences TAM polarization, which then impacts CRC malignancy. Results: The conditioning medium (CM) from CRC cells indeed promoted the polarization of macrophage toward the M2-like phenotype, whereas the CM from CRC pre-treated with L. plantarum OC01 metabolites induced a pro-inflammatory macrophage phenotype, characterized by NLRP3 inflammasome activation and reactive oxygen species (ROS) production, and by decreased expression of the M2 phenotype markers CD206 and CD163. Consistently, the expression of tumor growth factor (TGF)-β, a promoter of M2 macrophage polarization, was reduced in CRC cells treated with L. plantarum OC01. The pro-inflammatory macrophages inhibited CRC proliferation and migration. Conclusions: Overall, our study highlights the potential of metabolites from L. plantarum OC01 to reprogram the metabolism in cancer cells and thus reshape the TME by shifting TAMs toward a more inflammatory and anti-tumoral phenotype, emphasizing the promise of probiotics in advancing novel therapeutic approaches for CRC.

MiR-5586-5p Suppresses Hypoxia-induced Angiogenesis Through Multiple Targeting of HIF-1α, HBEGF and ADAM17 in Breast Cancer.

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role in the cellular response to hypoxia, which plays a crucial role in the induction of abnormal angiogenesis and metastasis. Understanding the mechanism for the regulation of angiogenesis by HIF-1α-regulating miRNA will contribute to developing the strategy to prevent metastasis. We conducted a functional screening for HIF-1α-inhibiting miRNAs by evaluating the effects of miRNA mimics on HIF-1α expression and identified miR-5586-5p as an angiogenesis inhibitor through a mechanistic study. Angiogenic activity was assessed by tube formation assays using HUVEC cells exposed to conditioned media from miRNA-transfected breast cancer cells. In vivo activity of miR-5586-5p was examined through intratumoral injection of miRNA in orthotopic xenograft mice established by injecting MDA-MB-231 cells into the mammary fat pads of BALB/c nu/nu mice. The expression of the critical proangiogenic factors vascular endothelial growth factor A (VEGFA) and angiopoietin-like protein 4 (ANGPTL4) was inhibited by miR-5586-5p. Migration and tube formation of human umbilical vein endothelial cells were reduced in the conditioned medium prepared from miR-5586-5p-transfected cells. miR-5586-5p also suppressed the expression of heparin-binding EGF-like growth factor (HBEGF) and a disintegrin and metalloprotease 17 (ADAM17), which play a role in hypoxic signaling to induce the expression of VEGFA and ANGPTL4. HIF-1α, HBEGF, and ADAM17 were verified as the direct targets of miR-5586-5p responsible for the angiogenesis-suppressing function of miR-5586-5p. Expression levels of miR-5586-5p were lower in tumor tissues than in neighboring normal tissues of breast cancer patients. The expression of miR-5586-5p was inversely correlated to those of HIF-1α, HBEGF, ADAM17, VEGFA, and ANGPTL4. Angiogenesis and subsequent tumor growth were suppressed by intratumoral injection of miR-5586-5p in orthotopic MDA-MB-231 xenografts in mice. A potent tumor-suppressive function of miR-5586-5p applicable for the development of a novel cancer treatment strategy is herein described.

Effect of 0.05% cyclosporine A eye drops on the healing process of corneal epithelial defects in rats

0.05% cyclosporine A eye drops is a kind of new medication for dry eye after corneal refractive surgeries. However, it is still unclear how this eye drops affect the healing process of corneal epithelial defects caused by operative procedures. In this vivo study, the effect of 0.05% cyclosporine A eye drops on the healing process of the corneal epithelium was assessed in a rat model featuring mechanically induced central corneal epithelial defects. These Sprague-Dawley rats were randomly divided into three groups, the 0.05% cyclosporine A eye drops group (CsA group), the 0.1% sodium hyaluronate eye drops group (HA group), and the model control group (MC group). The epithelial healing, tear secretion, epithelial microvilli, expression of apoptosis markers (TUNEL, p53, and bcl-2 proteins), inflammatory factors (IL-1β, TNF-α, and IL-6), and epidermal growth factor (EGF) were detected in the current study using corneal fluorescein sodium staining, phenol red thread test, transmission electron microscopy (TEM), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA), respectively. Compared to the other two groups, lower expression of apoptosis markers and inflammatory factors were exhibited in the CsA group, along with its faster and better epithelial healing and higher tear secretion (P<0.05). In conclusion, 0.05% cyclosporine A eye drops effectively promote the healing process for corneal epithelial defects in rats, potentially offering advantages for rapid corneal recovery after refractive surgical procedures.

Pulsed electromagnetic field prevents tooth relapse after orthodontic tooth movement in rat models.

Relapse after orthodontic treatment remains a crucial problem. Pulsed electromagnetic fields (PEMFs) accelerate osteoblastogenesis and inhibit osteoclastogenesis. However, their effect on tooth movement during the retention phase of orthodontic treatment has not been studied. This study investigated the role of PEMF stimulation in preventing tooth relapse after orthodontic tooth movement (OTM) in rat models. Thirty-six male Wistar rats were divided into control, PEMF 7, and PEMF 14 groups. The maxillary first molar was moved mesially with a 50g force of a Nickel Titanium closed coil spring for 21 days. Therefore, PEMF stimulations, including a frequency of 15Hz and intensity of 2.0mT, were applied to a retention phase for 2h daily for 7 and 14 days. The tooth relapse distance was evaluated on days 1, 3, 7, and 14; the number of osteoblasts, osteoclasts, and fibroblasts was assessed by hematoxylin and eosin staining; and the expression of fibroblast growth factor 2 (FGF-2) and type I collagen (Col-I) was evaluated by immunohistochemistry. The data were analyzed using one-way analysis of variance and post hoc test with p<0.05 considered statistically significant. Tooth relapse distance was significantly decreased in the PEMF 7 and PEMF 14 groups compared to the control group. A significant increase was detected in osteoblasts, fibroblasts, FGF-2, and Col-I in both PEMF groups, while osteoclasts decreased (p<0.05). The reduction of tooth relapse could be attributed to PEMF stimulation for 7 and 14 days by accelerating alveolar bone formation and periodontal ligament remodeling.

Interleukin 29 is a novel antiangiogenic factor in angiogenesis.

Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Despite the importance of Interleukin 29 (IL-29), a newly identified cytokine of type III interferon family, its role in angiogenesis remains unknown. We aimed to elucidate IL-29's impact on angiogenesis under both and physiological and pathological conditions. We employed various assays to evaluate IL-29's effect on proliferation, apoptosis, migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro. IL-29's angiogenic effect was assessed using mouse aortic rings ex vivo, and oxygen-induced retinopathy (OIR) mouse model in vivo. Signaling pathways possibly involved in IL-29-induced angiogenesis were investigated by Western blot. Finally, IL-29's impact on tube formation was blocked by inhibiting IL-29/interleukin 10 receptor 2 (IL-10R2) binding. IL-29 treatment inhibited endothelial cell migration, tube formation and vessel sprouting, without affecting proliferation or apoptosis. Notably, IL-29 (100ng/ml) attenuated vessel growth in pathological angiogenesis in OIR mice, accompanied by decreased expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). Mechanistically, IL-29 activated Stat3 signaling pathway, and blocking IL-29/IL-10R2 binding remarkably reversed IL-29's anti-angiogenic effect on tube formation. Our findings demonstrated that IL-29, at a relative low concentration, modulates angiogenesis in both physiological and pathological contexts. Targeting IL-29 or its receptor IL-10R2 offers a promising strategy for angiogenesis regulation in various conditions.

IGF2BP3 is upregulated in endometrial cancer and tightly regulates the growth of drug-resistant endometrial cancer cells via HMGA1.

Endometrial cancer (EC) is a malignant tumor with various histological subtypes and molecular phenotypes. The evaluation of drug resistance is important for cancer treatment. Progesterone resistance is the major challenge in EC. Knowledge of drug resistance in EC is important in the development of novel therapies. In this study, ten paracancerous and ten tumor tissues were collected to measure the expression of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and high-mobility group protein 1 (HMGA1). AN3CA and Ishikawa cells were used to explore the effects of IGF2BP3 on EC. The expression levels of IGF2BP3 and HMGA1 were higher in EC tumor tissues than in paracancerous tissues. IGF2BP3 and HMGA1 are highly expressed in cisplatin-resistant EC cells. IGF2BP3 knockdown decreased the growth of cisplatin-resistant EC cells. Knockdown of IGF2BP3 decreased the level of HMGA1 protein. HMGA1 knockdown decreased the growth of cisplatin-resistant EC cells. The findings demonstrate that IGF2BP3 is upregulated in EC and closely regulates the growth of drug-resistant EC cells via HMGA1. The findings will inform the development of novel therapies for EC.

Investigation of the Potential Treatment Effect of Botulinum Toxin Type A in Ovarian Torsion: Findings From the Rat Model.

The aim of this study was to investigate the effects of botulinum toxin A on histological abnormalities, loss of ovarian reserve, and angiogenesis within the ovarian torsion-detorsion paradigm. A total of 45 female Wistar albino rats were used for the study. The rats were randomly divided into five groups (n=9 in each group): Control, Torsion, Torsion+Detorsion, Torsion+Detorsion+Botulinum toxin, and Botulinum toxin only. Follicular cell degeneration, vascular congestion, hemorrhage, inflammation, and vascular endothelial growth factor (VEGF) expression scores were compared histopathologically between the groups. Follicle numbers were compared. Anti-mullerian hormone levels were measured before and after torsion, detorsion, and treatments. Follicular cell degeneration, vascular congestion, hemorrhage, inflammation, and VEGF expression differed significantly between groups for each score (p<0.001). The VEGF expression score was found to increase more in the torsion+detorsion+botulinum toxin group than in the torsion+detorsion group (2.67±0.71 and 2.22±0.67, respectively). There was a significant difference between the groups in secondary follicle counts (p=0.04). The groups showed statistically significant differences in their anti-mullerian hormone levels (p<0.001). This initial investigation of the effects of botulinum toxin on ovarian torsion (OT) has shown that botulinum toxin type A has the potential to be a useful adjunct treatment for fertility preservation. Our results proved the ovarian protective effect of botulinum toxin type A in rats with OT. Therefore, botulinum toxin type A may be a potential preventive agent against ovarian damage caused by torsion in the future.

NIR-responsive injectable nanocomposite hydrogels with enhanced angiogenesis for promoting full-thickness wound healing.

Angiogenesis plays a vital role in the treatment of full-thickness wounds. Deferoxamine (DFO) has been employed to promote neovascularization, however, smart drug delivery systems are needed to optimize its utilization. In this study, an injectable extracellular matrix (ECM)-mimicking hydrogel (HOG@P&D) was developed by leveraging the dynamic Schiff base and hydrogen bonds among a chitosan derivative (HACC), oxidized alginate (OSA), gelatin, and DFO-loaded polydopamine nanoparticles (P&D) for efficient wound healing. The incorporation of P&D enables HOG@P&D to respond to near-infrared (NIR) irradiation, converting laser energy into heat to trigger an on-demand, rapid release of DFO, thereby effectively enhancing angiogenesis. In vitro tube formation assays revealed that the number of meshes in the HOG@P&D group was fourfold higher than that of the control group. Additionally, HOG@P&D exhibited superior mechanical properties, tissue adhesion, and injectability, allowing it to cover wounds seamlessly. This hydrogel also demonstrated antibacterial and antioxidant properties, creating a conducive microenvironment for wound healing. In vivo studies further confirmed that HOG@P&D promoted angiogenesis and mitigated inflammation by upregulating angiogenic growth factor expression, thereby accelerating full-thickness wound healing. This nanocomposite hydrogel shows significant potential as a high-performance wound dressing.

Arsenic and the placenta: A review with emphasis on the immune system.

Chronic arsenic exposure affects over 140 million people globally. While arsenic easily crosses the placenta, the specific mechanisms impacting placental immune cell populations and fetal health are unclear. Maternal arsenic exposure is epidemiologically linked to increased infection risk, mortality, and cancer susceptibility in offspring, emphasizing the importance of understanding placentally-mediated immune effects. This review explores the potential role of the placenta, a key organ for immune transfer to the developing fetus, in mediating chronic low-dose arsenic exposure effects. Examining three potential pathways-direct contaminant transfer, altered immune transfer from the mother, and indirect impact on fetal immune programming via maternal and placental signaling-the review highlights studies associating maternal arsenic levels with immune-related outcomes, including changes in cord blood T cell populations and increased placental inflammation. Placental gene expression analysis reveals alterations in pathways related to oxidative stress, proteasome activity, and aquaglyceroporin transporter expression. Impact on placental DNA methylation and microRNA regulation as well as on trophoblast dysfunction is discussed, with evidence suggesting inhibited trophoblast migration and placental growth factor expression. The complexity of mixtures, nutrition, and environmental interactions add challenges to investigating the placenta's role in immune programming. Despite inconsistent findings on placental morphology alterations, evidence suggests a potential link between arsenic exposure, placental anomalies, and adverse birth outcomes. Further research is crucial to comprehend the effects of prenatal arsenic exposure on trophoblasts, placental immune cells, and subsequent long-term consequences for fetal immune development and birth outcomes.

Unveiling Hidden Dangers: Quantitative Analysis of Ischemic Risks in High-Risk Patients with ASCVD and Dyslipidemia.

Cardiovascular disease is one of the foremost causes of morbidity and mortality worldwide, with low-density lipoprotein cholesterol (LDL-C) identified as a significant risk factor for subsequent ischemic events. Elevated LDL-C contributes to vascular injury and fibrosis by upregulating the expression of connective tissue growth factor and collagen IV, which leads to endothelial cell dysfunction that initiates the process of atherosclerotic diseases. Currently, there is an absence of clear, risk-defined criteria to identify patients who are in greater needs for intensive LDL-C reduction, particularly with PCSK9 inhibitors. The data of ischemic risk associated with different patient types are scattered across the sub-analyses of FOURIER and ODYSSEY OUTCOMES trials, as well as trials that analyzed the plaque morphology of high-risk patients. It would be helpful to highlight the use of clinical features and plaque morphology and identify the patient types at higher ischemic risk. This article aims to provide a clear visualization of the ischemic risk associated with various types of patients with atherosclerotic cardiovascular disease (ASCVD) and dyslipidemia, and its implications to improve risk stratification for patients with unveiling hidden dangers.

Mammary Gland Reactive Stroma Characterization at Aging After Bisphenol A Exposure During Hormonal Susceptibility Windows.

Mammary glands development is influenced by endocrine signaling, which remodels epithelial and stromal compartments. Reactive stroma phenotype is observed when stromal disturbances occur, leading to changes in extracellular matrix composition and occurrence of reactive cell types. One of the triggers of these alterations is endocrine-disrupting chemical exposure, such as bisphenol A (BPA). Studies suggest that BPA acts on receptor binding sites of several hormones interfering the endocrine response. The aim of this study was to investigate the reactive stroma features on mammary glands of aged female gerbils (Meriones unguiculatus) exposed to BPA during windows of susceptibility. Thus, the analysis of cellular profile and growth factor expressions was provided. Fibroblastic population changed in BPA-exposed mammary glands, with a remarkable increase of myofibroblasts (vimentin+/α-SMA+) and active fibroblasts (FAP+). Normal fibroblasts (vimentin+/α-SMA-) were decreased mainly associated with the increase of FGF-10, an inductor of fibroblastic polarization. CD34+ stromal cells were also identified and detected among epithelial cells after BPA-induction disruption. Angiogenesis was supported by VEGF increasing in the gland tissue, which promoted an increase in blood vessel density. Thus, our results demonstrated that reactive stroma was raised in the mammary gland after BPA exposure. This profile was supported by changes in the fibroblastic population due to an induction to synthetic phenotypes and the expression of FGF-10, as well as the angiogenic activity that could corroborate with the malignancy and aggressiveness induced by BPA exposure.

Understanding the Dual Role of Macrophages in Tumor Growth and Therapy: A Mechanistic Review.

Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.

Anti-angiogenic therapy as potential treatment for adenomyosis

Adenomyosis is characterized by abnormal uterine bleeding, dysmenorrhea and subfertility. Increased expression of angiogenesis markers in adenomyosis presents a treatment opportunity and was studied in an adenomyosis mouse model. Mice were administered tamoxifen (1 mg/kg) on neonatal days 2–5. At six weeks of age, mice received oral treatment with axitinib 3 mg/kg (‘dose I/AX3’, n = 34), axitinib 25 mg/kg (‘dose II/AX25’ n = 34), or with vehicle-only (‘placebo’, n = 34). The prevalence and severity of adenomyosis were assessed. An adenomyosis severity index was calculated by multiplying mean grade/mouse by the percentage affected surface area. Angiogenesis-related gene expression was evaluated using real-time quantitative PCR. 101 mice completed adenomyosis induction and could be analyzed. The prevalence of adenomyosis was 30/33 (90.0%) in dose I, 29/34 (85.3%) in dose II, and 30/34 (88.2%) in placebo treated mice (p = 0.78). High grade (2/3) adenomyosis was significantly less prevalent in mice treated with axitinib dose II (n = 19, 55.9%) than in the placebo group (n = 27, 79.4%, p < 0.05). The adenomyosis severity index was reduced by 48% in the axitinib-treated groups (dose I, p < 0.05). The expression of angiogenic growth factors was reduced in the dose I and II axitinib-treated groups compared to the placebo-treated group. Following these promising first results, further research should focus on commonality among different angiostatic drugs, potential side effects, as well as the method and timing of application.

Dietary phytosterols increased the rate of weight gain, antioxidant capacity and growth of beneficial strains of bacteria in the gut and suppressed the population of potentially pathogenic bacteria in largemouth bass (Micropterus salmoides).

This study was to evaluate the effects of dietary adding of phytosterol (PS) on growth, antioxidant capacity, tissue morphology and gut microbiota of largemouth bass (Micropterus salmoides). A total of 540 largemouth bass (13.75 ± 0.37g) were selected and randomly divided into six groups and fed with diets supplemented with 0, 0.01 %, 0.02 %, 0.03 %, 0.04 % and 0.05 % of PS (ontrol, PS1-PS5) for 56 d. The results showed that the rate of weight gain (WGR) and condition factor (CF) of largemouth bass increased significantly (P < 0.05) with the increasing PS addition levels. In addition, PS significantly increased the activities of superoxide dismutase (SOD) and catalase (CAT) in serum compared to group C (P < 0.05), as well as increased relative expression of pituitary Insulin-like growth factor (igf1ra, igf1rb, and igf2r), hypothalamic growth hormone gh and insulin receptor ir, compared with group C (P < 0.05). Histopathological analysis showed that the addition of 0.04 % PS to the feed resulted in a tighter cellular arrangement and a significant reduction in vacuolisation in the liver of largemouth bass. It also significantly increased intestinal fold width and muscle wall thickness (P < 0.05). Analysis of the intestinal flora showed a significant decrease in the α-diversity of the flora in the PS4 group compared to the C group (P < 0.05). Notably, at the phylum level, the addition of PS to feed significantly reduced the relative abundance of Proteobacteria and Bacteroidota. At the genus level, PS significantly increased the relative abundance of Cetobacterium (P < 0.05). The addition of 0.04 % PS to the feed promotes growth, antioxidant capacity, improved tissue morphology and increased abundances of beneficial gut microbiotas in largemouth bass.

Concoctive principles of detoxification and retention of the main toxic hepatotoxicity of Tripterygium wilfordii and its anti-inflammatory efficacy by concocting with the medicinal excipient Spatholobi Caulis juice.

Tripterygium wilfordii (TW), which has severe hepatotoxicity, is commonly used as anti-rheumatism. Using the juice of auxiliary herbs in concocting poisonous herbs is a conventional method for toxicity reduction or efficacy enhancement. Traditional Chinese Pharmacy textbooks record that Spatholobi Caulis (SC) can alleviate the side effects caused by TW and also possesses excellent hepatoprotective effect. However, it is still unclear how the concoctive principles of hepatotoxicity reduction and anti-inflammatory efficacy retention of TW after being concocted with the medicinal excipient SC juice. Therefore, this study aimed to evaluate the hepatotoxicity and anti-inflammatory efficacy of concoction with SC juice on TW and preliminarily explored its detoxification mechanism. The attenuation effect of TW concocted with SC juice was determined by triptolide (TP) content, hepatic histological and serum biochemical indexes. The detoxification mechanism was predicted by network pharmacology and molecular docking, and confirmed by quantitative real-time PCR (qRT-PCR) and Western blot. Moreover, the anti-inflammatory efficacy was evaluated by paw edema test, and the major active ingredients in the SC juice introduced to TW concoction were detected. Concoction with SC juice significantly reduced TP content and serum biochemical indicator levels, alleviated liver pathological damage, introduced the main active ingredients, and inhibited the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Furthermore, the anti-inflammatory efficacy was retained. In summary, this study elucidated that concoction with SC juice alleviated the hepatotoxicity of TW by inhibiting HIF-1α/VEGFA signaling, decreasing TP content, and introducing the main active components. Moreover, the anti-inflammatory efficacy was retained.

CD34hi subset of synovial fibroblasts contributes to fibrotic phenotype of human knee osteoarthritis.

Osteoarthritis (OA) shows various clinical manifestations depending on the status of its joint components. We aimed to identify the synovial cell subsets responsible for OA pathophysiology by comprehensive analyses of human synovium samples in single-cell resolution. Two distinct OA synovial tissue groups were classified by gene expression profiles in RNA-Seq: inflammatory and fibrotic. The inflammatory group exhibited high expression of inflammatory cytokines, histologically inflammatory infiltrate, and a more severe pain score. The fibrotic group showed higher expression of fibroblast growth factor (FGFs) and bone morphogenetic proteins (BMPs), showed histologically perivascular fibrosis, and showed a lower pain score. In single-cell RNA-Seq (scRNA-Seq) of synovial cells, MERTKloCD206lo macrophages and CD34hi fibroblasts were associated with the inflammatory and fibrotic groups, respectively. Among the 3 fibroblast subsets, CD34loTHY1lo and CD34loTHY1hi fibroblasts were influenced by synovial immune cells, whereas CD34hi fibroblasts were influenced by mural and endothelial cells. Particularly, in CD34hi fibroblast subsets, CD34hiCD70hi fibroblasts promoted proliferation of Tregs, potentially suppressing synovitis and protecting articular cartilage. Elucidation of the mechanisms underlying the regulation of these synovial cell subsets may lead to novel strategies for OA therapeutics.

Differential expression of vascular endothelial growth factor A (VEGFA) and M1 macrophage marker nitric oxide synthase 2 (NOS2) in lymph node granulomas of BCG-vaccinated and non-vaccinated cattle infected with Mycobacterium bovis.

Bovine tuberculosis is mainly caused by Mycobacterium bovis. Bacillus Calmette-Guérin (BCG) is an attenuated strain of M. bovis which provides variable disease protection. Lesions have been characterized in infected cattle, but little comparison has been done with lesions which form in BCG-vaccinates. Here, in situ hybridization examined differences in expression of M. bovis RNA, inducible nitric oxide synthase 2, and vascular endothelial growth factor A in relation to vaccination status and granuloma grade, using two different groups of cattle. Data found no differences between vaccination groups or granuloma grade in average copies of M. bovis mRNA per μm2 of total granuloma area or per μm2 of necrotic areas. Within a vaccination group high-grade granulomas had more NOS2 per cell, per μm2 and a higher percentage of cells expressing NOS2 than low-grade granulomas. Non-vaccinates had a higher percentage of cells producing NOS2 than vaccinates. Differences in NOS2 expression varied by group. Vaccination status and granuloma grade did not affect the average copies of VEGFA per cell or the percent of cells expressing RNA, however VEGFA copies per μm2 varied between groups. These findings suggest NOS2 and VEGFA are likely not mechanisms of BCG vaccination protection but may impact disease severity.

Assessing the Protective Role of Wharton's Jelly-Derived Mesenchymal Stem Cell Secretomes in Inducing Apoptosis in SKBR3 Breast Carcinoma Cells

Background: Breast carcinoma (BC) is the most prevalent form of cancer in women and is classified into various subtypes based on the expression of ER, PR, and human epidermal growth factor 2 (HER2) receptors. Human epidermal growth factor 2-positive BC, in particular, presents significant challenges due to its aggressiveness and limited treatment options. Modulating apoptotic pathways is crucial for reducing tumor burden and enhancing treatment efficacy. Objectives: This study aimed to evaluate the inhibitory effects of secretomes derived from Wharton's jelly mesenchymal stem cells (WJ-MSC secretomes) on the proliferation of the SKBR3 cell line, as well as the subsequent changes in apoptosis-related gene expression after treatment. The research provides new insights into the therapeutic potential of WJ-MSC secretomes for HER2-positive BC. Methods: SKBR3 cells were exposed to WJ-MSC secretomes at doses of 10, 25, and 50 μg/mL for 24 and 48 hours. MTT assays and colony formation assays were used to evaluate cell viability, while annexin V/PI staining and mRNA expression analyses were conducted to assess apoptosis. Results: Treatment with WJ-MSC secretomes led to a significant, concentration- and time-dependent reduction in colony numbers and cell viability in the 25 and 50 μg/mL groups. Early and late apoptotic indices increased significantly in the 25 μg/mL group, with P-values of &lt; 0.01 and &lt; 0.05, respectively. The mRNA expression levels of Caspase-9 (P &lt; 0.001), Caspase-3 (P &lt; 0.05), and the Bax/Bcl-2 ratio (P &lt; 0.01) significantly increased in the 25 μg/mL treatment group. Caspase-8 activity was unaffected by WJ-MSC secretomes. Conclusions: Wharton's jelly mesenchymal stem cells secretomes demonstrate potential as an anticancer agent for HER2-positive BC, acting through the intrinsic apoptotic pathway in a concentration- and time-dependent manner. This study is the first to detail the specific effects of WJ-MSC secretomes on HER2-positive SKBR3 cells, suggesting their novel application in targeted breast cancer therapy.