Levels Of TGF-beta Research Articles

Oxytocin: A Shield against Radiation-Induced Lung Injury in Rats.

Radiation-induced lung injury (RILI), a serious side effect of thoracic radiotherapy, can lead to acute radiation pneumonitis (RP) and chronic pulmonary fibrosis (PF). Despite various interventions, no effective protocol exists to prevent pneumonitis. Oxytocin (OT), known for its anti-inflammatory, antiapoptotic, and antioxidant properties, has not been explored for its potential in mitigating RILI. This study involved 24 female Wistar albino rats, divided into three groups: control group, radiation (RAD) + saline, and RAD + OT. The RAD groups received 18 Gy of whole-thorax irradiation. The RAD + OT group was treated with OT (0.1 mg/kg/day) intraperitoneally for 16 weeks. Computerizing tomography (CT) imaging and histopathological, biochemical, and blood gas analyses were performed to assess lung tissue damage and inflammation. Histopathological examination showed significant reduction in alveolar wall thickening, inflammation, and vascular changes in the RAD + OT group compared to the RAD + saline group. Biochemical analysis revealed decreased levels of TGF-beta, VEGF, and PDGF, and increased BMP-7 and prostacyclin in the RAD + oxytocin group (p < 0.05). Morphometric analysis indicated significant reductions in fibrosis, edema, and immune cell infiltration. CT imaging demonstrated near-normal lung parenchyma density in the RAD + oxytocin group (p < 0.001). Oxytocin administration significantly mitigates radiation-induced pneumonitis in rats, implying that is has potential as a therapeutic agent for preventing and treating RILI.

Comparative evaluation of the osteogenic capacity of second-generation platelet concentrates on dental pulp stem cells – An ex vivo study

Introduction: Clinical evidence of platelet-rich fibrin (PRF) benefits on bone repair is still emerging, prompting researchers to experiment with different PRF formulations as osteoconductive scaffolds. Aims: This study compared the osteoconductive effects of injectable PRF (i-PRF) and leukocyte-rich PRF (L-PRF) on the differentiation of dental pulp stem cells (DPSCs) into osteoblasts. Materials and Methods: Blood samples were collected from the volunteers to prepare L-PRF and i-PRF conditioned media (CM) by centrifugation. DPSCs were isolated from impacted third molars and cultured. Proliferation of DPSCs in response to L-PRF and i-PRF was assessed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Osteoinductive potential was evaluated through alkaline phosphatase (ALP) activity, alizarin red S (ARS) staining, growth factor levels (vascular endothelial growth factor [VEGF], transforming growth factor [TGF-beta]), and cytokine expression (interleukin 6 [IL-6], IL-8) after 7 days. Results: MTT assay results showed that both L-PRF and i-PRF increased DPSC proliferation relative to the control group. After 7 days in L-PRF and i-PRF CM, DPSCs exhibited increased ALP activity, higher red-colored calcium deposits with ARS staining, and elevated levels of VEGF and TGF-beta. In addition, higher concentrations of inflammatory cytokines IL-6 and IL-8 were observed in both L-PRF and i-PRF compared to the control. Conclusions: Using both L-PRF and i-PRF as scaffolds can enhance the osteoinductive ability of stem cells, offering a potential strategy for regenerative therapies.

Key Regulators of Angiogenesis and Inflammation Are Dysregulated in Patients with Varicose Veins.

Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and venous reflux. Previous studies indicate that enhanced angiogenesis and inflammation contribute to the progression and onset of VVs; however, dysregulations in signaling pathways associated with these processes in VVs patients are poorly understood. Therefore, in our study, we aimed to identify key regulators of angiogenesis and inflammation that are dysregulated in patients with VVs. Expression levels of 18 genes were analyzed in peripheral blood mononuclear cells (PBMC) using real-time PCR, as well as plasma levels of 6 proteins were investigated using ELISA. Higher levels of CCL5, PDGFA, VEGFC, TGF-alpha, TGF-beta 1, and VEGF-A, as well as lower levels of VEGFB and VEGF-C, were found to be statistically significant in the VV group compared to the control subjects without VVs. None of the analyzed factors was associated with the venous localization of the varicosities. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors in PBMC and plasma from VVs patients, providing new insight into molecular mechanisms that could contribute to the development of VVs and point out promising candidates for circulatory biomarkers of this disease.

Preliminary results of atezolizumab and pirfenidone in non-small cell lung cancer.

e15197 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis improved outcomes for stage IV non-small cell lung cancer (NSCLC). Poor response to PD-L1 antibody has been linked to increased cancer-associated fibroblasts (CAF), which interact with cytotoxic T cells (CTLs) similarly to regulatory T cells (Tregs). CAFs, through cytokine production, impair antitumor immunity by affecting CTL function (TGF beta) and inhibiting CTL recruitment into tumors, suggesting that CAFs could be a therapeutic target in CPI-resistant NSCLC. Pirfenidone (P) exhibits anti-fibrotic effects by blocking fibroblast differentiation into CAFs and suppressing TGF beta production and associated signaling pathways/collagens. Atezolizumab (A) targets PD-L1, inhibiting its interaction with PD-1 and B7-1 (CD80) receptors on T cells. We initiated a phase I/II trial to test the combination of AP in recurrent NSCLC after CPI progression. The phase I study aims to determine the maximum tolerated dose (MTD) of AP and assess its safety and tolerability. The phase II study will evaluate its efficacy. The Exploratory Objectives are to measure circulating levels of TGF beta and investigate the expression of CAF-related proteins. Methods: phase I will enroll 3 patients using P at 801 mg PO TID and A at 1200mg IV every 3 weeks. If there is ≤ 1 Dose Limiting Toxicity (DLT), the study will proceed to phase II. If there are ≥2 DLTs, P will be reduced to 534 mg TID. If there is ≤ 1 DLT at this dose, we will proceed to phase II. If there are ≥2 DLTs, then the study will be terminated. Phase II will enroll 16 patients to assess efficacy. The main inclusion criteria are patients with recurrent NSCLC without actionable mutation, after progression with first-line therapy CPI with or without platinum-based doublet chemotherapy, no more than 2 lines of therapy, measurable disease, ECOG 0-2, and adequate organ function. Results: The study enrolled a total of 5 patients (4 males, 1 female), median age of 63.4; 5 were white; 3 patients did not complete the required 21 days of therapy for evaluation (1 non-compliance, 1 disease progression,1 unrelated Urinary Tract Infection); 2 patients were evaluable for toxicity, without DLT; 1 exhibited a partial response to cutaneous metastatic disease, with overall stable disease, 1 had disease progression. Adverse events (AE) in more than 5% of patients included blood disorders, cardiac, gastrointestinal, administration site, metabolic, musculoskeletal, psychiatric, respiratory, and skin disorders. Serious AEs were noted in 2 patients: one experienced gastrointestinal bowel perforation due to disease progression resulting in death, and the other had a respiratory disorder. Conclusions: The combination of AP did not produce unexpected side effects or reach the dose-limiting toxicity threshold. After the phase I portion is completed, the study will proceed to phase II expansion to enroll patients with recurrent NSCLC. Clinical trial information: NCT04467723 .

A novel TGFbeta/TGILR axis mediates crosstalk between cancer-associated fibroblasts and tumor cells to drive gastric cancer progression

Transforming growth factor beta (TGFβ) signaling plays a critical role in tumorigenesis and metastasis. However, little is known about the biological function of TGFbeta-induced lncRNA in cancer. In this study, we discovered a novel TGFbeta-induced lncRNA, termed TGILR, whose function in cancer remains unknown to date. TGILR expression was directly activated by the canonical TGFbeta/SMAD3 signaling axis, and this activation is highly conserved in cancer. Clinical analysis showed that TGILR overexpression showed a significant correlation with lymph node metastasis and poor survival and was an independent prognostic factor in gastric cancer (GC). Depletion of TGILR caused an obvious inhibitory effect on GC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. More importantly, we demonstrated that TGFbeta signaling in GC was overactivated due to cancer-associated fibroblast (CAF) infiltration. Mechanistically, increased level of CAF-secreted TGFbeta activates TGFbeta signaling, leading to TGILR overexpression in GC cells. Meanwhile, TGILR overexpression inhibited the microRNA biogenesis of miR-1306 and miR-33a by interacting with TARBP2 and reducing its protein stability, thereby promoting GC progression via TCF4-mediated EMT signaling. In conclusion, CAF infiltration drives GC metastasis and EMT signaling through activating TGFbeta/TGILR axis. Targeted blocking of CAF-derived TGFbeta should be a promising anticancer strategy in GC.

Role of transforming growth factor beta in assessment of severity of hypersensitivity pneumonitis: a single center study

BackgroundHypersensitivity pneumonitis (HP) is a more frequently diagnosed picture of diffuse parenchymal lung disease. It is an inflammation of the lung tissue, provoked by immune mechanisms, which happens to prone individuals as a reaction to a wide range of antigens. There are different degrees of fibrosis and inflammation. A group of extracellular mediators both proinflammatory and profibrotic claimed to be involved in the pathogenesis of HP. Among these mediators, a significant role is played by transforming growth factor-beta (TGF-β).AimCorrelation between the severity of hypersensitivity pneumonitis and the serum level of TGF beta.Patients and methodsSixty subjects were included in the study who were classified into 30 patients newly diagnosed with hypersensitivity pneumonitis and 30 healthy subjects served as controls. All the participants were subjected to complete history taking, physical examination, spirometry, 6-min walk distance test, HRCT, and serum levels of TGF-β.ResultsThe serum level of TGF beta is elevated in newly diagnosed HP cases (fibrotic and non-fibrotic) in relation to control participants showing statistical significance p value < 0.001, and the serum level of TGF beta in the fibrotic group of HP patients is more than that in non-fibrotic group with statistical significance p value 0.012.ConclusionThe serum level of transforming growth factor can be used in the assessment of the severity of hypersensitivity pneumonitis as regards the intensity of lung parenchymal changes.

Pre-Transplant Cytokine Levels as Signatures of Microvascular Inflammation in Kidney Allograft Biopsies.

The presence of microvascular inflammation (MVI) characterized by leukocyte margination in the glomeruli (glomerulitis, Banff score 'g') and peritubular capillaries (peritubular capillaritis, Banff score 'ptc') is a hallmark histological feature of antibody-mediated rejection (AMR), even in the absence of circumferential C4d positivity. In this study, we assessed the efficacy of pre-transplant plasma cytokines as an ancillary screening tool to identify MVI in kidney allograft indication biopsies to facilitate better graft survival. This single-center prospective analytical study comprises 38 kidney transplant recipients whose peripheral blood was collected before transplant and assessed for the plasma cytokine concentrations of FOXP3, IL-6, TGF beta, and IL-17 using enzyme-linked immunosorbent assays (ELISA). Histopathological assessment was done in post-transplant indication biopsies, and Banff scores of 'g+ ptc' were calculated to categorize recipients into three MVI groups. The correlational, regression, and ROC curve analyses were used to assess the association and predictive ability of the cytokines with respect to MVI. In our study cohort, 27 recipients had MVI=0, five had MVI=1, and six had MVI≥2. A significant difference in plasma cytokines was observed between these groups, and we found a strong negative correlation of FOXP3 with MVI, whereas a strong positive correlation of IL-6, TGF beta, and IL-17 was recorded with MVI. We have also assessed the predictive ability of these cytokines, FOXP3, IL-6, TGF-beta, and IL-17, through the ROC curve, which showed an AUC of 0.70, 0.76, 0.84, and 0.72, respectively. Our findings suggest that the pre-transplant levels of cytokines FOXP3, IL-6, TGF-beta, and IL-17 could be measured to identify recipients at risk of post-transplant MVI, which could further serve as an additional tool for effective management of the kidney allograft.

Assessing the impact of dental restorative materials on fibroblast cells: an immunohistochemical and ELISA analysis.

In this study, our aim was to investigate the effects of restorative materials such as composite, compomer and high viscosity glass ionomer, which are frequently used in dentistry, on L929 fibroblast cells by evaluating the oxidative stress parameters, pro- and anti-inflammatory cytokines, and apoptosis markers. L929 fibroblast cells were cultured, and dental filling materials were applied in two doses (50 and 100µl). Immunohistochemical staining was performed for experimental groups with Anti-Bax and Anti-Caspase 9 antibodies. Then, ELISA technique was used to detect the level of TNF-alpha, TGF-beta, IL-1-beta, IL-6, IL-10, LPO and CAT. In the light of the data, the examined dental filling materials were effective on increasing the TGF-beta, IL-10, LPO and CAT levels, and decreasing the TNF-alpha, IL-1-beta, and IL-6 levels. The histological micrographs were also support the issues. When the levels of H-score in Caspase 9 labeled micrographs were evaluated, the mean of the control group was lower than the mean of the experimental groups. Biocompatibility varies according to the content of the material, the amount of residual monomer, and its solubility. Although all the experimental groups have cytotoxic effects, the least effect is seen in the Omnichroma group.

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation.

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

Dysregulations of Key Regulators of Angiogenesis and Inflammation in Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a chronic vascular disease caused by localized weakening and broadening of the abdominal aorta. AAA is a clearly underdiagnosed disease and is burdened with a high mortality rate (65-85%) from AAA rupture. Studies indicate that abnormal regulation of angiogenesis and inflammation contributes to progression and onset of this disease; however, dysregulations in the molecular pathways associated with this disease are not yet fully explained. Therefore, in our study, we aimed to identify dysregulations in the key regulators of angiogenesis and inflammation in patients with AAA in peripheral blood mononuclear cells (using qPCR) and plasma samples (using ELISA). Expression levels of ANGPT1, CXCL8, PDGFA, TGFB1, VEGFB, and VEGFC and plasma levels of TGF-alpha, TGF-beta 1, VEGF-A, and VEGF-C were found to be significantly altered in the AAA group compared to the control subjects without AAA. Associations between analyzed factors and risk factors or biochemical parameters were also explored. Any of the analyzed factors was associated with the size of the aneurysm. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors potentially involved in AAA formation, giving new insight into the molecular pathways involved in the development of this disease and providing candidates for biomarkers that could serve as diagnostic or therapeutic targets.

Efficacy and immunological changes of sublingual immunotherapy in pediatric allergic rhinitis

BackgroundAllergen-specific immunotherapy, including subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), improves the disease progression of allergic rhinitis (AR). SCIT and SLIT exhibit similar efficacy, but SLIT has less systemic reactions. However, few studies have investigated the underlying mechanisms of SLIT treatment. In this study, we explored the efficacy of SLIT under different treatment durations and immunological changes. MethodsThis retrospective study was conducted from August 2017 to August 2022 in our hospital. A total of 314 children who underwent SLIT were divided into the following groups based on their treatment duration: the 1 year group (6 months–1 year), the 2 years group (1–2 years), and the 3 years group (2–3 years). The treatment efficacy was confirmed using a combined symptom and medication score (SMS). Multiple serum cytokines were measured using Luminex. Various immune cells in PBMCs were determined using flow cytometry. ResultsThe total nasal symptom score (TNSS), rescue medication score (RMS), and SMS of the 3 years group was significantly different from those of the 1 years and 2 years groups. At the end of the 2 years following cessation of SLIT, the following results were observed in the 3 years group: 1) the TNSS, RMS, and SMS had significantly improved, 2) the serum IL-10, TGF-beta, and IL-35 levels had increased significantly, and 3) the percentages of regulatory T cell, regulatory B cell, and follicular regulatory T cell increased significantly. ConclusionOur results suggest that 3 years of SLIT is necessary for long-term effects and continued immunological changes.

Trimetazidine provides protection against diabetic polyneuropathy in rats via modulation of soluble HMGB1.

The aim of this study was to evaluate the neuroprotective efficacy of trimetazidine (TMZ) in a diabetic neuropathy model of the sciatic nerve. We performed intraperitoneal (IP) single-dose streptozotocin (STZ) injection for a diabetes mellitus neuropathy model in 24 rats; 8 rats were in the control group, and no chemical administration was performed. 24 diabetic rats were randomly divided into 3 groups: Group 1 rats (n = 8; diabetes and saline groups) were given 1 ml/kg saline treatment. Diabetes and trimetazidine (TMZ)-treated rats (n = 8) were given TMZ 10 mg/kg/day i.p. in Group 2. Group 3 rats were given TMZ 20 mg/kg/day by i.p. for 4 weeks. At the end of the study, EMG and inclined plane testing were used, and blood samples were taken. Amplitudes of CMAP increased significantly in the TMZ treatment group when compared with the group that had been given saline treatment. The latency of CMAP was significantly shortened in the TMZ treatment group as compared to the saline treatment group. When compared to the saline treatment group, 10 mg/kg and 20 mg/kg TMZ treatment significantly reduced HMGB1, Pentraxin-3, TGF-beta, and MDA levels. We demonstrated the neuroprotective effect of TMZ on diabetic polyneuropathy in rats via modulation of soluble HMGB1.

Plasma Levels of Matrix Metalloproteinases 2 and 9 in Patients with Chronic Chagas Heart Disease and Systemic Arterial Hypertension: Correlation with TGF-Beta Plasma Levels.

Chronic Chagas heart disease (CCHD) and systemic arterial hypertension (SAH) frequently coexists in areas where Chagas disease is endemic. The effects of the association of both conditions (CCHD-SAH) on the extracellular matrix (ECM) remodeling are unknown. Matrix metalloproteinases (MMP) 2 and 9 are involved in ECM remodeling. The aim of this study was to evaluate MMP 2 and MMP9 in CCHD-SAH patients and to correlate their levels with those of the profibrogenic cytokine TGF-beta. We included 19 patients with CCHD-SAH, 14 patients with CCHD alone, and 19 controls matched by sex and age. MMP-2 and MMP-9 plasma levels were studied by gel zymography and showed as optical densities (OD). TGF-beta plasma levels were measured by double-ligand ELISA and expressed as pg/mL. Median (5th, 95th) MMP-2 plasma levels were 1224.7 OD (1160, 1433.5) in patients with CCHD alone, 1424.1 OD (1267.5, 1561) in patients with CCHD-SAH, and 940 OD (898.1, 1000.8) in controls (p=0.001). MMP-9 plasma levels were 1870 OD (1740, 1904.1) in patients with CCHD alone, 1754.6 OD (1650, 2049) in those with CCHD-SAH and 89.7 OD (80, 96) in controls (p=0.0003). MMP-9 plasma levels were higher than those of MMP 2 in patients with CCHD-SAH (p=0.01). No correlation was found between TGF-beta plasma levels with MMP-2 serum levels (r = 0.12; p=0.7), but a moderate negative correlation (r = -0.46; p=0.048) was observed between TGF-beta and MMP-9 plasma levels. MMP-2 and especially MMP-9 may play a role in the ECM remodeling process in patients with CCHD-SAH. TGF-Beta may counteract the MMP effect on the ECM remodeling process in patients with CCHD-SAH.

Role of echocardiography on early diagnosis of atrial remodelling and fibrosis in elite athletes.

There is emerging data indicating that long-standing vigorous exercise may be associated with atrial structural remodelling. This remodelling process is may be the cause of the increasing frequency of atrial arrythmias in athletes. Early diagnosis of atrial remodelling by atrial imaging could have a role in management of atrial arrythmias in elite athletes. In this study we aimed to diagnose early phases of atrial remodelling in elite athletes. Two groups of athletes including professional weight lifters (n = 33), professional marathoners (n = 32) and sedentary participants (n = 30) were enrolled. We also studied patients who received cardiotoxic chemotherapy (n = 10) for comparison. Serum TGF-beta level as a marker of fibrosis was measured. Both left atrial (LA) 3D volume and strain values were analysed. There was a positive correlation between serum TGF-beta levels and LA volumes and negative correlation between TGF-beta levels and strain values. TGF-beta levels were higher among chemotherapy and weight lifter groups, compared to control and marathoner groups [mean 0.57 ± 0.3 and 0.55 ± 0.2 vs. 0.45 ± 0.2 and 0.47 ± 0.2, respectively, p = 0.005]. LA volumes were higher among chemotherapy and weight lifter groups [median 33 (26-38) and 31 (23-36) respectively, p = 0.005], and strain values were lower in these two groups [mean 20.3 ± 2.5 and 24.6 ± 4.5, respectively, p < 0.005] compared to control and marathoner groups. Total exercise volume was higher in weight lifter group compared to marathoners [13,780 (2496-36,400) vs. 4732 (780-44928), respectively, p = 0.001]. There wasn't any difference between any group regarding left ventricular systolic and diastolic functions. Vigorous exercise causes atrial remodelling and fibrosis in elite athletes. Strength exercise carries higher risk for atrial fibrosis than endurance exercise. Burden of exercise is correlated with the severity of cardiac fibrosis. Echocardiographic evaluation of the left atrium and TGF-beta levels may help to detect subclinical cardiac remodelling and fibrosis.

Abstract 3314: Circulatory altruistic stem cells as a prognostic biomarker for platinum based chemotherapy in oral cancer

Abstract Background: Head &amp; neck cancer is the 4th common cancer, and most of them are diagnosed late, andtreated with cisplatin monotherapy. In these subsets of patients, immunotherapy has been tried, butwithout major success [1]. We speculate that circulating altruistic mesenchymal stem cells may serve asbiomarker for immunosuppression. Previously, we showed that oral cancer CSCs reprogram MSCs toaltruistic phenotype [2, 3], an embryonic stem cell like phenotype having niche defending ability [5].Here, we propose to test the immunosuppressive ability of ASCs, and their detection in the circulation ofhead &amp; neck cancer subjects undergoing platinum based chemotherapy. Method: The immunosuppression test: immunosuppressive secretory factors, mixed lymphocytereaction (MLR) assay, and a Boyden chamber based co-culture assay with NK cells [4]. Next, weobtained circulating CD271+/CD45- cells of stage IV head and neck cancer subjects (n=20) (5). Kaplan-Meier survival analysis and log-rank test to find association between the presence of circulatory ASCsand overall survival (OS). Result: CSCs including primary tumor obtained CSCs reprogram CD271+ MSCs to ASC phenotype;these cells secrete high level of Nitric oxide, IDO, TGF-beta, IL-10 and PGE-2. ASCs exhibited markedimmunosuppression in the MLR test. In Boyden chamber assay, ASCs markedly decreased the numberof NKG2D+ NK cells, and CD8+ T cells by 4-5 fold, whereas increased the CD4+/FoxP3/CD25- T-reg cells by 3-fold . Importantly, these 12 out of 20 patients showed poortreatment response to platinum therapy. The OS at 6 months was 24.6% for circulating ASC-positivepatients and 47.4% for circulating ASC- negative patients (log-rank test,). Conclusion: The circulatory ASCs could be a promising biomarkers for immunotherapy.

PS-B02-3: FGF23 EXACERBATES CARDIAC FIBROSIS IN DOCA-SALT HYPERTENSIVE MICE THROUGH LOCALLY ABNORMAL VITAMIN D METABOLISM

Backgrounds: Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease (CKD), but the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model that has mild CKD and hypertension, and heart failure with a preserved ejection fraction (HFpEF). Design and method: Wild type male mice (n = 16) were allocated randomly to four groups: normal control (NC), vehicle-treated DOCA-salt mice (V), FGF23-treated DOCA-salt mice (F), and FGF23 and calcitriol-treated DOCA-salt mice (C). The DOCA-salt mice received agents by CIV for ten days via an infusion mini-pump, uninephrectomized, and cardiac changes were evaluated in these mice. Results: DOCA-salt mice that received FGF23 showed a marked increase in serum FGF23 (249 pg/mL in V, 1416 pg/mL in F, and 1261 pg/mL in C) than NC (51 pg/mL). Echocardiography in these DOCA-salt mice revealed HFpEF. These mice also showed exacerbation of myocardial fibrosis area (7.0% in V, 13.2% in F, and 3.8% in C) concomitant with an inverse and significant correlation with Cyp27b1 expression (r = -0.79, P &lt; 0.01). Calcitriol treatment attenuated the FGF23-induced cardiac fibrosis (F vs. C, P &lt; 0.01) and improved diastolic function (early-to-atrial wave ratio in doppler echocardiography, 0.7 in F vs. 2.0 in C; P &lt; 0.01) via inhibition of transforming growth factor (TGF)-beta signaling. Protein expression levels of TGF-beta was significantly higher in F (1.32-fold to NC; P &lt; 0.01) than in NC, and significantly lower in C (0.96-fold to NC; P &lt; 0.05) than in F. This effect was independent of systemic and local FGF23 levels. Conclusions: These results suggest that CIV FGF23 loading induced cardiac fibrosis concomitantly with locally abnormal vitamin D metabolism, and this might have contributed to HFpEF progression in the DOCA-salt mice model. Thus, cardiac toxicity of FGF23 may be partly due to vitamin D inactivation in cardiac tissue. Calcitriol has cardioprotective effects by mediating TGF-beta signaling, independently of local and systemic FGF23 levels.

Dietary silver nanoparticles as immunostimulant on rohu (Labeo rohita): Effects on the growth, cellular ultrastructure, immune-gene expression, and survival against Aeromonas hydrophila

The current study aimed at assessing the immunostimulatory properties of silver nanoparticles (AgNPs) on Labeo rohita, and understanding how it affects the growth, cellular ultrastructure, the expression level of immune genes, and infection risk from Aeromonas hydrophila. Fish (avg wt: 30.1±3.26 g) were fed diets with four separate AgNP inclusion levels (0 µgKg−1 [basic diet, T1], 10 µgKg−1 [T2], 15 µgKg−1 [T3], and 20 µgKg−1 [T4]) for 56 days. After the feeding trial, growth, histological, immunological parameters, and protective immune response against A. hydrophila were assessed. The fish in the treatment groups including T1(control), the T3 growth indices, such as specific growth rate (7.56±0.26) and percent weight gain (231.05±3.21), was statistically higher (P < 0.05). In the immunological and oxidative parameters, levels of SOD and catalase decreased in correlation with a rise in the inclusion doses of AgNP in the liver, and a reduction in catalase values was recorded in the gill. With the addition of AgNP, the NBT value was decreased in the gill, and T3 had a considerably larger (P<0.05) value in the liver (0.493±0.02). The kidney of the L. rohita fed AgNP (0 and20 µgKg−1 AgNP) showed expansion through Bowman's gaps, severing of glomeruli with haemorrhage, as well as atrophic spots between its gaps. The liver showed fibrosis, karyolysis, and the removal of the hepatocytes wall. The gill, liver, kidney, and muscle of fish-fed diets supplemented with AgNP, showed that interleukin-8 (IL-8), and cyclooxygenase-2 (COX-2), were up-regulated. Expression was considerably higher in T3 compared with the control. However, the control group that wasn't given AgNP supplemented diet had increased levels of TGF-beta. Additionally, fish on the T3 diet showed much greater post-challenge survival rates (90%). These findings strongly suggest that dietary inclusion of AgNP (at 10 and 15 µgKg−1 feed) enhances growth, health, and protective immune response against A. hydrophila.

The Traditional Chinese Medicine Gedan Jiangya Decoction Alleviates Left Ventricular Hypertrophy via Suppressing the Ras/ERK1/2 Signaling Pathway.

Gedan Jiangya Decoction (GJD), a Chinese herbal medicine composed of six botanical medicines, was designed to treat hypertension (patent published number (CN114246896A)). The overexpression of the ERK (extracellular signal-regulated kinase) signaling pathway is essential in developing left ventricular hypertrophy (LVH). This study aimed to evaluate GJD's effects on LVH in spontaneously hypertensive rats (SHRs) and examine its potential mechanisms on Ras/ERK1/2 pathway regulation. Thirty-five ten-week-old SHRs were randomly assigned to one of five groups: GJD low dosage, medium dose, high dose, model, and captopril. Wistar-Kyoto (WKY) rats served as the control group. All rats received a 6-week treatment. The following parameters were measured: systolic (SBP) and diastolic blood pressure (DBP), left ventricular mass index (LVMI), and serum TGF-beta1. The pathologic structure was determined by H & E staining and Masson. TGF-beta1, Ras, ERK1/2, and C-Fos levels were determined using western blotting and real-time qPCR. SBP, DBP, and LVMI were reduced significantly in the GJD group compared with the model group. GJD inhibited TGF-beta1, Ras, ERK1/2, and C-Fos expression in LVH. In conclusion, GJD reduced the Ras/ERK1/2 pathway expression, which decreased hypertension-induced heart hypertrophy. GJD may protect hypertension-induced myocardial hypertrophy by altering gene expression patterns in the heart.

Prediction of prognosis, immune infiltration and immunotherapy response with N6-methyladenosine-related lncRNA clustering patterns in cervical cancer

LncRNAs and tumor microenvironment (TME) exert an important effect in antitumor immunity. Nonetheless, the role of m6A-related lncRNA clustering patterns in prognosis, TME and immunotherapy of cervical cancer (CC) remains unknown. Here, based on 7 m6A-related prognostic lncRNAs obtained from TCGA-CC dataset, two m6AlncRNA clustering patterns were determined. m6AlncRNA clusterA was characterized by immune cell infiltrates and immune activation. m6AlncRNA clusterB was characterized by enrichment of immune evasion and tumorigenic activation pathways as well as survival and clinical stage disadvantage. Then, principal component analysis algorithms were used to construct m6AlncRNAscore based on prognostic differentially expressed genes between two m6AlncRNA clusters to quantify m6AlncRNA clustering patterns. m6AlncRNAscore was an independent prognostic protective factor. Higher Th2 and Treg cells and enrichment of immunosuppressive pathways were observed in the low-m6AlncRNAscore group, with poorer survival. High-m6AlncRNAscore was characterized by increased infiltration of activated CD8 T cell, enrichment of immune activation pathways, lower IL-10 and TGF-beta1 levels, and higher immunophenscore values, indicating inflamed TME and better anti-tumor immunotherapy efficacy. Quantitative Real-Time Polymerase Chain Reaction was used for detection of m6A-related prognostic lncRNAs. Collectively, we identified two m6AlncRNA clustering patterns which play a nonnegligible role in the prognosis, TME heterogeneity and immunotherapy of CC patients.

Cytokines Profile and Lung Function in Children with Obesity and Asthma: A Case Control Study.

The existence of common inflammatory biomarkers linking obesity and asthma in children has been hypothesized. Nevertheless, laboratory and clinical characteristics of children with obesity and asthma are still poorly defined. The primary aim of the present study is to investigate the lung function and the cytokine profile, in children with obesity and asthma. In this prospective, cross-sectional pilot study, pulmonary function tests, biochemical parameters, and serum cytokines levels were compared in three groups of 28 children each, matched for age and sex. Obese children showed normal forced spirometry values except an increased distal airway resistance in subjects with obesity and no asthma. Both groups including obese children showed higher leptin and IL-10 levels and lower adiponectin and TNF-alpha levels compared to children with no obesity and asthma. IL-33 and TGF-beta1 levels were higher in children with obesity and asthma vs. children with normal weight and asthma. Finally, IL-6 was undetectable in approximately 70% of obese children with no asthma, in 57% obese asthmatic children and in 100% of children with normal-weight and asthma. Children with obesity and asthma show the most striking cytokine profile, suggesting a pro-inflammatory role of fat mass in asthma development.