ABSTRACT
Brain aging is a physiological event, and oxidative stress and apoptosis are involved in the natural aging process of the brain. Curcumin is a natural antioxidant with potent anti-aging and neuroprotective properties. Therefore, we investigated the protective effects of curcumin on brain apoptosis and oxidative stress, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) in aged rats. Old female Wistar rats were randomly divided into three groups (n = 7); as follows: (1) control; (2); saline and (3) curcumin (received 30 mg/kg of curcumin, 5 days/week for 8 weeks, intraperitoneally). Our results indicated that treatment with curcumin in aged rats attenuates brain lipid peroxidation, which was accompanied by a significant increase in the BDNF, VEGF, superoxide dismutase (SOD) activity, and anti-apoptotic protein BCl-2. No significant change in brain anti-apoptotic Bax protein levels was observed after curcumin treatment. The study indicates that curcumin could alleviate brain aging which may be due to attenuating oxidative stress, inhibiting apoptosis, and up-regulating SOD activity, which in turn enhances VEGF and BDNF. Therefore, curcumin has potential therapeutic value in the treatment of neurological apoptosis, neurogenesis, and angiogenesis changes caused by brain aging.
Subject(s)
Aging , Apoptosis , Brain-Derived Neurotrophic Factor , Brain , Curcumin , Oxidative Stress , Rats, Wistar , Vascular Endothelial Growth Factor A , Animals , Curcumin/pharmacology , Curcumin/therapeutic use , Oxidative Stress/drug effects , Apoptosis/drug effects , Aging/drug effects , Aging/metabolism , Female , Brain/drug effects , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Rats , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/drug effects , Antioxidants/pharmacology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Superoxide Dismutase/metabolism , Lipid Peroxidation/drug effectsABSTRACT
PURPOSE: The purpose of this research is to demonstrate echinacoside promotes osteogenesis and angiogenesis and inhibits osteoclast formation. METHODS: We conducted a cell experiment in vitro to study how echinacoside affects angiogenesis, osteogenesis and osteoclast formation. We used polymerase chain reaction and Western blotting to detect the expression levels of proteins and genes related to angiogenesis, osteogenesis and osteoclast formation. We established a bone fracture model with rats to test angiogenesis, osteogenesis and osteoclast formation of echinacoside. We labelled osteogenic markers, blood vessels and osteoclastic markers in fracture sections of rats. RESULTS: The in vitro cell experiments showed echinacoside improved the osteogenic activity of mouse embryo osteoblast precursor cells and promoted the migration and tube formation of human umbilical vein endothelial cells. In addition, it inhibited differentiation of mouse leukaemia cells of monocyte macrophage. Echinacoside increased the expression of related proteins and genes and improved angiogenesis and osteogenesis while inhibiting osteoclast formation by repressing the expression of related proteins and genes. From in vivo experiments, the results of IHC and HE experiments demonstrated echinacoside significantly decreased the content of MMP-9 and improved the content of VEGF and OCN. The fluorescence immunoassay showed echinacoside promoted the activities of RUNX2 and VEGF and inhibited CTSK. Echinacoside reduced the content of TNF-α, IL-1ß and IL-6, thus demonstrating its anti-inflammatory activity. CONCLUSION: Echinacoside improved angiogenesis and osteogenesis and inhibited osteoclast formation to promote fracture healing.
Subject(s)
Glycosides , Human Umbilical Vein Endothelial Cells , Matrix Metalloproteinase 9 , Neovascularization, Physiologic , Osteoclasts , Osteogenesis , Animals , Osteogenesis/drug effects , Osteoclasts/drug effects , Mice , Neovascularization, Physiologic/drug effects , Humans , Human Umbilical Vein Endothelial Cells/drug effects , Rats , Glycosides/pharmacology , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/drug effects , Male , Cell Differentiation/drug effects , Osteoblasts/drug effects , Osteoblasts/metabolism , Rats, Sprague-Dawley , Cell Movement/drug effects , Osteocalcin/metabolism , Osteocalcin/drug effects , Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 1 Subunit/drug effects , AngiogenesisABSTRACT
Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db (T2DM) mice. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 µL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Digital images of wound were obtained once a day from D0 to D14 post-wounding. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. At the molecular level, GDF11 greatly increased HIF-1É expression to enhance the activities of VEGF and SDF-1É, thereby neovascularization. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1É-VEGF/SDF-1É pathway. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW.
Subject(s)
Diabetes Mellitus, Experimental , Endothelial Progenitor Cells , Growth Differentiation Factors , Wound Healing , Animals , Humans , Mice , Bone Morphogenetic Proteins/metabolism , Chemokine CXCL12/drug effects , Chemokine CXCL12/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Endothelial Progenitor Cells/metabolism , Endothelial Progenitor Cells/pathology , Growth Differentiation Factors/therapeutic use , Growth Differentiation Factors/metabolism , Neovascularization, Physiologic , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , Wound Healing/drug effects , Recombinant Proteins/metabolism , Recombinant Proteins/therapeutic use , Hypoxia-Inducible Factor 1, alpha Subunit/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/metabolismABSTRACT
Angiogenesis is a complex process encompassing endothelial cell proliferation, migration, and tube formation. While numerous studies describe that curcumin exerts antitumor properties (e.g., targeting angiogenesis), information regarding other dietary curcuminoids such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BisDMC) is scant. In this study, we evaluated the antiangiogenic activities of these three curcuminoids at physiological concentrations (0.1-5 µM) on endothelial cell migration and tubulogenesis and the underlying associated mechanisms on human aortic endothelial cells (HAECs). Results showed that the individual compounds and a representative mixture inhibited the tubulogenic and migration capacity of endothelial cells dose-dependently, while sparing cell viability. Notably, DMC and BisDMC at 0.1 and 1 µM showed higher capacity than curcumin inhibiting tubulogenesis. These compounds also reduced phosphorylation of the VEGFR2 and the downstream ERK and Akt pathways in VEGF165-stimulated cells. In silico analysis showed that curcuminoids could bind the VEGFR2 antagonizing the VEGF-mediated angiogenesis. These findings suggest that physiologically concentrations of curcuminoids might counteract pro-angiogenic stimuli relevant to tumorigenic processes.
Subject(s)
Diarylheptanoids , Neovascularization, Pathologic , Vascular Endothelial Growth Factor Receptor-2 , Angiogenesis Inhibitors/pharmacology , Cell Movement , Cell Proliferation , Curcumin/therapeutic use , Diarylheptanoids/metabolism , Diarylheptanoids/pharmacology , Diarylheptanoids/therapeutic use , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/drug effects , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from Papaver somniferum that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.
Subject(s)
Cell Movement , Neoplasms , Papaverine , Vascular Endothelial Growth Factor A , Antineoplastic Agents , Cell Line , Cell Movement/drug effects , Humans , Papaverine/pharmacology , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth FactorsABSTRACT
We investigated the effect of tofogliflozin, a sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i), on retinal blood flow dysregulation, neural retinal dysfunction, and the impaired neurovascular coupling in type 2 diabetic mice. Tofogliflozin was added to mouse chow to deliver 5 mg/kg/day and 6-week-old mice were fed for 8 weeks. The longitudinal changes in the retinal neuronal function and blood flow responses to systemic hyperoxia and flicker stimulation were evaluated every 2 weeks in diabetic db/db mice that received tofogliflozin (n =6) or placebo (n = 6) from 8 to 14 weeks of age. We also evaluated glial activation and vascular endothelial growth factor (VEGF) expression by immunofluorescence. Tofogliflozin treatment caused a sustained decrease in blood glucose in db/db mice from 8 weeks of the treatment. In tofogliflozin-treated db/db mice, both responses improved from 8 to 14 weeks of age, compared with vehicle-treated diabetic mice. Subsequently, the electroretinography implicit time for the oscillatory potential was significantly improved in SGLT2i-treated db/db mice. The systemic tofogliflozin treatment prevented the activation of glial fibrillary acidic protein and VEGF protein expression, as detected by immunofluorescence. Our results suggest that glycemic control with tofogliflozin significantly improved the impaired retinal neurovascular coupling in type 2 diabetic mice with the inhibition of retinal glial activation.
Subject(s)
Benzhydryl Compounds/pharmacology , Glucosides/pharmacology , Neurovascular Coupling/physiology , Sodium-Glucose Transporter 2/metabolism , Animals , Benzhydryl Compounds/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetic Retinopathy/prevention & control , Glucosides/metabolism , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Neurovascular Coupling/drug effects , Retina/drug effects , Retina/metabolism , Sodium-Glucose Transport Proteins/antagonists & inhibitors , Sodium-Glucose Transport Proteins/metabolism , Sodium-Glucose Transporter 2/drug effects , Sodium-Glucose Transporter 2 Inhibitors/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVE: Endometriosis, defined as the growth of endometrial glands and stromal cells in a heterotopic location under the cyclic influence of ovarian hormones, is a common gynecological disorder manifested by chronic pelvic pain and infertility. In traditional Chinese medicine, endometriosis is characterized by stagnation of vital energy (qi) and blood stasis. Guizhi Fuling Wan (GFW) was first described in Chinese canonical medicine to treat disorders associated with stagnation of qi and blood stasis, including endometriosis. Therefore, the current study aimed to test the effects of combining GFW with western medicine on the suppression of endometriosis. MATERIALS AND METHODS: Endometriosis was generated by suturing endometrial tissue on the peritoneal wall of C57BL/6JNarl mice. The mice were subsequently treated with either GFW or current hormonal therapies or in combination for 28 days. RESULTS: Endometriosis development was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone or GFW + medroxyprogesterone acetate (MPA). The expression of intercellular adhesion molecule 1 (ICAM-1) was inhibited by GFW, Gestrinone, MPA, Visanne, GFW + Gestrinone, GFW + MPA and GFW + Visanne. Vascular endothelial growth factor (VEGF) expression was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone and GFW + MPA. Both ICAM-1- and VEGF-reducing effects of GFW were attenuated by western medicines. Administration of GFW, MPA, Visanne, GFW + MPA and GFW + Visanne also correspondingly reduced macrophage population in peritoneal fluid. GFW, MPA, Visanne, GFW + MPA and GFW + Visanne enhanced B-cell population in peritoneal fluid. CONCLUSION: The current study reveals the therapeutic effects of GFW on endometriosis. However, the combination of GFW and current hormonal therapies potentially impedes the efficacy of each individual agent in treating endometriosis.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Endometriosis/drug therapy , Gestrinone/therapeutic use , Intercellular Adhesion Molecule-1/drug effects , Medroxyprogesterone Acetate/therapeutic use , Vascular Endothelial Growth Factor A/drug effects , Animals , Female , Mice , Mice, Inbred C57BLABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Oxytropis falcata Bunge is a legume distributed in Northwest China, which is mainly used to treat knife wounds and inflammation. Quercetin is a bioactive flavonoid in O. falcata and becomes a promising healing compound for its angiogenic and anti-inflammatory activities. However, the healing mechanism of quercetin in cutaneous wound remains elusive. AIM OF THE STUDY: The purpose of this study was to evaluate the healing effect of quercetin on cutaneous wound models in vivo and in vitro, and to reveal the Wnt/ß-catenin pathway and Telomerase reverse transcriptase (TERT) involved mechanisms. MATERIALS AND METHODS: The effects of quercetin on the proliferation and migration of 4 kinds of skin cells were determined by CCK-8 and scratch assay. The wound-healing capacity of quercetin was evaluated in cutaneous wound model of C57BL/6 mice and the wound healing degree was observed by histological staining. The expressions of inflammatory factors, growth factors and the related proteins were detected via Western blot and RT-qPCR analyses. The molecular docking was adopted to evaluate the binding ability of quercetin and TERT. RESULTS: Quercetin could promote both proliferation and migration of fibroblasts, and enhance cutaneous wound healing capacity in mice. Compared to the control group, the wound healing rates in low (1.5 mg/mL), medium (3.0 mg/mL) and high dose (6.0 mg/mL) quercetin groups reached 94.67%, 97.31% and 98.42%, respectively. Moreover, the dermal structure in quercetin treated mice restored normal and the content of collagen fiber became abundant after administration. The levels of inflammatory factors, including tumor necrosis factor-α, interleukin-1ß and interleukin-6 were significantly reduced after quercetin administration. Among which, the level of IL-1ß in cutaneous wound was 0.007 times higher than that of the control group when treated with quercetin of high dose (6.0 mg/mL). The improved level of GSH in quercetin treated cutaneous wounds also indicated its higher antioxidant ability. In addition, dose-dependent positive associations were found in the expression levels of vascular endothelial growth factor, fibroblast growth factor and alpha smooth muscle actin in quercetin treated cutaneous wounds. The significantly upregulated protein levels of Wnt and ß-catenin further indicated the important role of quercetin in promoting wound healing in mice. According to molecular docking analysis, the formed hydrogen bonds between quercetin and Ala195, Gln308, Asn369 and Lys372 residues of TERT also indicated the indispensable role of TERT in improving wound healing capacity. CONCLUSION: Quercetin effectively promoted cutaneous wound healing by enhancing the proliferation and migration of fibroblasts, as well as inhibiting inflammation and increasing the expression of growth factors in mice via Wnt/ß-catenin signaling pathway and TERT. It provides a basis for a more thorough understanding of mechanism of action of O. falcata Bunge in the treatment of knife wounds and burns.
Subject(s)
Oxytropis/chemistry , Quercetin/pharmacology , Telomerase/drug effects , Wnt Signaling Pathway/drug effects , Wound Healing/drug effects , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , China , Dose-Response Relationship, Drug , Fibroblast Growth Factors/drug effects , Humans , Inflammation Mediators , Interleukin-1beta/drug effects , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Skin/drug effects , Tumor Necrosis Factor-alpha/drug effects , Vascular Endothelial Growth Factor A/drug effectsABSTRACT
SUMMARY: Laser photobiomodulation (laser PBM) is known to be able to accelerate burn wound healing in the animal model; however little evidence exists on the action of laser PBM on the expression of important proteins in wound healing in the animal model, such as VEGF and TGF-ß1. The aim of this study was to carry out a systematic review in order to analyse the effect of laser PBM on VEGF and TGF-ß expression during burn wound repair in the animal model. A systematic review was carried out of the EMBASE, PubMed/ MEDLINE and LILACS databases. The studies included were preclinical studies that analysed the action of laser PBM on the expression of VEGF and TGF-ß (1, 2, 3) during burn wound repair in the animal model. The SYRCLE risk of bias tool was used. Random effect models were used to estimate the combined effect. Increased VEGF expression was observed with the use of laser PBM at 4.93 J/cm2 per point in the first two weeks after induction of the burn wound, with greater size of effect in the second week (SDM = 5.72; 95% CI: 3.14 to 8.31, I2 = 0 %; very low certainty of evidence). We also observed that the effect of laser PBM on TGF-ß1 expression was greater than in the control in the first week (SDM = -0.45; 95% CI: -1.91 to 1.02, I2 = 51 %; very low certainty of evidence), but diminished in the third week after induction of the lesion (SDM = -2.50; 95% CI: 3.98 to -1.01, I2 = 0 %; very low certainty of evidence). Laser PBM has an effect on TGF-ß1 and VEGF expression, promoting burn wound repair in the animal model.
RESUMEN: Es sabido que la fotobiomodulación por láser (FBM láser) puede acelerar el proceso de curación de heridas por quemadura en modelo animal, sin embargo aún se carece de mayor evidencia sobre la acción de la FBM láser en la expresión de proteínas importantes en el proceso de curación de heridas en modelo animal, como VEGF y TGF-ß1. Así, el objetivo de este estudio fue realizar una revisión sistemática a fin de analizar el efecto de la FBM láser sobre la expresión de VEGF, TGF-ß durante el proceso de reparación de heridas por quemadura en modelo animal. Se realizó una búsqueda sistemática en las bases de datos EMBASE, PubMed/MEDLINE y LILACS. Se incluyeron estudios preclínicos que analizaron la acción de la FBM láser en la expresión de VEGF, TGF-ß (1, 2, 3) durante el proceso de reparación de heridas por quemadura en modelo animal. Se utilizó la herramienta de riesgo de sesgo SYRCLE. Se utilizaron modelos de efectos aleatorios para estimar el efecto combinado. Observamos aumento de la expresión de VEGF con el uso de FBM láser 4.93 J/cm2 por punto, en las dos primeras semanas tras inducción de la herida por quemadura, con mayor tamaño de efecto en la segunda semana (SDM = 5,72; IC del 95%: 3,14 a 8,31, I2 = 0 %; certeza de la evidencia muy baja). También se observó el efecto de la FBM láser en la expresión del TGF- ß1 que fue mayor que el control en la primera semana (SDM = - 0,45; IC del 95%: -1,91 a 1,02, I2 = 51 %; certeza de la evidencia muy baja), disminuyendo en la tercera semana tras inducción de la lesión (SDM = -2,50; IC del 95%: -3,98 a -1,01; I2 = 0 %; certeza de la evidencia baja). La TFB por láser ejerce influencia en la expresión de TGF-ß1 y VEGF favoreciendo el proceso de reparación de heridas por quemadura en modelo animal.
Subject(s)
Animals , Wound Healing/radiation effects , Transforming Growth Factor beta/drug effects , Low-Level Light Therapy , Vascular Endothelial Growth Factor A/drug effects , Burns/radiotherapy , Disease Models, AnimalABSTRACT
BACKGROUND: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES: We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1ß, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1ß (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS: The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.
Subject(s)
COVID-19 Drug Treatment , Chemokines/drug effects , Cholecalciferol/administration & dosage , Cytokines/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/drug effects , Vascular Endothelial Growth Factor A/drug effects , Vitamins/administration & dosage , Adult , Aged , Brazil , COVID-19/immunology , Double-Blind Method , Female , Humans , Intercellular Signaling Peptides and Proteins/blood , Male , Middle Aged , SARS-CoV-2/immunologyABSTRACT
Hepatocellular carcinoma (HCC) is one of the most burdened tumors worldwide, with a complex and multifactorial pathogenesis. Current treatment approaches involve different molecular targets. Phytochemicals have shown considerable promise in the prevention and treatment of HCC. We investigated the efficacy of two natural components, 1,8 cineole (Cin) and ellagic acid (EA), against diethylnitrosamine/2-acetylaminofluorene (DEN/2-AAF) induced HCC in rats. DEN/2-AAF showed deterioration of hepatic cells with an impaired functional capacity of the liver. In addition, the levels of tumor markers including alpha-fetoprotein, arginase-1, alpha-L-fucosidase, and ferritin were significantly increased, whereas the hepatic miR-122 level was significantly decreased in induced-HCC rats. Interestingly, treatment with Cin (100mg/kg) and EA (60mg/kg) powerfully restored these biochemical alterations. Moreover, Cin and EA treatment exhibited significant downregulation in transforming growth factor beta-1 (TGF-ß1), Fascin-1 (FSCN1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and epithelial-mesenchymal transition (EMT) key marker, vimentin, along with a restoration of histopathological findings compared to HCC group. Such effects were comparable to Doxorubicin (DOX) (2mg/kg); however, a little additive effect was evident through combining these phytochemicals with DOX. Altogether, this study highlighted 1,8 cineole and ellagic acid for the first time as promising phytochemicals for the treatment of hepatocarcinogenesis via regulating multiple targets.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular , Ellagic Acid , Eucalyptol , Phytochemicals/pharmacology , Animals , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carrier Proteins/drug effects , Carrier Proteins/metabolism , Disease Models, Animal , Ellagic Acid/administration & dosage , Ellagic Acid/pharmacology , Eucalyptol/administration & dosage , Eucalyptol/pharmacology , Humans , Liver Neoplasms/chemically induced , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , MicroRNAs/drug effects , MicroRNAs/metabolism , Microfilament Proteins/drug effects , Microfilament Proteins/metabolism , Rats , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vimentin/drug effects , Vimentin/metabolismABSTRACT
Cranberry extract (CBE) is a major source of the antioxidant polyphenolics but suffers from limited bioavailability. The goal of this research was to encapsulate the nutraceutical (CBE), into bile salt augmented liposomes (BSALs) as a promising oral delivery system to potentiate its hepatoprotective impact against dimethylnitrosamine (DMN) induced liver injury in rats. The inclusion of bile salt in the liposomal structure can enhance their stability within the gastrointestinal tract and promote CBE permeability. CBE loaded BSALs formulations were fabricated utilizing a (23) factorial design to explore the impact of phospholipid type (X1), phospholipid amount (X2), and sodium glycocholate (SGC) amount (X3) on BSALs properties, namely; entrapment efficiency percent, (EE%); vesicle size, (VS); polydispersity index; (PDI); zeta potential, (ZP); and release efficiency percent, (RE%). The optimum formulation (F1) exhibited spherical vesicles with EE% of 71.27 ± 0.32%, VS; 148.60 ± 6.46 nm, PDI; 0.38 ± 0.02, ZP; -18.27 ± 0.67 mV and RE%; 61.96 ± 1.07%. Compared to CBE solution, F1 had attenuated DMN-induced hepatic injury, as evidenced by the significant decrease in serum level of ALT, AST, ALP, MDA, and elevation of GSH level, as well as SOD and GPX activities. Furthermore, F1 exhibited an anti-inflammatory character by suppressing TNF-α, MCP-1, and IL-6, as well as downregulation of VEGF-C, STAT-3, and IFN-γ mRNA levels. This study verified that when CBE was integrated into BSALs, F1, its hepatoprotective effect was significantly potentiated to protect the liver against DMN-induced damage. Therefore, F1 could be deliberated as an antioxidant, antiproliferative, and antifibrotic therapy to slow down the progression of hepatic damage.
Subject(s)
Bile Acids and Salts/chemistry , Chemical and Drug Induced Liver Injury/drug therapy , Liposomes/chemistry , Plant Extracts/pharmacology , Vaccinium macrocarpon , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemistry, Pharmaceutical , Dimethylnitrosamine/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Carriers , Drug Liberation , Inflammation Mediators/metabolism , Liver Function Tests , Male , Oxidative Stress/drug effects , Rats , Rats, Wistar , Receptors, CCR2/drug effects , STAT3 Transcription Factor/drug effects , Surface Properties , Vascular Endothelial Growth Factor A/drug effectsABSTRACT
Despite considerable advances in cancer treatment, chemotherapy remains a cornerstone in breast cancer therapy. Therefore, reducing chemoresistance and adverse effects of chemotherapy is a priority. In this regard, Baicalin (BA) is the dominant natural flavonoid extracted from the roots of Scutellaria baicalensis showed fascinating antitumor activity in many types of cancers, including breast cancer. The present study aimed to explore the chemopreventive and antitumor action of baicalin alone and in combination with 5-FU in addition to its ability to enhance the antitumor effect of 5-FU on breast cancer using the Ehrlich solid tumor-mice model. MATERIALS AND METHODS: A total of 70 female mice were divided into seven groups (1st group, saline group; 2nd group, DMSO group; 3rd group, BA+EST group; 4th group, EST group; 5th group, EST+5-FU; 6th group, EST+BA group; 7th group, EST+5-FU+BA).tumors were assessed by weight and histopathological examination. Inflammation, angiogenesis, and apoptosis were examined by ELISA, qRT-PCR, and immunohistochemical examinations. RESULTS: showed that pre-treatment with baicalin and treatment with baicalin and/or 5-FU significantly reduced inflammation and angiogenesis indicated by suppression of NF-kB/ IL-1ß and VEGF amplification loop with marked elevation in apoptosis indicated by up-regulation of apoptotic caspase-3, pro-apoptotic p53, Bax and downregulation of anti-apoptotic Bcl-2. CONCLUSION: BA is a promising preventive or adjuvant therapy in breast cancer treatment with 5-FU mainly via cooperative inhibition of inflammation, angiogenesis, and triggering apoptotic cell death.
Subject(s)
Breast Neoplasms/pathology , Flavonoids/pharmacology , Fluorouracil/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols , Disease Models, Animal , Drug Synergism , Female , Inflammation Mediators/metabolism , Mice , Neovascularization, Pathologic/metabolism , Tumor Burden , Vascular Endothelial Growth Factor A/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Naringenin, a flavonoid, possesses antiangiogenic potential and inhibits corneal neovascularization (CNV); however, its therapeutic use is restricted due to poor solubility and limited bioavailability. In this study, we developed a naringenin microemulsion (NAR-ME) for inhibiting CNV. NAR-ME formulation was composed of triacetin (oil phase), Cremophor RH40 (CRH40), PEG400, and water, its droplet size was 13.22 ± 0.13 nm with a narrow size distribution (0.112 ± 0.0014). The results demonstrated that NAR-ME released higher and permeated more drug than NAR suspension (NAR-Susp) in in vitro drug release and ex vivo corneal permeation study. Human corneal epithelial cells (HCECs) toxicity study showed no toxicity with NAR-ME, which is consistent with the result of ocular irritation study. NAR-ME had high bioavailability 1.45-fold, 2.15-fold, and 1.35-fold higher than NAR-Susp in the cornea, conjunctiva, and aqueous humor, respectively. Moreover, NAR-ME (0.5% NAR) presented efficacy comparable to that of dexamethasone (0.025%) in the inhibition of CNV in mice CNV model induced by alkali burning, resulting from the attenuation of corneal vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-14) expression. In conclusion, the optimized NAR-ME formulation demonstrated excellent physicochemical properties and good tolerance, enhanced ocular bioavailability and corneal permeability. This formulation is promising, safe, and effective for the treatment of CNV.
Subject(s)
Corneal Neovascularization/pathology , Drug Carriers/chemistry , Emulsions/chemistry , Flavanones/pharmacology , Animals , Cell Line , Cell Survival , Chemistry, Pharmaceutical , Cornea/metabolism , Disease Models, Animal , Drug Liberation , Drug Stability , Flavanones/administration & dosage , Flavanones/adverse effects , Humans , Hydrogen-Ion Concentration , Male , Matrix Metalloproteinase 14/drug effects , Mice , Mice, Inbred BALB C , Ophthalmic Solutions , Particle Size , Rabbits , Surface Properties , Vascular Endothelial Growth Factor A/drug effectsSubject(s)
Flavanones/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/drug effects , Toll-Like Receptor 4/drug effects , Vascular Endothelial Growth Factor A/drug effects , Antineoplastic Agents, Hormonal/metabolism , Antineoplastic Agents, Hormonal/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/physiopathology , Flavanones/therapeutic use , Humans , Signal Transduction/drug effects , Tamoxifen/metabolism , Tamoxifen/therapeutic useABSTRACT
Dermal papilla cells (DPCs) are a source of nutrients and growth factors, which support the proliferation and growth of keratinocytes as well as promoting the induction of new hair follicles and maintenance of hair growth. The protection from reactive oxygen species (ROS) and the promotion of angiogenesis are considered two of the basal mechanisms to preserve the growth of the hair follicle. In this study, a noncrosslinked hyaluronic acid (HA) filler (HYDRO DELUXE BIO, Matex Lab S.p.A.) containing several amino acids was tested with in vitro assays on human follicle dermal papilla cells (HFDPCs). The experiments were carried out to investigate the possible protection against oxidative stress and the ability to increase the vascular endothelial growth factor (VEGF) release. The results demonstrated the restoration of cell viability against UVB-induced cytotoxicity and an increase in the VEGF secretion. These data demonstrate the capability of the product to modulate human dermal papilla cells, suggesting a future use in mesotherapy, a minimally invasive local intradermal therapy (LIT), after further clinical investigations.
Subject(s)
Dermis/metabolism , Hair Follicle/metabolism , Hyaluronic Acid/pharmacology , Cells, Cultured , Dermis/drug effects , Dermis/growth & development , Hair/growth & development , Hair Follicle/drug effects , Humans , Hyaluronic Acid/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolismABSTRACT
MicroRNA (miRNA)-26a is one of the tumor suppressor genes that has been down regulated during the development of hepatocellular carcinoma (HCC). This work was conducted to evaluate the possible preventive effect of exogenous miRNA-26a administration on diethylnitrosamine (DEN)-mediated HCC. Balb/C mice were intraperitoneally injected with saline (Normal group), DEN (HCC group) or miRNA-26a (HCC+miRNA-26a group). On week 8, 12, 16 and 20, the concentrations of alpha-fetoprotein (AFP), des-gamma carboxyprothrombin (DCP), the levels of helper T cells-associated cytokines, and the vascular endothelial growth factor (VEGF), were measured. Flow cytometry determined the frequencies of regulatory T (Treg) cells. The concentrations of AFP, DCP and VEGF, as well as the frequency of Treg cells showed significantly lower values following miRNA-26a administration than in HCC group. miRNA-26a administration has reduced the levels of IL (interleukin)-2 and TNF (tumor necrosis factor)-α, in contrast, IL-10 level was markedly elevated in comparison to HCC model at all experimental time points. The restore of miRNA-26a function significantly (P<0.001) down regulated the expression levels of survivin & caspase-3 compared to HCC group. The obtained data introduce an evidence for the suppressive impact of miRNA-26a on liver tumor formation and its possible manipulation as a therapeutic design for HCC.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms/metabolism , Liver/drug effects , MicroRNAs/pharmacology , Alkylating Agents/toxicity , Animals , Apoptosis/drug effects , Biomarkers/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Caspase 3/drug effects , Caspase 3/metabolism , Cytokines/drug effects , Cytokines/metabolism , Diethylnitrosamine/toxicity , Interleukin-10/metabolism , Interleukin-2/metabolism , Liver/metabolism , Liver/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms, Experimental/genetics , Liver Neoplasms, Experimental/pathology , Mice , Protein Precursors/drug effects , Protein Precursors/metabolism , Prothrombin/drug effects , Prothrombin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survivin/drug effects , Survivin/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/metabolism , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , alpha-Fetoproteins/drug effects , alpha-Fetoproteins/metabolismABSTRACT
Tinzaparin is an anticoagulant and antiangiogenic drug with inhibitory properties against tumor growth. VEGF stimulates angiogenesis, while an association between reactive oxygen species (ROS) and angiogenesis is involved in tumor progression. The present study aimed to investigate the effect of tinzaparin on VL30 retrotranspositionpositive mouse HC11 mammary stemlike epithelial cells, previously reported to be associated with induced mammosphere/cancer stem cell (CSC) generation and tumorigenesis. Under 24 h serum starvation, 15.2% nominal retrotransposition frequency was increased to 29%. Additionally, while treatment with 312 ng/ml VEGF further induced retrotransposition frequency in a dosedependent manner (up to 40.3%), preincubation with tinzaparin (2 IU/ml) for 0.54 h reduced this frequency to 18.3% in a timedependent manner, confirmed by analogous results in NIH3T3 fibroblasts. Treatment with 1040 pg/ml glucose oxidase (GO) for 24 h induced HC11 cell retrotransposition in a dosedependent manner (up to 82.5%), while a 3 h preincubation with tinzaparin (1 or 2 IU/ml) elicited a 13.5 or 25.5% reduction in retrotransposition, respectively. Regarding tumorigenic VL30 retrotranspositionpositive HC11 cells, treatment with 2 IU/ml tinzaparin for 5 days reduced proliferation rate in a timedependent manner (up to ~55%), and after 3 weeks, disaggregated soft agarformed foci, as well as lowadherent mammospheres, producing single mesenchymallike cells with a ~50% reduced retrotransposition. With respect to the VL30 retrotransposition mechanism: While 12 ng/ml VEGF increased the level of VL30 and endogenous reverse transcriptase (enRT) transcripts ~1.41 and ~1.16fold, respectively, subsequent tinzaparin treatment reduced both endogenous/ROS and VEGFinduced levels 1.15 and 0.40fold (VL30) and 0.60 and 0.52fold (enRT), respectively. To the best of our knowledge, these data demonstrate for the first time, the novel inhibition activity of tinzaparin against ROS and VEGFinduced VL30 retrotransposition, and the proliferation and/or aggregation of mouse HC11 mammosphere/tumorinitiating CSCs, thus contributing to the inhibition of VL30 retrotranspositioninduced primary tumor growth.
Subject(s)
Neoplastic Stem Cells/drug effects , Oxidative Stress/drug effects , Tinzaparin/pharmacology , Vascular Endothelial Growth Factor A/drug effects , Animals , Anticoagulants/pharmacology , Cell Proliferation , Cells, Cultured , Female , Mice , Mice, Inbred BALB C , NIH 3T3 CellsABSTRACT
Betulinic acid (3ß-Hydroxy-20(29)-lupaene-28-oic acid, BA) has excellent anti-cancer activity but poor solubility and low bioavailability. To improve the antitumor activity of BA, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) graft copolymer (Soluplus) encapsulated BA micelle (Soluplus-BA) was fabricated. The Soluplus-BA micelles presented a mean size of 54.77 ± 1.26 nm and a polydispersity index (PDI) of 0.083. The MTT assay results showed that Soluplus-BA micelles increased the inhibitory effect of BA on MDA-MB-231 cells, mainly due to the enhanced accumulation of reactive oxygen species (ROS) and the destruction of mitochondrial membrane potential (MMP). Soluplus-BA micelles induced the DNA double-strand breaks (DSBs) as the γH2AX foci increased. Moreover, Soluplus-BA also inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), and inhibited the neovascularization of the chicken chorioallantoic membrane (CAM). This angiogenesis inhibitory effect may be accomplished by regulating the HIF-1/VEGF-FAK signaling pathway. The in vivo study confirmed the improved anti-tumor effect of Soluplus-BA and its inhibitory effect on angiogenesis, demonstrating the possibility of Soluplus-BA as an effective anti-breast cancer drug delivery system.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/pathology , Micelles , Pentacyclic Triterpenes/administration & dosage , Polyethylene Glycols/chemistry , Polyvinyls/chemistry , Animals , Animals, Outbred Strains , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Chickens , Drug Carriers/chemistry , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1/drug effects , Membrane Potential, Mitochondrial/drug effects , Mice , Neovascularization, Pathologic/metabolism , Pentacyclic Triterpenes/pharmacology , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Surface Properties , Vascular Endothelial Growth Factor A/drug effects , Betulinic AcidABSTRACT
Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality.