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The vascular endothelial growth factor (VEGF) family plays a crucial role in cancer progression, but the prognostic significance and biological functions of VEGF family members in colon adenocarcinoma (COAD) remain unclear. Using data from The Cancer Genome Atlas, Gene Expression Omnibus, Gene Set Cancer Analysis, cBioPortal, GeneMANIA, String, MethSurv and starBase database, we identified vascular endothelial growth factor B (VEGFB) as a key gene associated with COAD prognosis, with its abnormal expression linked to methylation dysregulation. In vitro experiments confirmed VEGFB expression was significantly higher in colon cancer tissues compared to normal tissues, as shown by Real-time quantitative PCR and immunohistochemistry. Cell Counting Kit-8 and colony formation assay showed that decreased VEGFB expression in SW480 cells resulted in decreased cell viability and proliferation ability. Scratch assay showed that VEGFB downregulation impaired SW480 cell migration. In addition, our research suggests that VEGFB not only promotes angiogenesis but is also involved in the tumor microenvironment and immune regulation. The SHNG17-miR-375-VEGFB regulatory axis provides a potential therapeutic target for COAD, highlighting VEGFB’s role in immune activation during anti-angiogenic therapy and potential reversal of drug resistance. [ABSTRACT FROM AUTHOR]

Platelet-rich plasma (PRP) is an autologous preparation used to accelerate regeneration; however, this form of therapy is not always effective. Vascular endothelial growth factor B (VEGFB), which affects vessel survival, pathological angiogenesis, and muscle development may differentiate the risk and treatment of lateral elbow tendinopathy (LET). In this study, we analyzed the influence of VEGFB gene polymorphisms on the effectiveness of LET treatment with PRP. Therapeutic effectiveness was analyzed in 107 patients (132 elbows) using patient-reported outcome measures (PROMs), specifically the visual analog scale (VAS); quick version of disabilities of the arm, shoulder, and hand score (QDASH); and patient-rated tennis elbow evaluation (PRTEE), for two years (weeks 2, 4, 8, 12, 24, 52, and 104). The polymorphisms selected for the study were rs72922019, rs12366035, rs4930152, rs594942, and rs595880, being in strong linkage disequilibrium. Patients with TT (rs72922019), TT (rs12366035), AA (rs4930152), CC (rs594942), and GG (rs595880) genotypes showed better treatment effectiveness. Statistically important differences were shown for rs72922019 VAS (week 2), QDASH (weeks 0–4), and PRTEE (week 2); rs12366035 and rs4930152 VAS (week 2), QDASH (week 2), and PRTEE (weeks 2 and 4); and rs594942 and rs595880 VAS (weeks 2 and 4), QDASH (week 2), and PRTEE (weeks 2, 52, and 104). The studied polymorphisms also showed an association with blood morphological parameters, including mean platelet volume, platelet distribution width, and eosinophil levels, as well as some comorbidities (heart failure). Genotyping due to patient selection for therapy may be considered for any of the rs72922019, rs12366035, or rs4930152 polymorphisms. [ABSTRACT FROM AUTHOR]

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. Methods In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. Results We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Conclusions Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor. Graphical Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. Methods: In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. Results: We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Conclusions: Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a highly prevalent malignancy affecting the digestive system on a global scale. This study aimed to explore the previously unexplored role of CHPF in the progression of CRC. Our results revealed a significant upregulation of CHPF expression in CRC tumour tissues compared to normal tissues, with its levels correlating with tumour malignancy. In vitro experiments using CRC cell lines demonstrated that inhibiting CHPF expression suppressed cell proliferation, colony formation and cell migration, while promoting apoptosis. Conversely, overexpressing CHPF had the opposite effect. Additionally, our xenograft models in mice confirmed the inhibitory impact of CHPF knockdown on CRC progression using various cell models. Mechanistic investigations unveiled that CHPF may enhance VEGFB expression through E2F1‐mediated transcription. Functionally, suppressing VEGFB expression successfully mitigated the oncogenic effects induced by CHPF overexpression. Collectively, these findings suggest that CHPF may act as a tumour promoter in CRC, operating in a VEGFB‐dependent manner and could be a potential target for therapeutic interventions in CRC treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a highly vascularized tumor, one of the most common and lethal cancer-related tumor deaths worldwide, with cell proliferation playing a key role. In this study our western blot results and data from TAGC demonstrate a strong association between Sorcin (SRI) overexpression and poor outcomes in HCC. Moreover, SRI overexpression was remarkably effective in promoting proliferation in vitro and increasing tumor growth in vivo, which were attenuated by knocking down SRI. Mechanistically, SRI regulated vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor B (VEGFB) through PI3K/Akt/FOXO1 signal pathway. Overall, our study indicates that SRI stimulates HCC growth by controlling VEGFA/B, which presents a fresh insight into the pathogenesis of hepatocarcinogenesis and a new therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Abstract Objective Vascular endothelial growth factor B (VEGFB) was regarded to improve lipid metabolism and reduce obesity-related hyperlipidemia. Whether VEGFB participates in lipid metabolism in nonalcoholic fatty liver disease (NAFLD) has not been clear yet. This study investigated the involvement of VEGFB in lipid metabolism and insulin resistance via the AMPK signaling pathway in NAFLD. Methods We constructed the animal and cell model of NAFLD after VEGFB gene knockout to detect liver damage and metabolism in NAFLD. Bioinformatics analysis of VEGFB and the AMPK signaling pathway relative genes to verify the differential proteins. And mRNA levels of NAFLD fatty acid metabolism-related genes were detected. Results After the systemic VEGFB knockout mice were fed with high fat, the body fat, serum lipoprotein, NAFLD score, and insulin resistance were increased. Animal and cell experiments showed that the expression levels of phosphorylated proteins of CaMKK2 and AMPK decreased, the expression of proteins related to AMPK/ACC/CPT1 signaling pathway decreased, and the target genes CPT1α and Lcad decreased accordingly, reducing fatty acid oxidation in hepatocyte mitochondria; The expression of AMPK/SREBP1/Scd1 signaling pathway relative proteins increased, ACC1 and FAS increased correspondingly, which increased lipid synthesis in the endoplasmic reticulum. Conclusion VEGFB can participate in lipid metabolism and insulin resistance of NAFLD through the AMPK signaling pathway.

Elisha J Fogel,1 Avishai Samouha,1 Sanjay Goel,2 Radhashree Maitra1,2 1Department of Biology, Yeshiva University, New York, NY, 10033, USA; 2Albert Einstein College of Medicine at Montefiore Medical Center, Bronx, NY, 10461, USACorrespondence: Radhashree MaitraDepartment of Biology, Yeshiva University, 500 W 185th Street, New York, NY, 10033, USATel +1 718-801-1359Email Radhashree.maitra@yu.eduPurpose: Reovirus propagates with high efficiency in KRAS mutated colorectal cancer (CRC). About 45– 50% of CRC patients possess a KRAS mutation. Oncolytic reovirus treatment in combination with chemotherapy was tested in patients possessing KRAS mutated metastatic CRC. This study evaluates the biological responses to reovirus treatment by determining the gene expression patterns in RAS-related signaling pathways.Methods: Reovirus was administered as a 60-min intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3× 1010. Peripheral blood mononuclear cells (PBMCs) were isolated from whole-blood pre- and post-reovirus administration at 48 hr, day-8, and day-15. Clariom_D_Human_Assay was used to determine the expression of vital genes compared to pre-reovirus treatment by RNA sequencing. Using exported sample signals, ΔΔCt method was used to analyze the fold changes of genes within seven gene pathways. Significance was calculated by students-two-tail-t-test. Hierarchical clustering dendrogram was constructed by calculating Pearson’s correlation coefficients.Results: As compared to the control, SOS1[48 hr; 2.49X], RRAS [48 hr; 2.24X], PIK3CB [D8, D15; 2.27X, 3.16X], MIR 16– 2 [D15; 1.70X], CHORDC1 [48 hr, D15; 1.89X, 4.54X], RTN4 [48 hr; 4.66X], FAM96A [48 hr; 4.54X], NFKB [D8, D15; 19.0X, 1.42X], CASP8 [D8, D15; 2.11X, 1.77X], and CASP9 [D8; 1.45X] are upregulated post-reovirus. NOS3 [D15; 0.61X], SYNE1 [D8, D15; 0.78X, 0.71X], ANGPT1 [D8; 0.62X], VEGFB [48 hr, D8, D15; 0.44X, 0.28X, 0.28X], JUN [D15; 0.69X], and IGF2 [D8; 0.73X] are downregulated post-reovirus. Fold change values were significant [p< 0.05].Conclusion: This study highlights reovirus as a novel treatment option for KRAS mutated CRC and showcases its effect on the expression of crucial genes.Keywords: transcriptome, reovirus, CRC, KRAS, CASP8, CHORDC1, RTN4, VEGFB

Objective: Vascular endothelial growth factor B (VEGFB) was regarded to improve lipid metabolism and reduce obesity-related hyperlipidemia. Whether VEGFB participates in lipid metabolism in nonalcoholic fatty liver disease (NAFLD) has not been clear yet. This study investigated the involvement of VEGFB in lipid metabolism and insulin resistance via the AMPK signaling pathway in NAFLD.Methods: We constructed the animal and cell model of NAFLD after VEGFB gene knockout to detect liver damage and metabolism in NAFLD. Bioinformatics analysis of VEGFB and the AMPK signaling pathway relative genes to verify the differential proteins. And mRNA levels of NAFLD fatty acid metabolism-related genes were detected.Results: After the systemic VEGFB knockout mice were fed with high fat, the body fat, serum lipoprotein, NAFLD score, and insulin resistance were increased. Animal and cell experiments showed that the expression levels of phosphorylated proteins of CaMKK2 and AMPK decreased, the expression of proteins related to AMPK/ACC/CPT1 signaling pathway decreased, and the target genes CPT1α and Lcad decreased accordingly, reducing fatty acid oxidation in hepatocyte mitochondria; The expression of AMPK/SREBP1/Scd1 signaling pathway relative proteins increased, ACC1 and FAS increased correspondingly, which increased lipid synthesis in the endoplasmic reticulum.Conclusion: VEGFB can participate in lipid metabolism and insulin resistance of NAFLD through the AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]

Excessive fat accumulation causes obesity and many diseases. Previous study demonstrates VEGFB universal knockout induces obese phenotypes including expansion of white adipose tissue, whitening of brown adipose tissue, increase of fat accumulation and reduction in energy consumption. However, roles of VEGFB in adipose tissues are not clear. In this study, we have generated a mouse model w ith adipose-specific VEGFB repression using CRISPR/dCas9 system (VegfbAdipoDown) and investigated the roles of VEGFB in adipose development and energy metabolism. VEGFB repression induced significant changes in adipose tissue structure and function. VegfbAdipoDown mice have larger body sizes, larger volume of white adipose tissues than its wild type littermates. Adipose-specific VEGFB repression induced morphological and functional transformation of adipose tissues toward white adipose for energy storage. Metabolic processes are broadly changed in VegfbAdipoDown adipose tissues including carbohydrate metabolism, lipid metabolism, nucleotide metabolism and amino acid metabolism. We have demonstrated that adipose VEGFB repression can recapitulate most of the phenotypes of the whole body VEGFB knockout mouse. Intriguingly, approximately 50% VEGFB repression in adipose tissues can almost completely mimic the e ffects of universal Vegfb deletion, suggesting adipose VEGFB is a major regulator of energy metabolism and may be important in prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

To investigate (1) the effect of vascular endothelial growth factor B (VEGFB) on lipid accumulation and the alteration of fatty acids and fatty acid-related enzymes in C2C12 myotubes incubated with fatty acids and (2) the regulatory effect of VEGFB on skeletal muscle lipid metabolism. Mouse C2C12 myotubes were incubated with oleic acid (OA) and palmitic acid (PA), and differentiated mature C2C12 myotubes were treated with VEGFB. Oil-red O staining, BODIPY staining and cell triglycerides (TG) content were examined. Total RNA was isolated, and real-time PCR analysis was performed. Treatment with 100 μM OA and 50 μM PA induced lipid droplet accumulation and increased TG content (p <.01), and 100 ng/mL VEGFB reduced lipid droplet accumulation and decreased TG content (p <.01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of fatty acid transport protein 1 (FATP1) (p <.01) and FATP4 (p <.01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of adipose TG lipase and hormone-sensitive lipase (p <.01) as well as carnitine palmitoyltransferase I (p <.01), peroxisome proliferator-activated receptor-γ coactivator-1α (p <.01), acyl-coa dehydrogenase very long chain (p <.05), acyl-coa synthetase long-chain family member 1 (p <.01), peroxisomal acyl-coenzyme A oxidase 1 (p <.05), and mitochondrial uncoupling protein 3 (p <.01). VEGFB enhanced FATP1and FATP4 expression, promoted C2C12 myotube fatty acid oxidation and TG decomposition, and inhibited C2C12 myotube fatty acid re-esterification, thus inhibiting lipid accumulation in C2C12 myotubes incubated with fatty acids. [ABSTRACT FROM AUTHOR]

In diabetes, compromised glucose utilization leads the heart to use FA almost exclusively for ATP generation. Chronically, this adaptation unfortunately leads to the conversion of FA to potentially toxic FA metabolites. Paired with increased formation of reactive oxygen species related to excessive mitochondrial oxidation of FA, can provoke cardiac cell death. To protect against this cell demise, intrinsic mechanisms must be available to the heart. Vascular endothelial growth factor B (VEGFB) may be one growth factor that plays an important role in protecting against heart failure. As a member of the VEGF family, initial studies with VEGFB focused on its role in angiogenesis. Surprisingly, VEGFB does not appear to play a direct role in angiogenesis under normal conditions or even when overexpressed, but has been implicated in influencing vascular growth indirectly by affecting VEGFA action. Intriguingly, VEGFB has also been shown to alter gene expression of proteins involved in cardiac metabolism and promote cell survival. Conversely, multiple models of heart failure, including diabetic cardiomyopathy, have indicated a significant drop in VEGFB. In this review, we will discuss the biology of VEGFB, and its relationship to diabetic cardiomyopathy.

Vascular endothelial growth factor B (VEGFB), unlike other members of the VEGF family such as VEGFA, shows only limited potential in angiogenesis in mammals, but is involved in lipid metabolism, especially in transporting dietary lipids present in circulation through the vascular endothelium to peripheral tissues. However, the role of Vegfb in invertebrates such as decapod crustaceans with an open circulatory system is still poorly understood. Here, cDNA of a vegfb -like gene was cloned and characterized for the first time from a decapod crustacean, mud crab Scylla paramamosain. The mud crab vegfb -like gene encoded a polypeptide of 386 amino acids that possessed all the typical features of the Vegf family, and shared high homology with other crustacean Vegf orthologs. Relative expression levels of the vegfb -like gene were higher in metabolically active tissues such as gill, heart and muscle, and increased in ovary of female crabs as ovary matured. Knockdown of the vegfb -like gene in vivo reduced the contents of triglyceride in hemolymph and hepatopancreas, as well as total lipid in hepatopancreas. In addition, knockdown of the vegfb -like gene increased tissue expression levels of genes related to fatty acid transportation, allocation and hydrolysis, such as long-chain acyl-CoA synthetase 3/4 (acsl3/4), fatty acid transport protein 1 (fatp1), and hormone-sensitive lipase (hsl), and decreased the expression levels of the genes related to fatty acid synthesis like acetyl-CoA carboxylase (acc). These results in mud crab suggest that Vegfb might play important roles in regulating fatty acid absorption, utilization and allocation in crustaceans. • The Vegfb-like gene is first cloned and function characterized from decapod crustacean Scylla paramamosain. • The Vegfb-like potentially contributes to ovarian lipid accumulation during ovarian maturation of mud crab. • The Vegfb-like is involved in lipid accumulation and metabolism in crustacean. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor B (VEGFB) plays a crucial role in glucolipid metabolism and is highly associated with type 2 diabetes mellitus (T2DM). The role of VEGFB in the insulin secretion of β cells remains unverified. Thus, the present study aimed to discuss the effect of VEGFB on regulating insulin secretion in T2DM development, and its underlying mechanism. A high-fat diet and streptozocin (STZ) were used for inducing T2DM in mice model, and VEGFB gene in islet cells of T2DM mice was knocked out by CRISPR Cas9 and overexpressed by adeno-Associated Virus (AAV) injection. The effect of VEGFB and its underlying mechanism was assessed by light microscopy, electron microscopy and fluorescence confocal microscopy, enzyme-linked immunosorbent assay, mass spectrometer and western blot analysis. The decrement of insulin secretion in islet β cell of T2DM mice were aggravated and blood glucose remained at a high level after VEGFB knockout (KO). However, glucose tolerance and insulin sensitivity of T2DM mice were improved after the AAV–VEGFB186 injection. VEGFB KO or overexpression can inhibit or activate PLCγ/IP3R in a VEGFR1-dependent manner. Then, the change of PLCγ/IP3R caused by VEGFB/VEGFR1 will alter the expression of key factors on the Ca2+/CaMK2 signaling pathway such as PPP3CA. Moreover, VEGFB can cause altered insulin secretion by changing the calcium concentration in β cells of T2DM mice. These findings indicated that VEGFB activated the Ca2+/CaMK2 pathway via VEGFR1-PLCγ and IP3R pathway to regulate insulin secretion, which provides new insight into the regulatory mechanism of abnormal insulin secretion in T2DM. [ABSTRACT FROM AUTHOR]

Purpose: We have investigated the epigenetic regulation by dietary fatty acids of Vegfb levels in rats' white adipose tissue and 3T3-L1 cells. Methods: A group of rats were assigned to three diets, each one with a different composition of saturated, monounsaturated and polyunsaturated fatty acids. Samples of white adipose tissues were taken for the methylation and expression studies. Additionally, 3T3-L1 cells were treated with palmitic, oleic, and linoleic fatty acids. After treatment, cells were harvested and genetic material was extracted for the analysis of Vegfb levels. Results: We report evidence of changes in the methylation levels of the CpG island at the Vegfb promoter and in the Vegfb expression levels in vivo and in vitro by dietary fatty acid, with the main contribution of the linoleic fatty acid. Vegfb promoter methylation levels were closely related to the Vegfb gene expression. Conclusion: According to our results, the regulation of Vegfb gene expression by dietary fatty acids may be mediated, at least in part, by epigenetic modifications on Vegfb promoter methylation. Considering the deep association between angiogenesis and tissue growth, we suggest the nutriepigenetic regulation of Vegfb as a key target in the control of the adipose tissue expansion. [ABSTRACT FROM AUTHOR]

Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumorbearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients. [ABSTRACT FROM AUTHOR]

Background and aim: As an oncogenic long noncoding RNA, differentiation antagonizing non-protein coding RNA (DANCR) was identified in many kinds of cancers. However, the specific function of DANCR in melanoma remains unclear. Here, we aimed to clarify the role of DANCR played in melanoma progression and the underlying mechanisms. Methods: TCGA data base and patients' tissue samples were used to analyzed the function of DANCR in melanoma progression. Transwell assay was used to detect cell migration and tube formation assay was employed to assess the ability of angiogenesis. Western blot, qRT-PCR, ELISA and IHC assay were used to examine VEGFB expression and secrection. Luciferase assay verified the binding of DANCR and miRNA. Results: We found that the expression of DANCR was positively related to poor clinical prognosis of melanoma. DANCR knockdown suppressed melanoma progression with a more significant suppression in vivo compared with it in vitro . Further detection showed that beyond promoting proliferation, DANCR also enhanced angiogenesis via upregulating VEGFB. Mechanistic analysis revealed that DANCR upregulating VEGFB through sponging miR-5194, which negatively regulated VEGFB expression and secretion. Conclusion: We demonstrated a novel oncogenic role DANCR played in melanoma and suggested a new avenue for melanoma therapy by targeting the DANCR/miR-5194/VEGFB signaling., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Skeletal muscle is the major effector organ for exercise. It has been proposed that VEGFB is significantly related to apoptosis in various cell types but not yet in skeletal muscle. We hypothesize that the decrease of VEGFB in skeletal muscle participates in the occurrence of skeletal muscle apoptosis and that exercise inhibits apoptosis by elevating the expression of VEGFB in skeletal muscle cells. Based on this hypothesis, we developed in vitro experiments to mimic the effect of exercise through electrical pulse stimulation (EPS) to observe the effect of EPS on apoptosis and the change in VEGFB expression in differentiated myotubes. In addition, we employed RNA interference to explore whether VEGFB is directly involved in the regulation of myotube apoptosis during EPS. Our results showed that exogenous VEGFB 167 significantly inhibited C2C12 myotube apoptosis induced by TNF-α treatment and that endogenous VEGFB in differentiated C2C12 myotubes was significantly upregulated by EPS. In addition, EPS significantly changed the expression of the apoptotic indicators Bax and Bcl-2 at the mRNA level and downregulated the protein expression of cleaved caspase-3. The antiapoptotic effect of EPS weakened substantially as VEGFB in C2C12 myotubes was inhibited. Taken together, these results indicate that exercise-like EPS inhibits apoptosis by increasing the expression of C2C12 myotube-derived VEGFB. • VEGFB inhibited C2C12 myotube apoptosis induced by TNF-α treatment. • VEGFB in C2C12 myotube was markly upregulated by EPS, meanwhile the apoptosis was significantly downregulated by EPS. • The antiapoptotic effect of EPS weakened as VEGFB was inhibited. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor 165 (VEGF)-mediated autocrine stimulation of tumor cells enhances the progression to a malignant phenotype. VEGFb competes with VEGF and binds to vascular endothelial growth factor receptor (VEGFR), resulting in inhibition of downstream signal transduction pathways. This study was designed to investigate the role of VEGFb in the migration and invasion of human lung adenocarcinoma A549 cells. The full-length of VEGFb was constructed and cloned into an expression plasmid (pVEGFb), and then transfected into A549 cells. Dimethylthiazolyl- 1 -2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect the effect of VEGFb on proliferation of transfected cells. Reverse transcription polymerase chain reaction (RT-PCR) was employed to examine the effect of VEGFb on the expression of VEGF in transfected cells. Wound-healing assays were used to investigate the effect of VEGFb on migration of transfected cells. Matrix metalloproteinase (MMPs) activity assay and in vitro invasion assay were used to determine the role of VEGFb in invasion of transfected cells. There was no significant change in proliferation of A549 cells after transfection of pVEGFb, but the expression of VEGF, migration and invasion in A549 cells were inhibited. Furthermore, exogenous VEGFb inhibited the activity of MMP9 in the supernatant of A549 cells and the subsequent invasion capacity of those cells. We therefore conclude that exogenous VEGFb can inhibit the expression of VEGF, as well as the migration and invasion of A549 cells, but has no effect on the proliferation of A549 cells. [ABSTRACT FROM AUTHOR]

Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, is used in non-small cell lung carcinoma treatment and represses vascular endothelial cell growth factor (VEGF) levels in tumor cell. However, precise affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF) or antiangiogenic VEGF isoforms (VEGFb) is not clear. We therefore tested the hypothesis that rh-endostatin could alter expression of these isoforms to regulate tumor growth. A549 cells were exposed to rh-endostatin, and the expression of VEGF and VEGFb was detected. The role of SP1 as a regulator of isoform expression was investigated. We then examined the anticancer and antiangiogenic efficacy of rh-endostatin in combination with exogenous VEGFb against A549 cells, EA.HY 926 cells and xenograft model of human lung cancer. rh-Endostatin reduced VEGF and induced VEGFb as well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also developed those changes. VEGFb-rh-endostatin combination was highly synergistic and inhibited growth, survival, and migration of A549 cells, VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic vascular endothelial growth factor A (VEGFA) isoform and upregulates antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, VEGFb sensitizes A549 to rh-endostatin treatment and enhances the anticancer effect of rh-endostatin. [ABSTRACT FROM AUTHOR]

It has been demonstrated that vascular endothelial growth factor B (VEGFB) plays a vital role in regulating vascular biological function. However, the role of VEGFB in regulating skeletal muscle cell proliferation and differentiation remains unclear. Thus, this study aimed to investigate the effects of VEGFB on C2C12 myoblast proliferation and differentiation and to explore the underlying mechanism. For proliferation, VEGFB significantly promoted the proliferation of C2C12 myoblasts with the upregulating expression of cyclin D1 and PCNA. Meanwhile, VEGFB enhanced vascular endothelial growth factor receptor 1 (VEGFR1) expression and activated the PI3K/Akt signaling pathway in a VEGFR1-dependent manner. In addition, the knockdown of VEGFR1 and inhibition of PI3K/Akt totally abolished the promotion of C2C12 proliferation induced by VEGFB, suggesting that VEGFB promoted C2C12 myoblast proliferation through the VEGFR1-PI3K/Akt signaling pathway. Regarding differentiation, VEGFB significantly stimulated the differentiation of C2C12 myoblasts via VEGFR, with elevated expressions of MyoG and MyHC. Furthermore, the knockdown of VEGFR1 rather than NRP1 eliminated the VEGFB-stimulated C2C12 differentiation. Moreover, VEGFB activated the PI3K/Akt/mTOR signaling pathway in a VEGFR1-dependent manner. However, the inhibition of PI3K/Akt/mTOR blocked the promotion of C2C12 myoblasts differentiation induced by VEGFB, indicating the involvement of the PI3K/Akt pathway. To conclude, these findings showed that VEGFB promoted C2C12 myoblast proliferation and differentiation via the VEGFR1-PI3K/Akt signaling pathway, providing new insights into the regulation of skeletal muscle development. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor B (VEGFB) is a pleiotropic trophic factor, which in contrast to the closely related VEGFA is known to have a limited effect on angiogenesis. VEGFB improves survival in various tissues including the nervous system, where the effect was observed mainly for peripheral neurons. The neurotrophic effect of VEGFB on central nervous system neurons has been less investigated. Here we demonstrated that VEGFB promotes neurite outgrowth from primary cerebellar granule, hippocampal, and retinal neurons in vitro . VEGFB protected hippocampal and retinal neurons from both oxidative stress and glutamate-induced neuronal death. The VEGF receptor 1 (VEGFR1) is required for VEGFB-induced neurotrophic and neuroprotective effects. Using a structure-based approach, we designed short peptides, termed Vefin1-7, mimicking the binding interface of VEGFB to VEGFR1. Vefins were analyzed for their secondary structure and binding to VEGF receptors and compared with previously described peptides derived from VEGFA, another ligand of VEGFR1. We show that Vefins have neurotrophic and neuroprotective effects on primary hippocampal, cerebellar granule, and retinal neurons in vitro with potencies comparable to VEGFB. Similar to VEGFB, Vefins were not mitogenic for MCF-7 cancer cells. Furthermore, one of the peptides, Vefin7, even dose-dependently inhibited the proliferation of MCF-7 cells in vitro . Unraveling the neurotrophic and neuroprotective potentials of VEGFB, the only nonangiogenic factor of the VEGF family, is promising for the development of neuroprotective peptide-based therapies.

Background: Despite the success of genome-wide association studies for allergic rhinitis (AR), no definitive causal variants have been identified, and a substantial portion of the heritability of the disease is yet to be discovered., Methods: Four families, each with at least 1 parent and one child suffering from dust mite (DM) AR, were recruited, and whole-genome sequencing was performed on samples from 9 eligible individuals from these families. Conjoint analysis was performed for existing gene expression profiling data in the literature and the whole genome sequencing data obtained for these individuals; for presence of family-specific variants segregating with AR and the pathways involved. Similar analyses were also performed with data obtained for 96 sporadic house dust mite (HDM) AR patients and 96 healthy controls., Results: Three rare variants in three genes (FLT1&#95;c.603A ​> ​T; VEGFB&#95;c.322A ​> ​C; and ITGA2&#95;c.502+1G ​> ​A), which are involved in Focal Adhesion pathway, were identified in affected, but not unaffected, subjects in two families. VEGFB&#95;c.322A ​> ​C and/or ITGA2&#95;c.502+1G ​> ​A were further detected in all DM AR patients but not in any healthy individuals in 1 family; which was further investigated for members. The 3 identified variants were not found in any of the sporadic DM AR patients or healthy controls., Conclusion: Despite the relatively small sample size, this study has identified several potentially functional rare variants in AR candidate genes, and it provides a platform for future work in larger numbers of families and sporadic individuals for a better understanding of the genetic basis of AR.

In response to assorted stimuli, the heart will develop into cardiomyocyte hypertrophy, but sustained cardiomyocyte hypertrophy will finally lead to heart failure. This research is aimed to examine the effect of VEGFB on cardiomyocyte hypertrophy by using the cardiomyocyte-derived cell line H9C2 of cultured rates. It turns out that VEGFB can positively prevent the Ang II-induced rising in the size of cardiomyocyte as well as reduce Ang II-induced mRNA and protein levels of β-MHC (β-myosin heavy chain), BNP (brain natriuretic peptide), and ANP (atrial natriuretic peptide). Moreover, VEGFB can regulate the decline of the Ang II-induced rising in Ca 2+ . After VEGFR1 knockdown, these effects of VEGFB were partially reversed. Moreover, VEGFB attenuated the suppression of PKG I, p-VASP, and RGS2 caused by Ang II; whereas VEGFR1 knockdown partially abolished the indicated effect of VEGFB. In a word, the effect of VEGFB on relevant downstream targets and the pathways of PKG I by VEGFR1 may explain its efficacy on cardiomyocyte hypertrophy. Thus, it can be suggested that it is feasible to apply VEGFB-VEGFR1 for reducing the symptoms of cardiomyocyte hypertrophy., (© 2017 Wiley Periodicals, Inc.)