Expression Of Endothelial Growth Factor Research Articles

Testosterone improved erectile function by upregulating transcriptional expression of growth factors in late androgen replacement therapy model rats.

We previously showed that castration of rats reduced erectile function over time; when testosterone replacement therapy was started 4 weeks after castration, erectile function improved. In this study, we examined the mechanism of improvement in erectile function following testosterone replacement therapy in rats. Thirty 12-week-old rats were divided into castrated (Cast), castrated with subcutaneous administration of testosterone (Cast + T), and sham (Sham) groups. Erectile function and mRNA and protein expression were evaluated in the rats by using standard methods. To assess erectile function, we measured the intracavernosal pressure, mean arterial pressure, mRNA expression of endothelial growth factors, and protein expression of endothelial nitric oxide synthase (eNOS). The intracavernosal pressure/mean arterial pressure ratio was significantly lower in the Cast group, and testosterone administration significantly improved (P = 0.017). Compared to the Cast group, the Cast+T group exhibited significantly increased mRNA expressions of vascular endothelial growth factor A (VEGF-A), intercellular adhesion molecule 1 (ICAM-1), transforming growth factor-β (TGF-β), nerve growth factor (NGF), α-smooth muscle actin (α-SMA), caveolae associated protein 1 (Cavin-1), Cavin-2, Cavin-3, sirtuin 1 (Sirt-1), sphingosine-1-phosphate 1 (S1P1), S1P2, and S1P3 and eNOS protein expression. Testosterone replacement therapy improved erectile function in castrated rats by increasing growth factors and eNOS protein.

1,25(OH)2D3 alleviates LPS-induced preeclampsia-like rats impairment in the protective effect by TLR4/NF-kB pathway

IntroductionAccumulating epidemiological studies support that Vitamin D deficiency is associated with the pathogenesis of preeclampsia. However, it is unknown whether vitamin D can be used as a treatment for preeclampsia. This study aimed to explore whether vitamin D supplementation could improve the rat model of preeclampsia. MethodsLPS was used to establish a rat model of preeclampsia. Inflammatory cytokines were examined by QRT-PCR and ELISA assays, and the concentration of sfit-1 and NO was assessed by ELISA. Analyzing the pathological features of the placenta with hematoxylin-eosin. The spatial learning and memory abilities of offspring were evaluated by the Morris water maze. Immune histology and western blot were performed to evaluate the expression levels of inflammatory pathway-associated Factor and vascular endothelium-associated Factor in the placenta. ResultsVitamin D treatment reduced the blood pressure and urine protein of PE model rats, alleviated pathological damage to the placenta and pregnancy outcomes, and protected PE offspring from impaired memory and learning abilities. Moreover, TLR4 signaling pathway in the placenta was inhibited. Furthermore, vitamin D supplementation increased the expression of endothelial growth factor and vascular relaxing factor, and there was no significant difference compared with the control group. DiscussionWe generated the result that Vitamin D supplementation significantly improved the phenotype of preeclampsia and adverse pregnancy outcome caused by an abnormal inflammatory reaction and endothelial dysfunction in the placenta, and improved the learning and cognitive ability of offspring.

The Specifically Androgen-Regulated Gene (SARG) Promotes Papillary Thyroid Carcinoma (PTC) Lymphatic Metastasis Through Vascular Endothelial Growth Factor C (VEGF-C) and VEGF Receptor 3 (VEGFR-3) Axis.

The papillary thyroid carcinoma (PTC) metastasizes through lymphatic spread, but the follicular thyroid cancer (FTC) metastasis occurs by following hematogenous spread. To date, the molecular mechanism underlying different metastatic routes between PTC and FTC is still unclear. Here, we showed that specifically androgen-regulated gene (SARG) was significantly up-regulated in PTC, while obviously down-regulated in FTC through analyzing the Gene Expression Omnibus (GEO) database. Immunohistochemistry assay verified that the PTC lymph node metastasis was associated with higher levels of SARG protein in clinical PTC patient samples. SARG-knockdown decreased TPC-1 and CGTH-W3 cells viability and migration significantly. On the contrary, SARG-overexpressed PTC cells possessed more aggressive migratory ability and viability. In vivo, SARG overexpression dramatically promoted popliteal lymph node metastasis of xenografts from TPC-1 cells mouse footpad transplanting. Mechanistically, SARG overexpression and knockdown significantly increased and decreased the expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor 3 (VEGFR-3), respectively, thereby facilitating or inhibiting the tube formation in HUVECs. The tube formation experiment showed that SARG overexpression and knockdown promoted or inhibited the number of tube formations in HUVEC cells, respectively. Taken together, we showed for the first time the differential expression profile of SARG between PTC and FTC, and SARG promotes PTC lymphatic metastasis via VEGF-C/VEGFR-3 signal. It indicates that SARG may represent a target for clinical intervention in lymphatic metastasis of PTC.

Effects of Electroacupuncture on the Expression of Glial Fibrillary Acidic Protein and Vascular Endothelial Growth Factor and Cell Structure in the Gliavascular Net of Cerebral Ischemic Tissues in Hypertensive Rats

Introduction: This study aims to explore the effects of electroacupuncture on the expression of GFAP and VEGF and cell structure in the glia vascular net of cerebral ischemic tissues in hypertensive rats. Material and Methods: Stroke-prone renovascular hypertensive rat (RHRSP) models and middle cerebral artery occlusion (MCAO) were established. After two hours of ischemia and at 1, 7, 14 and 28 days after reperfusion, the expression of GFAP and VEGF in rat cerebral ischemic tissues was detected by immunohistochemistry and light microscopy. Results: Positive GFAP cells were found in the semidarkness area after two hours of ischemic and one day of reperfusion in the control group, and these increased after 14 days, decreased after 14 days, and significantly decreased after 28 days, when compared to the sham group (P < 0.01). Compared to the control group, GFAP-positive cells significantly increased after 7, 14 and 28 days of ischemic and reperfusion in the electric acupuncture group. Then, this significantly increased and reached the maximum after seven days of reperfusion, but decreased after 14 days. Contrarily, this significantly decreased after 30 day, but remained higher than that in sham-operated group (P < 0.05). Compared to the control group, the number of positive VEGF cells increased after 7, 14 and 28 days of ischemic and reperfusion in the electric acupuncture group (P < 0.01). Conclusions: Electric acupuncture can promote neurofunctional recovery in the cerebral ischemic area. The mechanism may be correlated with the regulation of the expression of GFAP and VEGF, and the rebuilding of the gliavascular net of cerebral ischemic tissues, thereby decreasing cerebral ischemic damage.

Efficacy and safety study of fotemustine and bevacizumab in patients with recurrent glioblastoma.

e14041 Background: Glioblastoma (GBM) is highly vascularized tumor with elevated expression of vascular endothelial growth factor (VEGF). Bevacizumab (Bz) is a humanized monoclonal antibody against VEGF, which alone or associated with chemotherapy has obtained optimal results. However, the most suitable combination with bevacizumab is yet unknown. The objective of our study is to evaluate the efficacy and safety of Bz and fotemustine (Ft) in patients (pts) with recurrent GBM of the Huelva area and to compare our results with those published in the phase II study of the Italian Association of Neuro-oncology (AINO). Methods: Observational and descriptive study of the combination of Ft-Bz in GBM at first relapse after standard radiotherapy and TMZ concomitant in the hospital area of Huelva during the years 2010-2021. We used the same therapeutic scheme of the phase II study of AINO and the IBM SPSS Statistics 22 program to analyze the variables. Results: 42 pts were treated, 16 women and 25 men. Median age 52 years. ECOG 0-1 in 85.4%. 65.9% and 92.7% received antiepileptics and corticosteroids, respectively. In 90.2%, methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was not evaluated. Previously, 56.1% of the pts underwent total/subtotal resection, 29.3% partial and 14.6% were not resected, followed by concomitant radiotherapy and temozolamide in 100% of cases. 35.7% relapsed in less than 3 months after adjuvant treatment. 61% presented unifocal relapse and 39% multifocal. 46.3% of the pts had stable disease, 24.4% partial response and 2.4% complete response. 22% presented grade 3-4 toxicity. The most frequent toxicities are listed in the table. The median progression-free survival (PFS) was 6 months (95% CI 4.18-7.82) and the median overall survival (OS) was 7 months (95% CI 4.22-9.77). Conclusions: The results obtained in our study were similar to those of other previously published studies of Bz in combination with Ft. Although PFS was slightly higher than the phase II study AINO, OS was lower, probably due to the inclusion of a high rate of rapid progressors pts. Treatment tolerance was similar to that in the phase II study AINO. An increase in hematologic adverse events stands out in our pts. Therefore, this scheme can be a valid alternative in the management of recurrent GBM.[Table: see text]

Effect of subacute poisoning with lambdacyhalothrin on vascular endothelial growth factor 2 receptor in mice kidneys

BackgroundPyrethroids are used for insect control. They act on voltage-gated sodium channels in neurons. Lambdacyhalothrin (LCH) is a type II pyrethroid producing choreoatetosis and salivation in rodents. Vascular endothelial growth factor (VEGF) expression in the kidney is high in the glomerular podocytes and kidney tubules. VEGF receptor 2 (VEFGR2) is the main mediator in angiogenesis and it regulates blood vessel permeability. Lack of VEGF in podocytes impairs filtration. The nuclear factor κB (NFκB) is widely known as an important mediator of inflammation.The aim of the study was to check if subacute oral intoxication with 0.1LD50 of LCH affects kidney size, function and VEGFR2 and NFκB in mice kidneys.MethodsA total of 32 Albino Swiss mice was used: females controls, males controls, females receiving 2 mg/kg LCH, males receiving 2 mg/kg LCH orally for 7 days. On day 8 animals were sacrificed, blood and kidneys were obtained. Kidney mass was determined, creatinine concentration was measured in blood sera, VEGFR2 and NFκB in kidney homogenate supernatant with ELISA kit.ResultsThere was no statistically significant differences in kidney mass, creatinine concentration in blood sera nor NFκB but mean VEGFR2 concentration in the kidneys of females exposed to LCH was 128.01 ng/ml and showed statistically significant difference in comparison with control females. There was no statistically significant difference between VEGFR2 concentration in the kidneys of males exposed to LCH and control males.ConclusionThe VEGFR2 increases in the course of LCH intoxication in females probably due to the protective effect of oestrogens.

Activation of BDNF- and VEGF-mediated Neuroprotection by Treadmill Exercise Training in Experimental Stroke.

Early treatment of ischemic stroke is one of the most effective ways to reduce brains' cell death and promote functional recovery. This study was designed to examine the effect of aerobic exercise on post ischemia/reperfusion injury on concentration and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after inducing a neuronal loss in CA1 region of hippocampus in Male Wistar rats. Three experimental groups including sham(S), ischemia/reperfusion-control (IRC) and ischemia/reperfusion exercise (IRE) were used for this purpose. The rats in the IRE group received a bilateral carotid artery occlusion treatment. They ran for 45 minutes on a treadmill five days per week for eight consecutive weeks. Cresyl violet (Nissl), Hematoxylin (H & E) and Eosin staining procedure were used to determine the extent of damage. A ladder rung walking task was used to assess the functional impairments and recovery after the ischemic lesion. ELISA and immunohistochemistry method were employed to measure BDNF and VEGF protein expressions. The result showed that the brain ischemia/reperfusion condition increased the cell death in hippocampal CA1 neurons and impaired motor performance on the ladder rung task whereas the aerobic exercise program significantly decreased the brain cell's death and improved motor skill performance. It was concluded that ischemic brain lesion decreased the BDNF and VEGF expression. It seems that the aerobic exercise following the ischemia/reperfusion potentially promotes neuroprotective mechanisms and neuronal repair and survival mediated partly by BDNF and other pathways.

Mesh-like electrospun membrane loaded with atorvastatin facilitates cutaneous wound healing by promoting the paracrine function of mesenchymal stem cells

BackgroundFunctional electrospun membranes are promising dressings for promoting wound healing. However, their microstructure and drug loading capacity need further improvements. It is the first time to design a novel mesh-like electrospun fiber loaded with atorvastatin (ATV) and investigated its effects on paracrine secretion by bone marrow-derived mesenchymal stem cells (BMSCs) and wound healing in vivo.MethodsWe fabricated a mesh-like electrospun membrane using a copper mesh receiver. The physical properties of the membranes were evaluated by SEM, FTIR spectroscopy, tensile strength analysis, and contrast angle test. Drug release was measured by plotting concentration as a function of time. We tested the effects of conditioned media (CM) derived from BMSCs on endothelial cell migration and angiogenesis. We used these BMSCs and performed RT-PCR and ELISA to evaluate the expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) genes and proteins, respectively. The involvement of FAK and AKT mechanotransduction pathways in the regulation of BMSC secretion by material surface topography was also investigated. Furthermore, we established a rat model of wound healing, applied ATV-loaded mesh-like membranes (PCL/MAT) seeded with BMSCs on wounds, and assessed their efficacy for promoting wound healing.ResultsFTIR spectroscopy revealed successful ATV loading in PCL/MAT. Compared with random electrospun fibers (PCL/R) and mesh-like electrospun fibers without drug load (PCL/M), PCL/MAT induced maximum promotion of human umbilical vein endothelial cell (HUVEC) migration. In the PCL/MAT group, the cell sheet scratches were nearly closed after 24 h. However, the cell sheet scratches remained open in other treatments at the same time point. The PCL/MAT promoted angiogenesis and led to the generation of longer tubes than the other treatments. Finally, the PCL/MAT induced maximum gene expression and protein secretion of VEGF and b-FGF. As for material surface topography effect on BMSCs, FAK and AKT signaling pathways were shown to participate in the modulation of MSC morphology and its paracrine function. In vivo, PCL/MAT seeded with BMSCs significantly accelerated healing and improved neovascularization and collagen reconstruction in the wound area compared to the other treatments.ConclusionsThe mesh-like topography of fibrous scaffolds combined with ATV release creates a unique microenvironment that promotes paracrine secretion of BMSCs, thereby accelerating wound healing. Hence, drug-loaded mesh-like electrospun membranes may be highly efficacious for wound healing and as artificial skin. It is a promising approach to solve the traumatic skin defect and accelerate recovery, which is essential to developing functional materials for future regenerative medicine.

Piezoelectric stimulation from electrospun composite nanofibers for rapid peripheral nerve regeneration

Peripheral nerve injuries vary among patients. Cell-based or acellular nerve conduits have a high peripheral nerve regeneration potential. However, they are not ideal for complicated nerve differentiations and are prone to unclear effects of cytokine interactions. Delayed nerve axon regeneration could be ascribed to a lack of regulation of the regenerative microenvironment. Electrical stimulation influences nerve regeneration by regulating sensitive targets. Here, a piezoelectric nerve conduit was developed using a composite of PCL/ZnO nanofiber (PZNF) via electrospinning. Endogenous piezoelectric stimulation from PZNF facilitated sciatic nerve regeneration. This material inherits polycaprolactone characteristics and is a biocompatible material. It generated stable and desired endogenous electrical stimulations. PZNF demonstrated faster and superior sciatic nerve repair in vivo than polycaprolactone nanofiber and nerve bridging in situ. Piezoelectric stimulation of PZNF could substantially increase nerve growth factor/vascular endothelial growth factor expression. Furthermore, the PZNF considerably promoted rapid nerve repair and shortened function recovery (within 4 weeks) in vivo. Moreover, an increase in growth factor receptor-bound protein-2 (GRB2) expression activated downstrem pathway: RAS/MAPK pathway after piezoelectricity stimulation, indicating that GRB2 may be an electrically sensitive protein and a hint protein of electrical stimulation-induced regeneration. This study offers a novel strategy of applying piezoelectric stimulation in rapid peripheral nerve regeneration.

Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor

Post-inflammatory hyperpigmentation is a skin discoloration process that occurs following an inflammatory response or wound. As the skin begins to heal, macrophages first exhibit a proinflammatory phenotype (M1) during the early stages of tissue repair and then transition to a pro-healing, anti-inflammatory phenotype (M2) in later stages. During this process, M1 macrophages remove invading bacteria and M2 macrophages remodel surrounding tissue; however, the relationship between macrophages and pigmentation is unclear. In this study, we examined the effect of macrophages on melanin pigmentation using human induced pluripotent stem cells. Functional melanocytes were differentiated from human induced pluripotent stem cells and named as hiMels. The generated hiMels were then individually cocultured with M1 and M2 macrophages. Melanin synthesis decreased in hiMels cocultured with M1 macrophages but significantly increased in hiMels cocultured with M2 macrophages. Moreover, the expression of vascular endothelial growth factor was increased in M2 cocultured media. Our findings suggest that M2 macrophages, and not M1 macrophages, induce hyperpigmentation in scarred areas of the skin during tissue repair.

Uncarboxylated osteocalcin promotes proliferation and metastasis of MDA-MB-231 cells through TGF-\u03b2/SMAD3 signaling pathway

BackgroundTriple-negative breast cancer (TNBC) is the most severe type of breast cancer owing to its high heterogeneity, aggressiveness and lack of treatment. Studies have reported that uncarboxylated osteocalcin (GluOC) promotes the development of prostate and other cancers. Studies have also found elevated levels of serum osteocalcin in breast cancer patients with bone metastasis, and serum osteocalcin can be a marker of bone metastasis. However, whether GluOC promotes the development of TNBC and the related mechanisms need to be further clarified.ResultsOur results revealed that GluOC is associated with the proliferation and metastasis of MDA-MB-231 cells. GluOC increased the viability and proliferation of MDA-MB-231 cells. In addition, GluOC enhanced the metastatic ability of MDA-MB-231 cells by promoting the expression of matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-13 (MMP13), and vascular endothelial growth factor (VEGF) and inducing epithelial-mesenchymal transition (EMT). We also found that GluOC upregulated the expression of interleukin-8 (IL-8) and parathyroid hormone-related protein (PTHrP) genes in MDA-MB-231 breast cancer cells. Moreover, the promoting effect of GluOC was reversed in MDA-MB-231 breast cancer cells treated with specific inhibitor of SMAD3 (SIS3), a SMAD3 phosphorylation inhibitor.ConclusionOur research proved for the first time that GluOC facilitates the proliferation and metastasis of MDA-MB-231 cells by accelerating the transforming growth factor-β (TGF-β)/SMAD3 signaling pathway. Moreover, GluOC also promotes the gene expression of IL-8 and PTHrP. Both IL-8 and PTHrP can act as osteolytic factors in breast cancer cells. This study indicates that GluOC may be a useful target for preventing TNBC bone metastasis.

The Role of Syncytin in Placental Angiogenesis and Fetal Growth.

Background: Syncytin, a retroviral envelope protein, is specifically expressed on trophoblast cells and mediates formation of the syncytiotrophoblast through fusogenic activity. Decreased expression of Syncytin was found in fetal growth restriction placentas. Results: By generating an inducible knockout of the syncytin-a gene in mice, we show a specific disruption of placental angiogenesis with abnormal formation of two syncytiotrophoblast layers. Consistent with the defects observed in vivo, conditioned medium collected from trophoblast cells, following Syncytin-1 knockdown, contains lower expression of vascular endothelial growth factor and placental growth factor, and higher levels of soluble fms-like protein kinase-1 in BeWo and HTR-8/SVneo cells which related with suppressed PI3K/Akt/mTOR pathway, and is reduced in ability to induce tube formation by HUVECs. Conclusion: Syncytin participates in angiogenesis during placental development was first identified both in vivo and in vitro. Here, we give a new sight on understanding syncytin and pathophysiology of placenta related disease such as fetal growth restriction.

Ginkgo biloba extract 761 reduces vascular permeability of the ovary and improves the symptom of ovarian hyperstimulation syndrome in a rat model

Aims Ginkgo biloba extract (EGb) has been widely applied in the treatment of cerebrovascular and neurological diseases. However, the effect of EGb761 on ovarian hyperstimulation syndrome (OHSS), a vascular disorder and life-threatening complication of in vitro fertilization and intracytoplasmic sperm injection therapy (IVF/ICSI), has not been evaluated. Materials and methods Forty female Wistar rats aged 22-days old (D22) were divided into eight groups: Control rats received intraperitoneal injection of saline for five consecutive days (D22–D26); OHSS model group received 10 IU equine chorionic gonadotropin (eCG) for four consecutive days (D22–D25) and 30 IU of human chorionic gonadotropin (hCG) on the 5th day (D26); Prophylactic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 1 h before injection of eCG (hCG) for seven consecutive days; Therapeutic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 48 h after injection of eCG (hCG) for seven consecutive days. Results All three doses of EGb761 therapeutic medication significantly reduced ovarian mass index of OHSS model rats (p ≤ .01). Furthermore, therapeutic treatment group exhibited improved vascular permeability, decreased estradiol and progesterone levels, lower corpus luteum, and higher follicle numbers compared with the OHSS model. Elevated protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in both ovary and kidney of the OHSS model was restrained by EGb761 therapeutic treatment. Conclusions EGb761 therapeutic medication decreases vascular permeability in OHSS rat model by inhibiting VEGF and VEGFR expression, which may contribute to the treatment of OHSS.

Expression of vascular endothelial growth factor A (VEGFA), placental growth factor (PlGF) and insulin-like growth factor 1 (IGF-1) in serum from women undergoing frozen embryo transfer

VEGFA, PlGF and IGF-1 are three main angiogenic factors which play significant roles in embryo implantation. However, the relationship between serum expressions of VEGFA, PlGF and IGF-1 and pregnancy outcomes has not been fully illustrated. In this study, serum specimens were collected precisely on day 7 after the LH surge in a natural non-conception cycle from 38 infertile patients who underwent frozen embryo transfer (FET) treatment. ELISA was used to determine the concentrations of VEGFA, PlGF and IGF-1. Serum levels of VEGFA, PlGF and IGF-1 were compared between patients who conceived (n=25) and who did not (n=13). Correlation and linear regression analyses were used to investigate the correlations of serum angiogenic factors and β-hCG MoM levels in the pregnant group. The results demonstrated that no significant difference was found in serum VEGFA, PlGF or IGF-1 concentration between pregnant and non-pregnant women. Spearman correlation analysis revealed a positive correlation between IGF-1 concentration and β-hCG level in pregnant participants (rs = 0.490, p = 0.013). In conclusion, serum IGF-1 level correlated positively with β-hCG level in pregnant women, which may provide information on the prognostic value of IGF-1 in this group of women.

Effect of polycaprolactone scaffolds containing different weights of graphene on healing in large osteochondral defect model

Now it is possible to combine the different biomaterial properties of graphene and 3 D printing scaffolds produced by tissue engineering for cartilage repair. In the study graphene-containing (1, 3, 5, 10 wt%), porous and oriented poly-ε-caprolactone-based scaffolds were prepared by robocasting method to use in the regeneration of large osteochondral defects. The scaffolds were implanted into the full-thickness osteochondral defect in a rabbit model to evaluate the regeneration of the defect in vivo. For this purpose, twenty female New Zealand white rabbits were used and they were euthanized at 4 and 8 weeks of implantation. The reparative osteochondral tissues were harvested from rabbit distal femurs and then processed for gross appearance assessment, radiographic imaging, histopathological, histochemical and immunohistochemical examinations. Results revealed that graphene-containing graft materials caused significant amelioration at the defect areas. Graphene-containing graft materials improved the fibrous, chondroid and osseous tissue regeneration compared to the control group. The expressions of bone morphogenetic protein-2 (BMP-2), collagen-1 (col-1), vascular endothelial growth factor (VEGF) and alkaline phosphatase (ALP) expressions were more prominent in graphene-containing PCL implanted groups (p < .001). Picrosirrius red method was used for to evaluate connective and muscle tissues. Results also revealed that the ameliorative effect of graphene increased by the elevation in concentration. The most prominent healing was observed in 10 wt% graphene-containing PCL based composite scaffold implanted group. This study results showed that graphene-containing PCL scaffolds enhanced the healing significantly in large osteochondral defect areas compared to the control groups.

Effect of Tiaojingzhixue Fang on the expression of sex hormone and endometrial tissue mRNA in perimenopausal patients with abnormal uterine bleeding.

This study aimed to investigate the effect of Tiaojingzhixue decoction on the expression of sex hormone and endometrial mRNA in perimenopausal patients with abnormal uterine bleeding. For this purpose, 84 patients with perimenopausal abnormal uterine bleeding who were treated in our hospital from January 2018 to January 2019 were divided into study group and control group, the control group was treated with mifepristone for six months, the clinical efficacy, time of symptom relief and disappearance, endometrial thickness, menstrual volume, adverse events, expression of sex hormone (ER), Progesterone receptor (PR), Lutropin (LH), Follicle-stimulating hormone (FSH), Estradiol (e2) and Vascular endothelial growth factor in endometrial tissue were compared between the two groups. The results showed that the clinical efficacy of the study group (97.61%) was significantly higher than the control group (80.95%) (P<0.05). There was no significant difference in endometrial thickness between the two groups before treatment, but after treatment for 1 month, 3 months and 6 months, endometrial thickness was thinner in the study group (P<0.05). There was no significant difference in menstrual volume between the two groups before treatment (P <0.05), but it was lower in the study group (P <0.05). The incidence of adverse reactions in the study group was 11.90% lower than in the control group (26.19%). The expression levels of ER, PR, LH, FSH and E2 were almost the same before treatment and there was no significant difference between the two groups (P>0.05), but they were lower in the study group after treatment (P<0.05). Before treatment, there was no significant difference in the level of VEGF between the two groups (P>0.05); after treatment, the level of Vegf in the study group was lower than the control group (P<0.05). After treatment, the level of Vegf in both groups was significantly higher than before treatment (P<0.05). In general, Tiaojingzhixue decoction can decrease the level of sex hormone and increase the expression of VEGF in patients with perimenopausal abnormal uterine bleeding.

Association of leptin with migration, invasion, and cancer stem-like properties in gastric cancer cells.

352 Background: Obesity is a risk factor for various types of cancer, including gastric cancer. Leptin, an adipocyte-derived hormone, may function in stimulating the proliferation of gastric cancer cell. The purpose of this study was to evaluate the role of leptin in gastric cancer. Methods: Leptin level was assessed by ELISA and was compared in obese patients with gastric cancer (n=23) and non-obese patients with gastric cancer (n=23) as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the Janus kinase/signal transducer and activator of transcription (JAK-STAT) and MEK signaling pathways using wound healing assay, inhibition study, and ELISA. Cancer-initiating cells derived from gastric cancer cell lines were studied to investigate the effects of leptin to the maintenance of stemness and epithelial-mesenchymal transition using invasion assay, RT- PCR, and immunoblotting. Results: Obesity was associated with elevated leptin level and BMI has positive correlation with the leptin level ( p=0.001 for both). Overall survival was not significantly different between the two groups ( p=0.098). Leptin induces the migration and invasion of gastric cancer cells by activating AKT and ERK and up-regulating the expression of vascular endothelial growth factor (VEGF). Pharmacological inhibitors of JAK and MEK signaling pathways decreased both leptin-induced migration and invasion and the leptin-induced expression of VEGF. Leptin increased the mRNA and protein levels of the markers for stemness (CD44) and epithelial-mesenchymal-transition (Snail and N-cadherin). Conclusions: Leptin plays a role in gastric cancer by stimulating the migration and invasion of gastric cancer cells via activating the JAK-STAT and MEK pathways and contributes to the maintenance of cancer stemness and metastatic potential. Leptin presents evidence supporting the adverse effect of obesity in gastric cancer. Treatment targeting leptin-associated signaling pathways could be a potential strategy for managing gastric cancer.

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

BackgroundONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH).MethodsThe therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro.ResultsONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells.ConclusionsThe results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.

Effect of papain enzyme administration in pH alteration, VEGF phosphorylation, and its impact on collagen degradation using a rat model of abnormal scarring

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To analyze the effect of enzyme papain administration, after its injection into abnormal scars of Rattus norvegicus rats, on pH alteration (ΔpH) of scar tissue, vascular endothelial growth factor (VEGF) expression levels, and determine their impact on collagen degradation.&#x0D; Methods: This study used Rattus norvegicus as an experimental animal. The pH measurement of the scar tissue was carried out before papain injection at 12th weeks while abnormal scar was established after papain injection at 15th weeks. Expression of vascular endothelial growth factor (VEGF) was examined by Western blot technique, while hydroxyproline levels were measured using QuickZyme Total Collagen Assay.&#x0D; Results: Changes in ΔpH, VEGF expression, and hydroxyproline levels in the treatment group were significant (p &lt; 0.05) compared to control. Path analysis showed a direct relationship between the parameters (p &lt; 0.01), except for the correlation between VEGF and hydroxyproline value (p = 0.23).&#x0D; Conclusion: Papain enzyme administration increased ΔpH value of abnormal scar tissue. A high dose of papain also causes an increase of collagen degradation process, as a response to angiogenesis deflation.&#x0D; &#x0D; &#x0D; &#x0D;

Possibility of adiponectin use to improve islet transplantation outcomes

Although islet transplantation (ITx) is a promising therapy for severe diabetes mellitus, further advancements are necessary. Adiponectin, an adipokine that regulates lipid and glucose metabolism, exerts favorable effects on islets, such as reinforcement of the insulin-releasing function. This study evaluated the possibility of adiponectin use to improve ITx outcomes. We treated mouse islets with 10 µg/mL recombinant mouse adiponectin by overnight culture and then assessed the insulin-releasing, angiogenic, and adhesion functions of the islets. Furthermore, 80 syngeneic islet equivalents with or without adiponectin treatment were transplanted into the renal subcapsular space of diabetic mice. In in vitro assessment, released insulin at high glucose stimulation, insulin content, and expressions of vascular endothelial growth factor and integrin β1 were improved in adiponectin-treated islets. Furthermore, adiponectin treatment improved the therapeutic effect of ITx on blood glucose levels and promoted angiogenesis of the transplanted islets. However, the therapeutic effect was not pronounced in glucose tolerance test results. In conclusion, adiponectin treatment had preferable effects in the insulin-releasing, angiogenic, and adhesion functions of islets and contributed to the improvement of ITx. The future use of adiponectin treatment in clinical settings to improve ITx outcomes should be investigated.