Plasma TGF-β1 Research Articles

Features of laboratory indicators of severe community-acquired pneumonia.

Based on data from the prospective analysis of patients with severe community-acquired pneumonia over the year of observation, the article presents data on the features of laboratory indicators of the course of severe community-acquired pneumonia. Patients included in the study were hospitalized in the pulmonology department (or therapy), and in the intensive care unit of three clinical hospitals in the city of Dnipro, namely, the Dnipropetrovsk City Clinical Hospital N 6, the Dnipropetrovsk City Clinical Hospital N 2, the Dnipropetrovsk City Clinical Hospital N 16, which are the clinical bases of the SE “Dnipropetrovsk medical academy of Health Ministry of Ukraine”. In the course of studies, the dependence of the severity of patients' state on the severity of inflammatory markers and fibrosis markers was shown. The effect of the prognostic significance of the level of the enzyme TGFβ and C-reactive protein (CRP) for the evaluation of possibility of formation of long-term pathological changes after a severe community-acquired pneumonia has been examined. It was established that a high level of CRP (38.3 [11.3, 150.9] mg / L) and TGFβ (20149.1±424.0 pg/ml) in the blood plasma of patients can be considered as an additional marker of the severity of the course of community-acquired pneumonia. The results can be the basis for a more individual approach to the development of diagnostic and therapeutic programs for patients with severe community-acquired pneumonia

Circulating blood levels of IL-6, IFN-\u03b3, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study

BackgroundGastric adenocarcinoma is the third most common cause of cancer-associated death worldwide. Helicobacter pylori infection activates a signaling cascade that induces production of cytokines and chemokines involved in the chronic inflammatory response that drives carcinogenesis. We evaluated circulating cytokines and chemokines as potential diagnostic biomarkers for gastric cancer.MethodsWe included 201 healthy controls and 162 patients with distal gastric cancer who underwent primary surgical resection between 2009 and 2012 in Mexico City. The clinical and pathological data of patients were recorded by questionnaire, and the cancer subtype was classified as intestinal or diffuse. Pathological staging of cancer was based on the tumor–node–metastasis staging system of the International Union Against Cancer. Concentrations of IL-1β, IL-6, TNF-α, IL-10, and MCP-1 in serum were measured using multiplex analyte profiling technology and concentrations of IL-8, IFN-γ, and TGF-β in plasma were measured using enzyme-linked immunosorbent assay.ResultsLevels of IL-1β, IL-6, IFN-γ, and IL-10 were significantly higher and that of MCP-1 was lower in gastric cancer patients compared with controls. No differences in IL-8 or TNF-α levels were observed between gastric cancer and controls. IFN-γ and IL-10 were significantly higher in both intestinal and diffuse gastric cancer, whereas IL-1β and IL-6 were higher and TGF-β lower only in intestinal gastric cancer; MCP-1 was lower only in diffuse gastric cancer. IFN-γ and IL-10 levels were significantly higher in early (I/II) and late stage (III/IV) gastric cancer; IL-1β and IL-8 were higher and MCP-1 was lower only in late stage (IV) patients. Receiver-operating characteristic analysis showed that for diagnosis of GC, IL-6 had high specificity (0.97) and low sensitivity (0.39), IL-10 had moderate specificity (0.82) and low sensitivity (0.48), and IL-1β and IFN-γ showed low specificity (0.43 and 0.53, respectively) and moderate sensitivity (0.76 and 0.71, respectively).ConclusionsIncreased levels of IL-6, IFN-γ, and IL-10 might be useful as diagnostic biomarkers for GC; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. IL-1β, IL-6, MCP-1, and TGF-β differentiate intestinal from diffuse GC. IFN-γ and IL-10 might be useful for diagnosis of early stage GC, and IL-1β, IL-8, and MCP-1 for late stages of the disease.

Elevated Plasma Transforming Growth Factor β1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study.

Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine. There is growing evidence that TGF-β1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-β1 induced vascular hypertrophy and remodelling in various vascular diseases, there are no longitudinal data on hypertension in the epidemiological studies. The present study tested the hypothesis whether elevated TGF-β1 levels can predict the development of hypertension. In 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. We examined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-β1 were obtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-β1 levels were significantly associated with the development of hypertension after adjustment for confounding factors. To further examine the association between them, we performed logistic regression analysis. We divided the baseline plasma TGF-β1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582 (95% confidence interval, 1.025-12.525)] for the development of hypertension was found in the highest group of TGF-β1 level vs. the lowest group after adjustment for confounders. This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-β1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese.

Ethyl pyruvate alleviates radiation-induced lung injury in mice

ObjectiveRadiation-induced lung injury (RILI) is a common complication of thoracic cancer radiation therapy. Ethyl pyruvate (EP) was reported to have an ameliorating effect on a variety of systemic inflammation reactions, including acute lung injury. However, the protective effect of EP on RILI has not been explored. Materials/MethodsRILI was induced by a single thoracic irradiation of 16Gy X-rays in C57BL/6 mice. Mice were divided into four groups: control, radiation, 100mg/kg EP, and 200mg/kg dexamethasone. Inflammation and fibrosis grade of lung tissue were scored by H&E and Masson's trichrome staining. Cytokines include IL-1β, IL-6, TNF-α, GM-CSF, M-CSF, TGF-β1, and HMGB1 were measured after irradiation. Colony formation assay was performed to determine the protective effect of EP in RAW264.7 and HBE cells. The effect of EP on HMGB1 was also explored in vitro. ResultThe cytoplasm of bronchial epithelium cells in mice was positive-stained of HMGB1 accompanying with an increase of HMGB1, IL-6, IL-1β, GM-CSF, M-CSF, TNF-α, and TGF-β1 after irradiation. EP prescription significantly reduced pulmonary inflammation infiltration of RILI, along with a decrease of HMGB1, IL-6, IL-1β, and GM-CSF at 4 weeks after irradiation. Furthermore, EP decreased radiation-induced collagen deposition at 20 weeks after irradiation. Pro-fibrotic cytokines including TGF-β1 and HMGB1 in irradiated lung tissue and plasma obviously decreased in EP administration group in the later stage. In vitro, EP administration protected HBE cells from radiation injury. EP also rescued radiation-induced release but not translocation of HMGB1 in RAW264.7 and HBE cells. ConclusionEP treatment ameliorates RILI, including radiation-induced fibrosis in mice. The inhibition of production and release of pro-inflammatory or fibrotic cytokines, especially HMGB1, may partly attribute to its attenuating RILI effect.

Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors.

3006 Background: M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-β (TGF-β) receptor II, which acts as a TGF-β trap. We report preliminary data from a phase 1 trial of M7824 in patients (pts) with advanced solid tumors. Methods: NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible pts receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. Results: 16 heavily pretreated pts with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, and colitis with associated anemia); there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Conclusions: Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in pts with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. Clinical trial information: NCT02517398.

The study of using cordyceps-astragalus-salvia miltiorrhiza to treat acute lung injury induced by paraquat poisoning in rats

Objective: To study the therapy of cordyceps-astragalus-salvia miltiorrhiza in treating acute lung injury and pulmonary interstitial fibrosis induced by paraquat poisoning. Methods: All 120 adult Wister male rats were randomly assigned to three groups, the paraquat poisoning group (rats were intragastric administration paraquat 50 mg/kg body weight once at the beginning) , the cordyceps-astragalus-salvia miltiorrhiza therapy group (rats were given cordyceps-astragalus-salvia miltiorrhiza 90 mg/kg body weight intragastric administration half an hour after paraquat was given, then the same dose was given once a day) ; control group (rats were intragastric administration with physiological saline) . At 7th, 14th, 21st, and 28th day rats were sacrificed postanesthetic respectively after paraquat exposure, sample of lung tissue, bronchoalveolar lavage (BAL) , and venous blood were collected. GSH, SOD, TNF-α, TGF-β1, and HYP in plasma, bronchoalveolar lavage (BAL) , and the lung homogenates were determined. Optical microscope was performed to examine pathological changes in lung. Results: Each experimental time point paraquat group and the treatment group rats serum SOD content significantly lower than the control group (P<0.05) . Each experimental time point the treatment group rats serum SOD levels increased significantly than that of paraquat group (P<0.05) . Each experimental time point paraquat group rats serum GSH content significantly lower than that of the control group (P<0.05) . Treatment group rats 7 days time GSH content significantly lower than that of the control group (P<0.05) . Treatment group 21 days, 28 days GSH content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rats alveolar lavage SOD content was significantly lower than that of the control group (P<0.05) . Treatment group 7 days, 14 days time SOD content was significantly lower than that of the control group (P<0.05) , Treatment group 21 days, 28 days SOD content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group and the treatment group rats alveolar lavage GSH content significantly were lower than that of the control group (P<0.05) . Treatment group days 14 and 21 days, 28 days GSH content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rats alveolar lavage TNF α levels was higher than that of the control group (P<0.05) . Treatment group 7 days, 14 days the rat alveolar lavage TNF α levels was higher than that of the control group (P<0.05) . Treatment group 21 days, 28 days TNF α content significantly was decreased than that of paraquat group (P<0.05) . Paraquat group days 14 and 21 days, 28 days HYP content was significantly higher than that of control group (P<0.05) . Treatment group 21 days HYP content was significantly higher than that of control group (P<0.05) . Treatment group 28 days time HYP content in lung tissue of rats was significantly decreased than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rat lung tissue (tissue homogenate) TGF-β1 content was higher than that of the control group, the difference was statistically significant (P<0.05) . Under optical microscope, the tissue damage of lung was aggravated, and reduced after cordyceps-astragalus-salvia miltiorrhiza was administrated. Conclusion: Cordyceps-astragalus-salvia miltiorrhiza can reduce inflammation factor releasing, and relieve lung injury. It has therapeutic effect on lung injury induced by paraquat poisoning.

Usefulness of Preoperative Transforming Growth Factor-Beta to Predict New Onset Atrial Fibrillation After Surgical Ventricular Septal Myectomy in Patients With Obstructive Hypertrophic Cardiomyopathy

Postoperative atrial fibrillation (AF) occurs frequently after cardiac surgery and contributes significantly to mortality. Transforming growth factor-beta (TGF-β) is associated with postoperative AF after coronary artery bypass grafting and valve surgery. We performed a prospective study to evaluate the role of TGF-β as a predictor of AF after myectomy. A total of 109 consecutive obstructive hypertrophic cardiomyopathy patients without previous AF who underwent myectomy were identified. We measured plasma TGF-β levels before surgery, monitored heart rhythm until discharge, and followed patients for a mean of 36±10months. AF was documented in 19 patients (17%). AF patients were older (50 ± 10 vs 43 ± 15years, p= 0.037). Patients who developed AF had higher plasma TGF-β levels (1,695 ± 2,011 vs 1,099 ± 2,494 pg/ml, p= 0.011), more major adverse cardiac events (32% vs 7%, p= 0.006), and more strokes (16% vs 0%, p= 0.005) than patients who did not. TGF-β level ≥358 pg/ml predicted AF with sensitivity and specificity of 58% and 77% (p= 0.011), respectively. Higher TGF-β levels were associated with pulmonary hypertension (25% vs 8%, p= 0.033). In multivariable regression analysis, age (odds ratio 1.05, 95% confidence interval 1.00 to 1.11, p= 0.041) and TGF-β levels (odds ratio 2.42, 95% confidence interval 1.30 to 4.50, p= 0.005) predicted AF independently. In conclusion, elevated preoperative TGF-β value is an independent predictor of postoperative AF in hypertrophic cardiomyopathy patients after surgical ventricular septal myectomy.

The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock.

Short-chain fatty acids (SCFAs) with the anti-inflammatory capacity are produced by intestinal bacteria; however, their effect on the acute systematical inflammation remains unclear. This study aimed to investigate the effects of SCFAs, acetate, propionate and butyrate, on septic shock and the underlying mechanism. The LPS-induced septic model was used to evaluate the function of SCFAs by survival rate observation. Only butyrate, but not acetate or propionate, significantly decrease the mortality of septic mice. At 2h and 6h of LPS administration, the levels of TNF-α, IL-6 and IL-1β in plasma were measured by ELISA to estimate the effects of butyrate pretreatment on excessive inflammation. And the anti-inflammatory mediators including TGF-β, IL-10 and LXT4 in plasma were detected for further mechanism study in septic mice. Moreover, the murine macrophage-like RAW 264.7 cells were stimulated by LPS to further confirm the finding invivo. Pretreatment with butyrate led to significant attenuation of the LPS-induced elevation of TNF-α, IL-6 and IL-1β levels. However, when detecting the anti-inflammatory factors, a significant increase in IL-10, but not TGF-β or LXT4, was shown in butyrate-pretreated group. Pretreatment of RAW 264.7 cells with butyrate led to downregulation of LPS-induced pro-inflammatory mediators, IL-6 and IL-1β, but did not affect the level of TNF-α, and increased IL-10 (P<0.01). In conclusion, SCFA butyrate significantly attenuated the inflammation against sepsis through upregulation of anti-inflammatory IL-10.

Platelet-activated serum might have a therapeutic effect on damaged articular cartilage.

Platelet-activated serum (PAS) was collected from rabbits. This contains high concentrations of growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, and transforming growth factor-beta (TGF-β). PAS was injected into the knee joints of Japanese White rabbits subjected to anterior cruciate ligament transection (ACL-T) to investigate its therapeutic effects on articular cartilage. The effect of Avastin (an anti-VEGF monoclonal antibody) on VEGF expression was also investigated. The levels of VEGF, PDGF-BB, and TGF-β in PAS, platelet-rich plasma (PRP) and autologous serum from untreated rabbits were analysed by enzyme-linked immunosorbent assays. The samples (n = 24 rabbits) were divided into control (C), PAS (S), Avastin (A) and PAS + Avastin (S + A) treatment groups. Intra-articular injections were administered weekly for 7 weeks after ACL-T, during which the weight distribution ratios of the damaged limbs were evaluated. Histological evaluation was performed 12 weeks after ACL-T using Mankin score. The VEGF, PDGF-BB and TGF-β expression levels were significantly higher (P < 0.05) in the PAS than in the PRP or autologous serum samples. The weight distribution ratios of damaged limbs improved significantly after ACL-T in all treatment groups (P < 0.05). The proximal medial, distal medial and lateral aspects of joints in the treatment groups showed significant differences in Mankin scores compared with controls (P < 0.05). The damaged limb weight distribution ratios, Mankin scores and articular cartilage structure did not differ significantly among the three treatment groups, which all showed significant improvements in structure compared with controls. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of Acute Confinement Stress-induced Hypothalamic-pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive, and neuroprotective properties. The hypothalamic-pituitary-adrenal axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg intramuscular). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand conditions. Since there were no rearing effects at baseline or for any of the conditions tested—either for cortisol or TGF-β—the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and cerebrospinal fluid cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in cerebrospinal fluid but not in serum. Together, the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occur in the face of hypothalamic-pituitary-adrenal axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompt exploration of protective measures against glucocorticoid-induced neurotoxicity.

Genotype-phenotype association of TGF-β1 and GST with chemo-radiotherapy induced toxicity

Background: Normal �ssue toxicity con�nues to remain as a major challenge for radia�on oncologists for delivering the total dose to the tumour cells in cancer pa�ents. Cellular, molecular and plasma based early biomarkers to predict the overreac�ons and non-overreac�ons of normal �ssue toxicity before the ini�a�on of radiotherapy can be valuable for personalised treatment. The aim of the current study was to analyse the interrela�onship between polymorphisms in Glutathione S- Transferases (GSTs) and Transforming Growth Factor-β1 (TGF-s1), the plasma level/ac�vity of these proteins with the development of chemo-radiotherapy induced oral mucosi�s and skin reac�on in head and neck cancer (HNC) pa�ents. Materials and Methods: We analysed polymorphisms in TGF-β1 and GST by restric�on diges�on of the PCR amplified products and we also assessed circula�ng TGF- β1 levels and GST ac�vity by Enzyme Linked Immunosorbent Assay (ELISA). Results: The results indicate that pre-radiotherapy plasma TGF-β1 levels and total GST ac�vity has no correla�on with radia�on induced normal �ssue skin reac�on and oral mucosi�s in HNC pa�ents. Conclusion: The selected polymorphisms in TGF-β1 and GST had no influence on TGF-β1 levels and total GST ac�vity. Plasma TGF-β1 and GST ac�vity was not affected by the presence of selected polymorphisms and lacks significance in predic�ng skin reac�on and oral mucosi�s prior to chemo-radiotherapy.

The relationship of level of transforming growth factor beta 1 with liver fibrosis in children with congenital diseases of hepatobilliary system.

The article considers results of studying level of transforming growth factor beta 1 (TGF-β1) in blood plasma of children with terminal stage of hepatic failure before and after transplantation of liver. The relationship of level of cytokine with degree of of liver fibrosis is analyzed. It is demonstrated that level of TGF-β1 in blood plasma of children with hepatic failure is lower in comparison with healthy children and depends on degree of severity of liver fibrosis. Thus, level of cytokine in blood of patients is higher under fibrosis severity stage II and III, than under fibrosis of severity stage I and IV. After kindred transplantation of hepatic lobe, level of TGF-β1in blood plasma of patients increases independently of initial degree of severity of fibrosis.

Regulating the Balance of Th17/Treg via Electroacupuncture and Moxibustion: An Ulcerative Colitis Mice Model Based Study.

Aim To investigate the relationship between the effects of electroacupuncture/moxibustion and the balance of Th17/Treg in treating ulcerative colitis (UC) and to preliminary compare the effects of the above two methods. Methods DSS-induced UC mice were treated by electroacupuncture and moxibustion. Disease activity index (DAI) was scored; intestinal pathological structure and ultrastructure were observed. The levels of IL-2, IL-6, IL-10, IL-17A, IL-17F, and TGF-β in plasma were measured by ELISA. The percentages of Treg and Th17 in spleen lymphocytes were analyzed by flow cytometry. Also, the expressions of TLR2, TLR4, RORγt, and FOXP3 in the distal colon were detected by immunohistochemistry or western blot. Results Both electroacupuncture and moxibustion can relieve UC. These effects are further supported by ELISA results. In addition, the ratio of Treg and Th17 in spleen lymphocytes and the expression of TLR2 and TLR4 are significantly improved. Also, the expression of RORγt and FOXP3 in distal colon were improved. Besides, the effect of moxibustion is better than that of electroacupuncture on TLR2, TLR4, and FOXP3 expression (P < 0.05). ConclusionBoth electroacupuncture and moxibustion may ameliorate UC by regulating the balance of Th17/Treg. Whether moxibustion has better efficacy than electroacupuncture needs further study.

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing.

The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA. TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.

Changes in skin structure of the Zip13-KO mouse by Makomo (Zizania latifolia) feeding.

Ehlers-Danlos syndrome (EDS) is a group of disorders caused by abnormalities in the extracellular matrix (ECM). Transforming growth factor-β (TGF-β) plays a crucial role in formation of the ECM by the SMAD (Sma-and Mad-related protein, mothers against decapentaplegic homolog) pathway. It has been reported that loss of function of zinc transporter ZRT/IRT-like protein 13 (ZIP13) is the cause of the spondylocheiro dysplastic form of EDS (SCD-EDS: OMIM 612350). Our previous study suggested that TGF-β1 has a relationship with the skin pathological condition in the Zip13-Knockout (KO) mouse, which is a model of SCD-EDS. Thus far, effective treatment based on modern medicine for this syndrome has not yet been established. According to an approach of traditional Chinese medicine, the present study investigates the medicinal effects of Makomo (Zizania latifolia) on certain aspects of SCD-EDS, such as skin morphology and plasma TGF-β1, in Zip13-KO mice. Increases in densities of collagen fibers and fibrils without a significant change in thickness of the dermal layer were observed in the group of mice fed a Makomo-containing diet. No change in the amount of collagen suggests that Makomo feed does not elevate collagen synthesis, but changes the length of glycosaminoglycan chains and decreases the distance between collagen fibrils. In conclusion, the changes of the skin structure suggest that Makomo can increase the mechanical strength of skin.

Absence of transforming growth factor beta 1 in murine platelets reduces neointima formation without affecting arterial thrombosis.

Platelet degranulation at the site of vascular injury prevents bleeding and may affect the chronic vascular wound healing response. Transforming Growth Factor (TGF)-β1 is a major component of platelet α-granules known to accumulating in thrombi. It was our aim to determine the role of TGFβ1 released from activated platelets for neointima formation following arterial injury and thrombosis. Mice with platelet-specific deletion of TGFβ1 (Plt.TGFβ-KO) underwent carotid artery injury. Immunoassays confirmed the absence of active TGFβ1 in platelet releasates and plasma of Plt.TGFβ-KO mice. Whole blood analyses revealed similar haematological parameters, and tail cut assays excluded major bleeding defects. Platelet aggregation and the acute thrombotic response to injury in vivo did not differ between Plt.TGFβ-KO and Plt.TGFβ-WT mice. Morphometric analysis revealed that absence of TGFβ1 in platelets resulted in a significant reduction of neointima formation with lower neointima area, intima-to-media ratio, and lumen stenosis. On the other hand, the media area was enlarged in mice lacking TGFβ1 in platelets and contained increased amounts of proteases involved in latent TGFβ activation, including MMP2, MMP9 and thrombin. Significantly increased numbers of proliferating cells and cells expressing the mesenchymal markers platelet-derived growth factor receptor-β or fibroblast-specific protein-1, and the macrophage antigen F4/80, were observed in the media of Plt.TGFβ-KO mice, whereas the medial smooth muscle-actin-immunopositive area and collagen content did not differ between genotypes. Our findings support an essential role for platelet-derived TGFβ1 for the vascular remodelling response to arterial injury, apparently independent from the role of platelets in thrombosis or haemostasis.

Response Gene to Complement-32 Promotes the Imbalance of Treg/Th17 in Patients with Dilated Cardiomyopathy

Background/Aims: The imbalance of Treg/Th17 cells plays important role in the pathogenesis of dilated cardiomyopathy (DCM). Response gene to complement (RGC)-32 is a cell cycle regulator that plays an important role in cell proliferation. We evaluated whether the upregulation of RGC-32 was implicated in the homeostasis of Treg/Th17 cells in DCM. Methods: The levels of plasma RGC-32, IL-17 and TGF-β1, and the frequencies of circulating CD4⁺ RGC-32⁺ T cells, Th17 and Treg cells in patients with DCM were determined by Cytokine-specific sandwich ELISA and the flow cytometer (FCM), respectively. Results: A significant elevation of plasma RGC-32 in patients with DCM compared with healthy control (HC) subjects was observed. This upregulation was associated with an increase in frequency of Th17 and a decrease in frequency of Treg cells. To further assessed the role of RGC-32, we investigated the effects of RGC-32 up- or down-regulation on frequencies of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) from subjects. Importantly, overexpression of RGC-32 was accompanied by an augmentation of Th17 and a reduction of Treg expression. Conclusion: In summary, our study demonstrated the up-regulation of RGC-32 contributed to the imbalance of Treg/Th17 cells in patients with DCM.

Effects of Angelica dahurica and Rheum officinale Extracts on Excisional Wound Healing in Rats

The main objective of wound treatments is to restore the functional skin properties and prevent infection. Traditional Chinese medicine provides alternative anti-inflammatory, antimicrobial, and wound healing therapies. Both Angelica dahurica extract (AE) and Rheum officinale extract (RE) possess antimicrobial activity. In this study, AE and RE were applied in wound treatment to investigate their healing effects. Thirty Sprague-Dawley rats with dorsal full-thickness skin excision were divided into normal saline (NS), AE, RE, AE plus RE (ARE), and Biomycin (BM) groups. The treatment and area measurement of wounds were applied daily for 21 days. Wound biopsies and blood samples were obtained for histology examinations and cytokine analysis. Results showed that wound contraction in ARE group was significantly higher than that in NS and BM groups (P < 0.05). Histological analysis showed that more inflammatory cell infiltration, collagen fibers, and myofibroblasts were observed in ARE treated group than those in NS group on days 3–5. In ARE group, plasma IL-6 levels were elevated during days 3–5 (P > 0.05), and plasma TGF-β1 levels were significantly lower than those in the NS group on days 3-4 (P < 0.05). In conclusion, ARE accelerates wound healing during inflammation and proliferation phases.

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer

There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment. To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor β1 (TGF-β1). A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model. The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested. Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-β1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects. Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-β1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-β1-induced suppression of antitumor immunity. clinicaltrials.gov Identifier: NCT00265941.

Changes of Plasma uPA and TGF-β1 in Patients with Preeclampsia

Changes of Plasma uPA and TGF-β1 in Patients with Preeclampsia