Levels Of PDGF-BB Research Articles

Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology

IntroductionDocumented Duchenne Muscular Dystrophy (DMD) biomarkers are confined to Caucasians and are poor indicators of cognitive difficulties and neuropsychological alterations. Materials and methodsThis study correlates serum protein signatures with cognitive performance in DMD patients of South Asian origin. Study included 25 DMD patients aged 6–16 years. Cognitive profiles were assessed by Wechsler Intelligence Scale for Children. Serum proteome profiling of 1317 proteins was performed in eight DMD patients and eight age-matched healthy volunteers. ResultsAmong the several novel observations we report, better cognitive performance in DMD was associated with increased serum levels of MMP9 and FN1 but decreased Siglec-3, C4b, and C3b. Worse cognitive performance was associated with increased serum levels of LDH-H1 and PDGF-BB but reduced GDF-11, MMP12, TPSB2, and G1B. Secondly, better cognitive performance in Processing Speed (PSI) and Perceptual Reasoning (PRI) domains was associated with intact Dp116, Dp140, and Dp71 dystrophin isoforms while better performance in Verbal Comprehension (VCI) and Working Memory (WMI) domains was associated with intact Dp116 and Dp140 isoforms. Finally, functional pathways shared with Alzheimer's Disease (AD) point towards an astrocyte-centric model for DMD. ConclusionAstrocytic dysfunction leading to synaptic dysfunction reported previously in AD may be a common pathogenic mechanism underlying both AD and DMD, linking protein alterations to cognitive impairment. This new insight may pave the path towards novel therapeutic approaches targeting reactive astrocytes.

The Concentration of Pro- and Antiangiogenic Factors in Saliva and Gingival Crevicular Fluid Compared to Plasma in Patients with Peripheral Artery Disease and Type 2 Diabetes.

Several studies have investigated various biomarkers in relation to peripheral artery disease (PAD) for disease stratification and early-onset detection. In PAD, angiogenesis is required for tissue restoration and tissue perfusion. Considering changes in angiogenesis in patients with PAD, angiogenic factors could be explored as one of the new prognostic molecules. In recent studies, saliva and gingival crevicular fluid (GCF) have gained recognition as new, easily obtained diagnostic materials. This study aimed to compare the levels of selected circulating angiogenic factors (VEGF-A, PDGF-BB, and ANG-1) in unstimulated whole saliva (WS) and GCF versus plasma at three points in time to find possible correlations between their concentrations among patients with PAD and diabetes type 2 in 32 patients with Rutherford stages 5 and 6. A significant positive correlation has been demonstrated between circulating PDGF-BB levels in GCF and plasma. In most cases, comorbidities do not have an impact on the change in general correlation for the whole group. Our results clearly showed that GCF could be a good source for PDGF assessment. However, future studies with a larger number of subjects are warranted to confirm this finding and identify the most accurate angiogenic biomarkers in saliva or GCF that could be applied in clinical practice.

Evaluation of Endothelial Progenitor Cell Characteristics as Clinical Biomarkers for Elderly Patients with Ischaemic Stroke.

Ageing impairs endothelial function and predisposes the person to ischaemic stroke (IS). Endothelial progenitor cells (EPCs) repair endothelial damage and induce post-ischaemic neovascularisation. Given the prevalence of IS in older population, this study explored whether changes in EPC number and function may reliably predict the type or outcome of stroke in patients ≥ 65years of age. For this, blood samples were collected once from healthy volunteers (HVs, n = 40) and four times (admission and days 7, 30 and 90 post-stroke) from participants with lacunar (n = 38) or cortical (n = 43) stroke. EPCs were counted with flow cytometry and defined as non-haematopoietic cells (CD45-) expressing markers for stemness (CD34 +), immaturity (CD133 +) and endothelial maturity (KDR +). Clonogenesis, tubulogenesis, migration and proliferation assays were performed as measures of EPC functionality. Biochemical profile of plasma inflammatory and angiogenic agents were studied using specific ELISAs. Primary outcome was disability or dependence on day 90 post-stroke, assessed by the modified Rankin Scale (mRS). Compared to HVs, EPC numbers were higher in stroke patients at all time points studied, reaching significance at baseline and day 30. No differences in EPC counts and functionality were observed between lacunar and cortical stroke groups at any time. Plasma endostatin, PDGF-BB, TNF-α and VEGF levels were higher in stroke patients vs HVs. Patient outcome, evaluated by mRS on day 90 post-stroke, did not correlate with EPC count or functionality. Baseline EPC counts may serve as a diagnostic marker for stroke but fail to distinguish between different stroke subtypes and predict post-stroke outcome.

72P Correlation of serum cytokine patterns and clinicopathological factors in breast carcinoma patients

Recent evidence support that the immune system has both positive and negative effects on tumorigenesis. Systemic inflammation has been linked to aggressive tumor growth, metastasis, and drug resistance in breast cancer (BC) patients. Therefore, serum cytokines (SC) may represent an exciting biomarker in the monitoring of BC pathogenesis. Pretreatment serum from 204 BC patients (23% Luminal A, 23.6% Luminal B/HER2-, 22.5% Luminal B/HER2+, 10.3% HER2-enriched, and 20.6% Triple-Negative/Basal-like -TNBL-) and 50 healthy donors was collected. Measurement of 62 SC was performed using LEGENDplex immunoassay. Fluorescence intensity was quantified by flow cytometry. The results were correlated with age, tumor size and grade, vascular invasion, necrosis, phenotype, tumor-infiltrating lymphocytes, lymph node status, and Ki67. Statistical analysis was done by Student’s t-test and Mann–Whitney U test. BC patients showed higher levels of SCF, MIP3α, EPO and 4-1BB but lower levels of IL-2RA, IL-8, IL-12p40, IL-18, IL-23, IL-27, PDGF-AA, Galectin 9, PDGF-BB, B7.2, MIP1β and PD1, compared to the healthy group. Furthermore, IL-23, IL-27, and EPO correlated with younger age (p≤0.041), in contrast to Galectin 9, MCP1, IL-2RA, and MIP1β (p≤0.003). IL-12p40 and IFNγ were elevated in cases with grade I tumors (p≤0.05) and, in addition to IL-11 and IL-27 in low Ki67 tumors (p≤0.030). Moreover, IL-12p40 and IL-23 were associated with positive lymph nodes (p≤0.031). In Luminal tumors, we detected high IL-12p40, IL-15, IL-23, IL-27, and IFNγ (p≤0.048). However, only PDGF-BB was seen in non-Luminal tumor patients (p=0.040). IL-12p40, IL-18, IL-23, IL-27, SCF, and EPO were mainly higher in Luminal A, while PDGF-AA in Luminal B/HER2-. Likewise, MIP1β, MIP3α, and EPO were elevated in Luminal B/HER2+ serum, whereas Galectin9, PDGF-BB, IL-2RA, B7.2, SCF, 4-1BB, and PD1 were found in TNBL, with no specific profile for HER2-enriched. Our results showed specific serum profiles of SC among BC phenotypes. Moreover, IL-12p40 and IL-23 were correlated with lymph node involvement in Luminal tumors, especially in Luminal A.

Epicatechin gallate promotes vascularization in co-culture of human osteoblasts and outgrowth endothelial cells.

Prevascularization is crucial for the survival of tissue-engineered bone and further bone repair/regeneration. Since epicatechin gallate (ECG), the most abundant flavanol in green tea, shows potential beneficial effects on endothelial cells and bone cells, we decided to investigate whether it promotes vascularization/angiogenesis and osteogenesis using a co-culture system containing human primary osteoblasts (POBs) and outgrowth endothelial cells (OECs). We found that treatment with ECG (1) significantly enhanced microvessel formation in co-culture of POB and OECs, (2) improved cell viability/proliferation and the angiogenic/osteogenic capacities of OEC/POBs, (3) significantly increased the levels of E-selectin, IL-6, TNF-α, IFN-γ, VEGF, and PDGF-BB in co-cultures of POB and OEC, and (4) upregulated HIF-1α, HIF-2α, NF-κB, iNOS, GLUT1, VEGF, and Ang1/2 but downregulated PHD1 in monocultures of OEC or POB. Our findings demonstrate that ECG promotes angiogenesis and osteogenesis (probably via HIF signaling) in co-cultures of OECs and POBs. ECG thus has potential applications in the promotion of angiogenesis/vascularization in many tissue constructs including those of bone.

Comparisons of Cytokines, Growth Factors and Clinical Efficacy between Platelet-Rich Plasma and Autologous Conditioned Serum for Knee Osteoarthritis Management

This study aimed to directly compare the contents and the clinical efficacy of the two autologous blood-derived products, platelet-rich plasma (PRP) and autologous conditioned serum (ACS) for osteoarthritis (OA) treatment. The contents of standard-prepared PRP and ACS prepared at 37 °C for 1 h, 3 h, 6 h, and 24 h from healthy volunteers were compared. The clinical efficacy of pain relief in patients with Stage III knee OA was evaluated by a patient-reported visual analog scale (VAS) pain rating. PDGF-BB levels in ACS 1 h were significantly higher than those in PRP, and the levels in ACS preparations remained stable. IGF-1 level of ACS 24 h showed a significant increase compared to those of other ACS preparations and PRP. ACS 3 h showed a turning of IL-1Ra level and revealed a time-dependent increase up to 24 h. ACS 6 h showed a turning increase in TNF-α levels. ACS 3 h was chosen for clinical comparison with PRP. The reduction in pain VAS in the ACS group was significantly more compared to those of the PRP group (p = 0.028). However, PRP showed significant earlier improvement (p < 0.001). Conclusion: ACS contained higher levels of PDGF-BB and IL-1Ra and provided better improvement in pain relief compared to PRP.

Prognostic prediction of subjective cognitive decline in major depressive disorder based on immune biomarkers: a prospective observational study

ObjectiveSubjective cognitive decline (SCD) is highlighted in patients with major depressive disorder (MDD), which impairs objective cognitive performance and worsens the clinical outcomes. Immune dysregulation is supposed to be the potential mechanism of cognitive impairment. However, the peripheral immune biomarkers in patients troubled with MDD and SCD are not conventionally described.MethodsA prospective-observational study was conducted for 8 weeks. Subjective cognitive function was measured using the Chinese version of the 20-item perceived deficits questionnaire-depression (PDQ-D) and depression symptoms were evaluated with Hamilton Depression Rating Scale-17 (HDRS-17). Luminex assays were used to measure 48 immune cytokines in plasma at baseline. Integrating these results and clinicopathological features, a logistic regression model was used to develop a prognostic prediction.ResultsTotally, 114 patients were enrolled in this study. Among the patients who completed follow-up, 56% (N = 50) had residual subjective cognitive decline, and 44% (N = 50) did not. The plasma levels of FGF basic, INF-γ, IL-1β, MCP-1, M-CSF and SCF were increased and the levels of IL-9, RANTES and PDGF-BB were decreased in the SCD group. Additionally, Basic FGF, IFN-γ, IL-1β, and SCF were positively correlated and IL-9, RANTES, and PDGF-BB were negatively correlated with the PDQ-D scores after treatment. Notably, combinations of cytokines (SCF and PDGF-BB) and PDQ-D scores at baseline showed good performance (The area under the receiver operating characteristic curve = 0.818) in the prediction of subjective cognitive decline.ConclusionA prognostic model based on protein concentrations of SCF, PDGF-BB, and scores of PDQ-D showed considerable accuracy in predicting residual subjective cognitive decline in depression.

Hysteroscopic injections of autologous endometrial cells and platelet-rich plasma in patients with thin endometrium: a pilot randomized study

The aim of this study was to evaluate the efficacy of hysteroscopically controlled injections of autologous platelet-rich plasma (PRP) and autologous endometrial cells as a treatment for infertile women with thin endometrium. The study enrolled 115 patients with thin endometrium (< 7 mm at implantation window) and infertility, who were divided into groups: Group 1 (the control) underwent conservative therapy; Group 2 received intraendometrial PRP injections instead of the conservative therapy; Group 3 received identical injections after conservative therapy; Group 4 received injections of the autologous endometrial cells suspended in PRP. A single injection dose of PRP contained 0.6–0.7 × 1011 of platelets. The levels of PDGF-BB and VEGF in PRP were increased compared with ordinary plasma. The autologous endometrial cells, obtained from pipelle biopsies, constituted heterogeneous cell populations containing stromal and epithelial cells. Intraendometrial PRP injections had significant impact on endometrial thickness and local microcirculation in Group 2 and Group 3. In Group 4, injections of PRP reinforced with endometrial cells also facilitated a significant increase in endometrial thickness. This work describes a novel approach for infertility treatment in patients with refractory thin endometrium. PRP injections and injections of the endometrial cells suspended in PRP into endometrium enhanced cell proliferation and angiogenesis.

Immunobiochemical profile of clear cell renal cell carcinoma (ccRCC): A preliminary study.

Clear cell renal cell carcinoma (ccRCC) is the most common variant of RCC. It is an aggressive disease with an unfavorable prognosis. The rich immune infiltrates present in the tumor microenvironment (TME) of ccRCC produce various signaling molecules, especially cytokines, which primarily activate the Jak/STAT pathway and significantly influence tumor pathogenesis. STAT3 has a well-defined oncogenic character. Using multiplex assays and ELISA, we have measured the concentrations of 27 cytokines and STAT3 in tumor and healthy renal tissue from 16 patients with histologically verified ccRCC. We have detected significantly higher levels of G-CSF, IL-6, CXCL10, CCL3, and CCL4 in tumor tissue than in their healthy counterparts. There were significant differences in the levels of IL-1β and PDGF-BB between tumors of different nuclear grades (NG). Intratumoral IL-12p70 and IL-15 showed a significant positive correlation with intratumoral STAT3. The concentration of STAT3 in tumors was significantly lower than in the kidney. An increase in tumor STAT3 levels was associated with an increase in the pathological stage of the disease (TNM), but not with NG. The results of our study confirm the significant role of various cytokines and STAT3 in the pathogenesis of ccRCC and indicate their clinical relevance.

Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes

Age-related macular degeneration (AMD) has been implicated as a risk factor for severe consequences from COVID-19. We evaluated the genetic architecture shared between AMD and COVID-19 (critical illness, hospitalization, and infections) using analyses of genetic correlations and pleiotropy (i.e., cross-phenotype meta-analysis) of AMD (n = 33,976) and COVID-19 (n ≥ 1,388,342) and subsequent analyses including expression quantitative trait locus (eQTL), differential gene expression, and Mendelian randomization (MR). We observed a significant genetic correlation between AMD and COVID-19 infection (rG = 0.10, p = 0.02) and identified novel genome-wide significant associations near PDGFB (best SNP: rs130651; p = 2.4 × 10-8) in the pleiotropy analysis of the two diseases. The disease-risk allele of rs130651 was significantly associated with increased gene expression levels of PDGFB in multiple tissues (best eQTL p = 1.8 × 10-11 in whole blood) and immune cells (best eQTL p = 7.1 × 10-20 in T-cells). PDGFB expression was observed to be higher in AMD cases than AMD controls {fold change (FC) = 1.02; p = 0.067}, as well as in the peak COVID-19 symptom stage (11-20 days after the symptom onset) compared to early/progressive stage (0-10 days) among COVID-19 patients over age 40 (FC = 2.17; p = 0.03) and age 50 (FC = 2.15; p = 0.04). Our MR analysis found that the liability of AMD risk derived from complement system dysfunction {OR (95% CI); hospitalization = 1.02 (1.01-1.03), infection = 1.02 (1.01-1.03) and increased levels of serum cytokine PDGF-BB {β (95% CI); critical illness = 0.07 (0.02-0.11)} are significantly associated with COVID-19 outcomes. Our study demonstrated that the liability of AMD is associated with an increased risk of COVID-19, and PDGFB may be responsible for the severe COVID-19 outcomes among AMD patients.

Translational perspective on bone-derived cytokines in inter-organ communications

Translational perspective on bone-derived cytokines in inter-organ communications

Biochemical factors in the blood serum of neuroendocrine tumor patients with carcinoid syndrome

Introduction. Carcinoid syndrome is the most common functional syndrome in patients with neuroendocrine tumors. More than 40 biochemical factors are responsible for the manifestation of carcinoid syndrome, among which serotonin is the most important. The study of biochemical markers of carcinoid syndrome and associated carcinoid heart disease is an important aim of laboratory examination in neuroendocrine tumors patients.Aim. Analysis of levels and diagnostic efficiency evaluation of chromogranin A (CgA), serotonin, pro-brain natriuretic peptide (proBNP) and platelet-derived growth factor (PDGF-BB) in the blood serum of neuroendocrine tumors patients with various clinical manifestations, including carcinoid syndrome and carcinoid heart disease.Materials and methods. 66 patients with neuroendocrine tumors of various localizations were examined (pancreas – 24 cases, small intestine – 21, large intestine – 6, lungs – 10, unkown primary focus – 5). 38 patients had liver metastases. In 43 patients, a clinic of carcinoid syndrome was observed, 16 had signs of carcinoid heart disease. The control group consisted of 30 practically healthy people. Serum levels of CgA, serotonin, and PDGF-BB were determined by enzyme immunoassay in microplate format: Chromogranin A NEOLISA (Eurodiagnostica, Sweden), Serotonin ELISA (IBL, German), and PDGF-BB ELISA Kit (Invitrogen, USA). The proBNP analysis was performed on a Cobas e601 automated analyzer (Roche, Switzerland).Results. In carcinoid syndrome, the medians of CgA, serotonin, and proBNP were the highest, differing statistically significantly from the control group. In patients with G3 tumors, the median PDGF-BB was statistically significantly higher than in controls, in contrast to G1 and G2. The highest diagnostic sensitivity in the general neuroendocrine tumors group was in CgA – 63.6 %, with a specificity of 100 %. In patients with carcinoid syndrome, the highest diagnostic sensitivity was characteristic of serotonin and chromogranin A (79 %), while in patients with CAD clinic, proBNP had the highest sensitivity – 93.8 %.Conclusion. The study revealed the high efficiency of СgA, with the highest sensitivity in common forms and tumors with high biological activity. Serotonin can be used in the diagnosis of carcinoid syndrome, associated with cardiofibrosis development. Pro-brain natriuretic peptide is a highly sensitive and specific marker of carcinoid heart disease. The highest levels of PDGF-BB are associated with a high grade of neuroendocrine tumors malignancy.

Adiponectin Contributes to the Inflammatory Milieu in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a severe chronic skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokine dysregulation is crucial in HS severity and progression. The aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomers in HS patients compared to both obese and healthy subjects. The concentrations of adiponectin and cytokines were measured using enzyme-linked immunosorbent assay (ELISA); the oligomeric distribution of adiponectin (low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers)was evaluated through Western Blotting analysis. Total adiponectin is statistically higher in HS patients compared to matched controls and obese subjects. Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1β, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFγ, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13. Our data confirmed that the complex network that links metabolism to immune homeostasis is dysregulated in HS and that adiponectin and its HMW oligomers are actively involved in this disease. In addition, the correlation between adiponectin and PDGF-BB, and IL-13 extends the role of this adipokine in modulation of the immune response, in particular regulating the innate immune system rather that the adaptive one. Further researches are needed to clarify the complex inflammatory milieu that characterizes HS syndrome.

Long-term effect of childhood trauma: Role of inflammation and white matter in mood disorders

Bipolar disorder (BD) and major depressive disorder (MDD) are severe psychiatric illnesses that share among their environmental risk factors the exposure to adverse childhood experiences (ACE). Exposure to ACE has been associated with long-term changes in brain structure and the immune response. In the lasts decades, brain abnormalities including alterations of white matter (WM) microstructure and higher levels of peripheral immune/inflammatory markers have been reported in BD and MDD and an association between inflammation and WM microstructure has been shown. However, differences in these measures have been reported by comparing the two diagnostic groups. The aim of the present study was to investigate the interplay between ACE, inflammation, and WM in BD and MDD. We hypothesize that inflammation will mediate the association between ACE and WM and that this will be different in the two groups. A sample of 200 patients (100 BD, 100 MDD) underwent 3T MRI scan and ACE assessment through Childhood Trauma Questionnaire. A subgroup of 130 patients (75 MDD and 55 BD) underwent blood sampling for the assessment of immune/inflammatory markers. We observed that ACE associated with higher peripheral levels of IL-2, IL-17, bFGF, IFN-γ, TNF-α, CCL3, CCL4, CCL5, and PDGF-BB only in the BD group. Further, higher levels of CCL3 and IL-2 associated with lower FA in BD. ACE were found to differently affect WM microstructure in the two diagnostic groups and to be negatively associated with FA and AD in BD patients. Mediation analyses showed a significant indirect effect of ACE on WM microstructure mediated by IL-2. Our findings suggest that inflammation may mediate the detrimental effect of early experiences on brain structure and different mechanisms underlying brain alterations in BD and MDD.

Pro-Inflammatory Profile of Children Exposed to Maternal Chikungunya Virus Infection during the Intrauterine Period: A One-Year Follow-Up Study.

Chikungunya virus (CHIKV) vertical transmission occurs due to maternal viremia in the prepartum. Clinical presentation in neonates can be varied; however, the consequences of intrauterine exposure on the immune response are unclear. Thus, we aimed to analyze inflammatory alterations in children exposed to maternal CHIKV infection. This is a cross-sectional study that included children exposed to maternal CHIKV infection (confirmed by RT-qPCR and/or IgM). Circulant immune mediators were analyzed by a multiplex assay. RESULTS: We included 33 children, with a mean age of 3 ± 2.9 months-old, and 19 (57.6%) were male. Only one child presented neurological alterations. CHIKV-exposed infants showed elevated levels of MIP-1α, MIP-1β, and CCL-2 (p < 0.05). Pro-inflammatory cytokines such as TNFα, IL-6, and IL-7 (p < 0.0001) were also increased. In addition, lower levels of PDGF-BB and GM-CSF were observed in the same group (p < 0.0001). Principal component (PC) analysis highlighted a distinction in the inflammatory profile between groups, where PC explained 56.6% of the alterations. Our findings suggest that maternal exposure to CHIKV can affect the circulating levels of pro-inflammatory cytokines during the infants’ first year of life. The long-term clinical consequences of these findings should be investigated.

Ataxia telangiectasia mutated: The potential negative regulator in platelet-derived growth factor-BB promoted proliferation of pulmonary arterial smooth muscle cells.

ObjectiveTo study the role of ataxia telangiectasia mutated (ATM) in the platelet-derived growth factor (PDGF)-BB-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs) through reactive oxygen species (ROS) formation.MethodsPrimary cultures of PASMCs were treated with different concentrations of PDGF-BB or exogenous hydrogen peroxide (H2O2). The activation level of ATM and the proliferation level of PASMCs were measured by immunofluorescence staining and Cell Counting Kit-8, respectively. Moreover, NADPH oxidase 2 (NOX2) and intracellular H2O2 were detected under the stimulation of different levels of PDGF-BB by Western blot and dihydroethidium staining.ResultsBoth the control group and 50 ng/ml of the PDGF-BB group showed significantly higher levels of phosphorylation ATM compared to other groups (P < 0.05). With the ATM inhibitor, 50 ng/ml of the PDGF-BB group showed further increased proliferative level compared to the 10 ng/ml (P < 0.05). Both the levels of NOX2 and H2O2 showed dose-dependent manners under PDGF-BB stimulation (P < 0.05). ATM could be activated by H2O2 upon a dose-dependent way, except for the 500 μM H2O2 group. Under 200 μM H2O2 stimulation, proliferation level decreased significantly (P < 0.05), while no significant difference was shown with the addition of ATM inhibitor (P > 0.05).ConclusionOur study first established ROS-induced ATM activation in PDGF-BB-stimulated proliferation of PASMCs. Inhibition of ATM had promoted effects on the proliferation of PASMCs under the excessive levels of PDGF-BB and H2O2. Our study might provide a novel promising target for the treatment of pulmonary arterial hypertension (PAH).

Pimitespib, an HSP90 inhibitor, augments nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop in rats with bleomycin-challenged lungs: Evolutionary perspective in managing pulmonary fibrosis

Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-β. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis.

Promotion of angiogenesis in vitro by Astragalus polysaccharide via activation of TLR4 signaling pathway.

During the implantation of functional tissue-engineered constructs for treating bone defects, a functional vascular network is critical for the survival of the construct. One strategy to achieve rapid angiogenesis for this application is the co-culture of outgrowth endothelial cells (OECs) and primary human osteoblasts (POBs) within a scaffold prior to implantation. In the present study, we aim to investigate whether Astragalus polysaccharide (APS) promotes angiogenesis or vascularization via the TLR4 signaling pathway in a co-culture of OECs and POBs. The co-cultures were treated with various concentrations of APS for 24 h and, subsequently, another 7 days, followed by CD31 staining and analysis of micro-vessel-formation areas using software. Additionally, APS (0.4mg/ml for 24 h) was added to monocultures of OECs or POBs for evaluating proliferation, apoptosis, angiogenesis, osteogenesis, TLR4 signaling pathway, and inflammatory cytokine release. We found that APS promoted angiogenesis in the co-culture at the optimal concentration of 0.4mg/ml. TLR4 activation by APS up-regulated the expression level of TLR4/MyD88 and enhanced angiogenesis and osteogenesis in monocultures of OECs and POBs. The levels of E-selectin adhesion molecules, three cytokines (IL-6, TNF-α, and IFN-γ), and VEGF and PDGF-BB, which can induce angiogenesis, increased significantly (p < .05) following APS treatment. Therefore, APS appears to promote angiogenesis and ossification in the co-culture system via the TLR4 signaling pathway. PRACTICAL APPLICATIONS: This study demonstrates that APS may promote angiogenesis and osteocyte proliferation in OEC and POB co-culture systems through the MyD88-dependent TLR4 signaling pathway. APS might represent a potential therapeutic strategy in tissue-engineered bone implantation for the treatment of large bone defects; additionally, it has the advantage of safety, as it exhibits low or no side effects. In the future, it is expected to be used in vitro for the construction of tissue-engineered bone and in vivo after implantation in patients with bone defects for promoting rapid vascularization and ossification of tissue-engineered bone and early fusion with the recipient's bone. In addition, as a food additive, Astragalus membranaceus can be used as a tonic material in patients recovering from a fracture for promoting blood-vessel formation at the fracture site and fracture recovery. Combining traditional Chinese medicine with tissue engineering can provide further strategies for promoting the development of regenerative medicine.

Influence of periodontitis and diabetes on structure and cytokine content of platelet-rich fibrin.

Platelet-rich fibrin (PRF) is a second-generation platelet concentrate with multiple applications in wound healing and regeneration in both periodontitis and diabetes. However, the three dimensional (3-D) structure and cytokine content of PRF might be altered in patients suffering from either/both of the chronic inflammatory conditions, ultimately influencing the efficacy of PRF as a biomaterial for regenerative medicine. The aim of the present study was hence to evaluate the effect of both these chronic inflammatory diseases on the 3-D structure of PRF membrane. An attempt was also made to compare the growth factor content between the plasma and RBC ends of the prepared PRF gel. L-PRF was prepared for twenty participants, healthy (5), periodontitis (5), T2DM (5) and T2DM with periodontitis (5). Porosity and fiber diameter of PRF membranes was visualized under FE-SEM and measured using ImageJ Software. PDGF-BB and TGF-β1 levels in PRF gel were assessed by ELISA. The average diameter of fibrin fibers under FE-SEM was 0.15 to 0.30 micrometers. Porosity was higher at the plasma end (p = 0.042). Red blood cell (RBC) end of the membrane had thinner fibers arranged in a comparatively more dense and compact structure with smaller porosities. Healthy subjects had the least porous PRF compared to subjects with either/both of the chronic conditions. PDGF-BB levels were similar along all the four groups. TGF-β1 levels were highest in healthy subjects. 3-D structure and growth factor content of PRF are influenced by a person's periodontal and/or diabetic status. The RBC end of the PRF membrane, as compared to the plasma end, has thinner fibers arranged in a comparatively more dense and compact structure with smaller porosities, and hence should be favored during periodontal regenerative procedures. Both periodontitis and diabetes have a significant influence on the 3-D structure and growth factor content of PRF produced.

Analysis of hepatic fibrosis markers in the serum of chronic hepatitis B patients according to basal core promoter/precore mutants

The A1762T/G1764A double mutant in the basal core promoter (BCP) region of the hepatitis B virus (HBV) is associated with severe hepatic lesions while the G1899A mutation with the double mutant is associated with a significant reduction in the risk of severe fibrosis. This study aims to measure a number of markers in the serum of patients with chronic HBV infection and to assess relationships between these markers and BCP/precore mutants with consideration of the stage of fibrosis. The serum levels of resistin, TGF-β1, MMP-1, TIMP-1, collagen IA1 and PDGF-BB, which are markers that are known to be involved in the process of hepatic fibrosis, were assayed. The serum levels of PDGF-BB and TIMP-1, and the mutation profile were independently associated with advanced fibrosis. A higher level of TIMP-1 was associated with advanced fibrosis regardless of the mutation status, and a higher level of PDGF-BB was associated with nonsevere fibrosis in patients infected with viruses harboring the A1762T/G1764A or A1762T/G1764A/G1899A mutations. Our results suggest an impact of the A1762T/G1764A mutant on the biological pathway related to TGF-β1 and PDGF-BB. In vitro studies are needed to understand the impact of these mutants on the serum secretion of markers involved in fibrosis severity.