POEMS Syndrome Diagnosis in a Patient with Mixed Polyneuropathy: Case Report.

POEMS syndrome is a rare condition of paraneoplasic origin characterized by the presence of a sensorimotor polyneuropathy associated with the presence of a proliferative disorder of plasmatic monoclonal cells and overproduction of vascular endothelial growth factor. The acronym "POEMS" represents multisystem findings including polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes; nevertheless, clinical presentation is heterogeneous. We describe a clinical case, the diagnostic and therapeutic approach in a patient with sensorimotor polyneuropathy in whom POEMS syndrome was diagnosed; to understand this pathology, its clinical and paraclinical manifestations in order to make a diagnosis or to avoid a delayed one and to provide an adequate treatment.

Propranolol inhibits cell viability and expression of the pro-tumorigenic proteins Akt, NF-ĸB, and VEGF in oral squamous cell carcinoma.

BACKGROUND: Propranolol (PPL) has been suggested as an option for the treatment of various types of cancer. However, data regarding its effectiveness against oral cancer are scarce. Thus, we aimed to evaluate the antitumor potential of PPL in oral squamous cell carcinoma (OSCC) in vitro. METHODS: OSCC cell lines, SCC-9, SCC-25, and Cal27, were treated with PPL at different times and concentrations. OSCC cells were treated with PPL alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of phosphorylated (p)-Akt, p-S6, p-PTEN, p-P65, and VEGF was verified by immunofluorescence. The migratory activity of OSCC cells was evaluated using a wound-healing assay. RESULTS: PPL reduced OSCC cell viability in a dose- and time-dependent manner. Concentrations above 300 µM, 110 µM, and 100 µM for SCC-9, Cal27, and SCC-25, respectively, significantly eliminated tumor cells. The combination of PPL with CDDP and 5-FU enhanced their antitumor effects. There was a modest difference between the use of the IC30 and IC50 of PPL in the combinatory options. PPL downregulated p-P65 NF-ĸB and VEGF expression in SCC-9 and Cal27 cells but not in SCC-25 cells. PPL inhibited the phosphorylation of Akt and s6 and increased the phosphorylation of PTEN in all OSCC cell lines studied. PPL inhibited OSCC cell migration after 24 h of treatment. CONCLUSION: PPL was effective against oral cancer cells and enhanced standard-of-care. PPL inhibited cell viability and the expression of pAkt, NF-ĸB, and VEGF.

Gene expression of HIF-1α and VEGF in response to hypoxia in sickle cell anaemia: Influence of hydroxycarbamide.

Hypoxia and hemoglobin S polymerization are two triggers responsible for initiating erythrocyte sickling and the consequent clinical sickle cell anemia (SCA) events. The objective of this study was to investigate the expression of hypoxia-responsive genes in SCA, testing for correlation with the clinical-laboratorial characteristics of the patient and hydroxyurea therapy. Our results showed, for the first time, a significantly increased expression of HIF-1α and VEGF genes in patients with SCA and an inverse dose-response relationship with hydroxyurea therapy. These results suggest that hypoxic stress may be involved in both the severity of SCA and its response to treatment.

Photobiomodulation of inflammatory-cytokine-related effects in a 3-D culture model with gingival fibroblasts.

The aim of this study was to assess the effects of IL-6 and IL-8 cytokines on human gingival fibroblasts (HGF) cultured in a 3-D model and the possible photobiomodulation (PBM) of such effects by low-level laser therapy. In complete culture medium (DMEM), HGF from a healthy patient were seeded in a type I collagen matrix inserted into 24-well plates. After 5 days of incubation, the cytokines were added or not to serum-free DMEM, which was applied to the cell-enriched matrices. Then, PBM was performed: three consecutive irradiations using LaserTable diode device (780 nm, 0.025 W) at 0.5 J/cm2 were delivered or not to the cells. Twenty-four hours after the last irradiation, cell viability and morphology, gene expression, and synthesis of inflammatory cytokines and growth factors were assessed. The histological evaluation demonstrated that, for all groups, matrices presented homogeneous distribution of cells with elongated morphology. However, numerous cytokine-exposed cells were rounded. IL-6 and IL-8 decreased cell viability, synthesis of VEGF, and gene expression of collagen type I. PBM enhanced cell density in the matrices and stimulated VEGF expression, even after IL-6 challenge. Reduced TNF-α synthesis occurred in those cells subjected to PBM. In conclusion, PBM can penetrate collagen matrix and stimulate HGF, highlighting the relevance of this research model for further phototherapy studies and in vitro biomodulation of the healing process.

Effects of islet neogenesis associated protein depend on vascular endothelial growth factor gene expression modulated by hypoxia-inducible factor 1-alpha.

BACKGROUND: Pharmacology has provided efficient tools to improve insulin effect/secretion but the decrease in ß-cell mass remains elusive. INGAP-PP could provide a therapeutic alternative to meet that challenge. AIM: To further understand the mechanism that links INGAP-PP effects upon ß-cell mass and function with islet angiogenesis. METHODOLOGY: Normal male Wistar rats were divided into 2 groups and injected with a single dose of 100 mg/Kg suramin or saline. Both groups were divided into 2 subgroups that received daily doses of 2 mg/kg INGAP-PP or saline for ten days. Plasma glucose, triacylglycerol, TBARS, and insulin levels were measured. Pancreas immunomorphometric analyses were also performed. Pancreatic islets were isolated to measure glucose-stimulated insulin secretion (GSIS). Specific islet mRNA levels were studied by qRT-PCR. Statistical analysis was done using ANOVA. RESULTS: No differences were recorded in body weight, food intake, or any other plasma parameter measured in all groups. Islets from INGAP-PP-treated rats significantly increased GSIS, ß-cell mass, and mRNA levels of Bcl-2, Ngn-3, VEGF-A, VEGF-R2, CD31, Ang1 and Ang2, Laminin ß-1, and Integrin ß-1, and decreased mRNA levels of Caspase-8, Bad, and Bax. Islets from suramin-treated rats showed significant opposite effects, but INGAPP-PP administration rescued most of the suramin effects in animals treated with both compounds. CONCLUSION: Our results reinforce the concept that INGAP-PP enhances insulin secretion and ß-cell mass, acting through PI3K/Akt/mTOR pathways and simultaneously activating angiogenesis through HIF-1α-mediated VEGF-A secretion. Therefore, INGAP-PP might be a suitable antidiabetic agent able to overcome two major alterations present in T2D.

Increased protein expression of VEGF-A, VEGF-B, VEGF-C and their receptors in the temporal neocortex of pharmacoresistant temporal lobe epilepsy patients.

The vascular endothelial growth factor (VEGF) system has been shown to play a crucial role in several neuropathological processes. Temporal lobe epilepsy (TLE) is the most common focal epilepsy type in adult humans. We assessed the protein expression levels of VEGF-A, VEGF-B, and VEGF-C, their specific receptors VEGFR-2 and -3, their accessory receptors neuropilins 1 and 2, and PI3 and Akt kinases, in temporal neocortex from pharmacoresistant TLE (PR-TLE) patients and control subjects by western blotting. All proteins were found to be significantly overexpressed in samples of PR-TLE patients, indicating that the VEGF system contributes to PR-TLE pathogenesis and should be further studied.

Immunohistological features related to functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction. Patients usually present with airway obstruction in pulmonary function tests (PFTs). Previous studies have shown correlations among histological parameters, lung function abnormalities and prognosis in LAM. We investigated the lung tissue expression of proteins related to the mTOR pathway, angiogenesis and enzymatic activity and its correlation with functional parameters in LAM patients. METHODS: We analyzed morphological and functional parameters of thirty-three patients. Two groups of disease severity were identified according to FEV1 values. Lung tissue from open biopsies or lung transplants was immunostained for SMA, HMB-45, mTOR, VEGF-D, MMP-9 and D2-40. Density of cysts, density of nodules and protein expression were measured by image analysis and correlated with PFT parameters. RESULTS: There was no difference in the expression of D2-40 between the more severe and the less severe groups. All other immunohistological parameters showed significantly higher values in the more severe group (p ≤ 0.002). The expression of VEGF-D, MMP-9 and mTOR in LAM cells was associated with the density of both cysts and nodules. The density of cysts and nodules as well as the expression of MMP-9 and VEGF-D were associated with the impairment of PFT parameters. CONCLUSIONS: Severe LAM represents an active phase of the disease with high expression of VEGF-D, mTOR, and MMP-9, as well as LAM cell infiltration. Our findings suggest that the tissue expression levels of VEGF-D and MMP-9 are important parameters associated with the loss of pulmonary function and could be considered as potential severity markers in open lung biopsies of LAM patients.

PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma.

BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.

Induction by innate defence regulator peptide 1018 of pro-angiogenic molecules and endothelial cell migration in a high glucose environment.

Synthetic innate defence regulator (IDR) peptides such as IDR-1018 modulate immunity to promote key protective functions including chemotaxis, wound healing, and anti-infective activity, while suppressing pro-inflammatory responses to non-pathological levels. Here we demonstrated that IDR-1018 induced, by up to 75-fold, pro-angiogenic VEGF-165 in keratinocytes but suppressed this isoform in endothelial cells. It also induced early angiogenin and prolonged anti-inflammatory TGFß expression on endothelial cells, while suppressing early pro-inflammatory IL-1ß expression levels. IDR-1018 also down-regulated the hypoxia induced transcription factor HIF-1α in both keratinocytes and endothelial cells. Consistent with these data, in an in vitro wound healing scratch assay, IDR-1018 induced migration of endothelial cells under conditions of hypoxia while in epithelial cells migration increased only under conditions of normoxia.

INGAP-PP effects on ß-cell mass and function are related to its positive effect on islet angiogenesis and VEGFA production.

Our aim was to determine whether islet angiogenesis and VEGFA production/release participate in the mechanism by which INGAP-PP enhances ß-cell function and mass. We used two models: a) in vivo (normal rats injected with INGAP-PP for 10 days) and b) in vitro (normal islets cultured for 4 days with INGAP-PP, VEGFA, Rapamycin, and the specific VEGF-Receptor inhibitor, SU5416). INGAP-PP administration enhanced insulin secretion, ß-cell mass, islet vascularization, and angiogenesis without affecting glucose homeostasis. Normal islets cultured with INGAP-PP and VEGFA increased insulin and VEGFA secretion while apoptosis decreased. INGAP-PP-induced effects were prevented by both Rapamycin and SU5416. INGAP-PP effects on ß-cell mass and function were significantly associated with a positive effect on islet angiogenesis and VEGFA production/release. VEGF-A possibly potentiates INGAP-PP effect through mTORC pathway.

Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6.

Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism, and neurodegeneration. In previous studies we showed that SIRT6 deficiency causes major retinal transmission defects, changes in the expression of glycolytic genes, and elevated levels of apoptosis. Given the importance of glucose availability for retinal function and the critical role of SIRT6 in modulating glycolysis, we aimed to analyze SIRT6 participation in the molecular machinery that regulates the development of experimental DR. Using non-obese diabetic mice, we determined by western blot that 2 weeks after the onset of the disease, high glucose concentrations induced retinal increase in a neovascularization promoting factor (vascular endothelial growth factor, VEGF), and the loss of a neuroprotective factor (brain-derived neurotrophic factor, BDNF) associated with reduced levels of SIRT6 and increased acetylation levels of its substrates (H3K9 and H3K56) suggesting a deregulation of key neural factors. Noteworthy, retinas from CNS conditionally deleted SIRT6 mice showed a resemblance to diabetic retinas exhibiting lower protein levels of BDNF factor and increased protein levels of VEGF. Moreover, cultured Müller glial cells subjected to high glucose concentrations exhibited decreased levels of SIRT6 and increased levels of H3K56 acetylation. In addition, the increment of VEGF levels induced by high glucose was reverted by the over-expression of SIRT6 in this cell type. Accordingly, siRNA experiments showed that, when SIRT6 was silenced, VEGF levels increased. Our findings suggest that epigenetically regulated neurodegenerative events may occur at an early diabetic stage prior to the characteristic proliferative and vascular changes observed at a later diabetic stage.

LQFM030 reduced Ehrlich ascites tumor cell proliferation and VEGF levels.

AIMS: This study reports the biological properties of LQFM030 in vivo, a molecular simplification of the compound nutlin-1. MAIN METHODS: Ehrlich ascites tumor (EAT)-bearing mice were treated intraperitoneally with LQFM030 (50, 75 or 150mg/kg) for 10days to determine changes in ascites tumor volume, body weight, cytotoxicity and angiogenesis. Moreover, flow cytometric expression of p53 and p21 proteins and caspase-3/7, -8 and -9 activation were investigated in EAT cells from mice treated. Acute oral systemic toxicity potential of LQFM030 in mice was also investigated using an alternative method. KEY FINDINGS: Treatment of EAT-bearing mice with LQFM030 resulted in a marked decline in tumor cell proliferation and the vascular endothelial growth factor (VEGF) levels along with enhanced survival of the mice. Apoptotic tumor cell death was detected through p53 and p21 modulation and increase of caspase-3/7, -8 and -9 activity. LQFM030 also showed orally well tolerated, being classified in the UN GHS category 5 (LD50>2000-5000mg/Kg). SIGNIFICANCE: LQFM030 seems to be a promising antitumor candidate for combinatory therapy with typical cytotoxic compounds, reducing the toxicity burden while allowing a superior anticancer activity. Moreover, these data also open new perspectives for LQFM030 as an antiangiogenic agent for treatment of diseases involving VEGF overexpression.

6-Gingerol inhibits hair cycle via induction of MMP2 and MMP9 expression.

6-Gingerol is the major active constituent of ginger. In the current study, we aimed to investigate the mechanisms underlying the effects of 6-Gingerol on hair growth. Mice were randomly divided into five groups; after hair depilation (day 0), mice were treated with saline, or different concentrations of 6-Gingerol for 11 days. The histomorphological characteristics of the growing hair follicles were examined after hematoxylin and eosin staining. The results indicated that 6-Gingerol significantly suppressed hair growth compared with that in the control group. And choose the concentration of 6-Gingerol at 1 mg/mL to treated with mice. Moreover, 6-Gingerol (1 mg/mL) significantly reduced hair re-growth ratio, hair follicle number, and hair follicle length, which were associated with increased expression of MMP2 and MMP9. Furthermore, the growth factors, such as EGF, KGF, VEGF, IGF-1 and TGF-ß participate in the hair follicle cycle regulation and regulate hair growth. We then measured the concentrations of them using ELISA assays, and the results showed that 6-Gingerol decreased EGF, KGF, VEGF, and IGF-1 concentrations, and increased TGF-ß concentration. Thus, this study showed that 6-Gingerol might act as a hair growth suppressive drug via induction of MMP2 and MMP9 expression, which could interfere with the hair cycle.

6-Gingerol inhibits hair cycle via induction of MMP2 and MMP9 expression

ABSTRACT 6-Gingerol is the major active constituent of ginger. In the current study, we aimed to investigate the mechanisms underlying the effects of 6-Gingerol on hair growth. Mice were randomly divided into five groups; after hair depilation (day 0), mice were treated with saline, or different concentrations of 6-Gingerol for 11 days. The histomorphological characteristics of the growing hair follicles were examined after hematoxylin and eosin staining. The results indicated that 6-Gingerol significantly suppressed hair growth compared with that in the control group. And choose the concentration of 6-Gingerol at 1 mg/mL to treated with mice. Moreover, 6-Gingerol (1 mg/mL) significantly reduced hair re-growth ratio, hair follicle number, and hair follicle length, which were associated with increased expression of MMP2 and MMP9. Furthermore, the growth factors, such as EGF, KGF, VEGF, IGF-1 and TGF-β participate in the hair follicle cycle regulation and regulate hair growth. We then measured the concentrations of them using ELISA assays, and the results showed that 6-Gingerol decreased EGF, KGF, VEGF, and IGF-1 concentrations, and increased TGF-β concentration. Thus, this study showed that 6-Gingerol might act as a hair growth suppressive drug via induction of MMP2 and MMP9 expression, which could interfere with the hair cycle.

PD-1/PD-L1 and VEGF-A/VEGF-C expression in lymph node microenvironment and association with melanoma metastasis and survival.

Regional lymph nodes are affected frequently by melanoma metastasis. Its microenvironment may be associated with tumor progression. We investigated sentinel nodes with and without tumor and negative nodes surrounding positive nodes, looking for patterns related to tumor immune interaction and lymphovascular progression. We quantified programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1, vascular endothelial growth factor (VEGF)-A/VEGF-C expressions in lymph nodes of 103 patients who underwent sentinel lymph node biopsy. Two groups were studied: negative sentinel lymph nodes and positive ones. Negative lymph nodes of sequential lymphadenectomy from positive cases were also studied. Markers were assessed by immunohistochemistry. Results were related to clinical/histological outcomes. VEGF-A/VEGF-C analysis showed higher positivity in metastatic nodes and higher positivity in the surrounding negative nodes from positive cases in comparison with nonmetastatic patients. Programmed cell death-ligand 1, studied only in metastasis, presented high positivity, not associated with prognosis. PD-1 expressions were similar in the groups with a 1% cutoff and higher in the metastasis with a 5% cutoff. Higher VEGF-A expression was related to higher pathological stages. PD-1 expression in the lymph node was associated with higher survival. Other clinical and histopatological variables were not associated with marker expression patterns. VEGF-A and VEGF-C expressions in lymph nodes were associated with the presence of lymph node metastasis. PD-1 expression in the lymph node was related to higher survival rates and this should be explored in the context of adjuvant immunotherapy.

Effect of estradiol on the expression of angiogenic factors in epithelial ovarian cancer.

INTRODUCTION: Ovarian cancer presents a high angiogenesis (formation of new blood vessels) regulated by pro-angiogenic factors, mainly vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). An association between endogenous levels of estrogen and increased risk of developing ovarian cancer has been reported. Estrogen action is mediated by the binding to its specific receptors (ERα and ERß), altered ERα/ERß ratio may constitute a marker of ovarian carcinogenesis progression. OBJECTIVE: To determine the effect of estradiol through ERα on the expression of NGF and VEGF in epithelial ovarian cancer (EOC). METHODOLOGY: Levels of phosphorylated estrogen receptor alpha (pERα) were evaluated in well, moderate and poorly differentiated EOC samples (EOC-I, EOC-II, EOC-III). Additionally, ovarian cancer explants were stimulated with NGF (0, 10 and 100 ng/ml) and ERα, ERß and pERα levels were detected. Finally, human ovarian surface epithelial (HOSE) and epithelial ovarian cancer (A2780) cell lines were stimulated with estradiol, where NGF and VEGF protein levels were evaluated. RESULTS: In tissues, ERs were detected being pERα levels significantly increased in EOC-III samples compared with EOC-I (p<0.05). Additionally, ovarian explants treated with NGF increased pERα levels meanwhile total ERα and ERß levels did not change. Cell lines stimulated with estradiol revealed an increase of NGF and VEGF protein levels (p<0.05). CONCLUSIONS: Estradiol has a positive effect on pro-angiogenic factors such as NGF and VEGF expression in EOC, probably through the activation of ERα; generating a positive loop induced by NGF increasing pERα levels in epithelial ovarian cells.

A simple method to induce hypoxia-induced vascular endothelial growth factor-A (VEGF-A) expression in T24 human bladder cancer cells.

Angiogenesis is an essential process for the establishment, development, and dissemination of several malignant tumors including bladder cancer. The hypoxic condition promotes the stabilization of hypoxia-inducible factor 1 alpha (HIF-1α), which translocates to the nucleus to mediate angiogenic factors including the vascular endothelial growth factor A (VEGF-A). AnaeroGen system was developed for microbiology area to create a low oxygen tension required to the growth of anaerobic bacteria. Here, we hypothesized the use of AnaeroGen system to induce hypoxia in T24 human bladder carcinoma cells, in order to promote the overexpression of VEGF-A. T24 cells were cultured in six-well plates containing McCoy medium. Exposures of T24 cells to hypoxia for 1, 8, 24, and 48 h were performed using the Oxoid AnaeroGen system, while T24 cells under normoxia were used as control. The expression of VEGF-A and HIF-1α was analyzed by real-time PCR. ELISA for HIF-1α was carried out. The VEGF-A expression increased significantly by Oxoid AnaeroGen-induced hypoxia in a time-depending manner, reaching the peak in 48 h of hypoxia. Although HIF-1α mRNA was not changed, HIF-1α protein was increased in the presence of hypoxia, reaching a peak at 8 h. These results demonstrated that the Oxoid AnaeroGen system is a simple method to expose T24 cells to hypoxia and efficiently to upregulate VEGF expression in T24 cells.

Effects of low-level laser therapy and epidermal growth factor on the activities of gingival fibroblasts obtained from young or elderly individuals.

This study evaluated the effects of low-level laser therapy (LLLT) and epidermal growth factor (EGF) on fibroblasts obtained from young and elderly individuals. Gingival fibroblasts from young (Y) and elderly (E) individuals were seeded in wells of 24-well plates with Dulbecco's modified Eagle's medium (DMEM) containing 10 % of fetal bovine serum (FBS). After 24 h, the cells were irradiated (LASERTable-InGaAsP-780 ± 3 nm, 25 mW, 3 J/cm2) or exposed to EGF (100 µM). After 72 h, cells were evaluated for viability, migration, collagen and vascular endothelial growth factor (VEGF) synthesis, and gene expression of growth factors. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests (α = 5 %). Y and E fibroblasts irradiated with laser or exposed to EGF showed increased viability and collagen synthesis. Enhanced cell migration was observed for Y fibroblasts after both treatments, whereas only the LLLT stimulated migration of E cells. VEGF synthesis was higher for Y and E cells exposed to EGF, while this synthesis was reduced when E fibroblasts were irradiated. Increased gene expression of VEGF was observed only for Y and E fibroblasts treated with LLLT. Regardless of a patient's age, the LLLT and EGF applications can biostimulate gingival fibroblast functions involved in tissue repair.

Tristetraprolin: a novel mediator of the anticancer properties of resveratrol.

Resveratrol is a natural compound that exhibits anticancer properties. Previous studies have proved that it can inhibit the proliferation of breast cancer cell lines and upregulate some cytokines such as cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). The initiation and progression of cancer are associated with the abnormal expression of multiple cytokines. Tristetraprolin (TTP), an mRNA-binding protein, is one of the key proteins that participate in regulating cytokine expression. Two different proliferation assays on MCF-7 cells showed that the cell proliferation rate significantly reduced following treatment with resveratrol. Most importantly, we found that resveratrol promoted TTP expression at both the mRNA and protein level in a dose- and time-dependent manner. In addition, the expression of COX-2 and VEGF were significantly suppressed by resveratrol while that of inducible nitric oxide synthase (iNOS) was upregulated. Lastly, the effects of resveratrol on both MCF-7 proliferation and expression of COX-2, VEGF, and iNOS were significantly inhibited by TTP knockdown, indicating that TTP mediates the anticancer properties of resveratrol. In summary, we conclude that resveratrol inhibits the proliferation of MCF-7 cells by TTP upregulation, which is associated with downregulation of COX-2 and VEGF and upregulation of iNOS.

Microarray analysis of microRNA deregulation and angiogenesis-related proteins in endometriosis.

We examined the aberrant microRNA (miRNA) expression profile responsible for the changes in angiogenesis observed in endometriotic lesions. This study revealed characteristic miRNA expression profiles associated with endometriosis in endometrial tissue and endometriotic lesions from the same patient, and their correlation with the most important angiogenic and fibrinolytic factors. miRNA expression was quantified using a microRNA array and reverse-transcription microRNA polymerase chain reaction. Levels of vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor 2 (EGFR2), phosphatase and tensin homolog (PTEN), and C-X-C chemokine receptor type 4 (CXCR4) were quantified using enzyme-linked immunosorbent assay. The endometrial tissue showed significantly lower levels of miR-200b, miR-15a-5p, miR-19b-1-5p, miR-146a-5p, and miR-200c, and higher levels of miR-16-5p, miR-106b-5p, and miR-145-5p. VEGFA was significantly upregulated, whereas EGFR2, PTEN, and CXCR4 were markedly downregulated, in the endometriotic tissues compared to that in the normal endometrial tissues. In conclusion, differences in the miRNA levels could modulate the expression of VEGFA, EGFR2, PTEN, and CXCR4, and may play an important role in the pathogenesis of endometriosis. The higher angiogenic and proteolytic activities observed in the eutopic endometrium might facilitate the implantation of endometrial cells at ectopic sites.