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Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used to enhance the flexibility and durability of various products. As an endocrine disruptor, DEHP can interfere with normal hormonal functions, posing substantial health risks to organisms. Given the critical role of the liver in DEHP metabolism, we investigated potential liver damage in offspring induced by prenatal exposure to low doses of DEHP in Sprague Dawley rats. Pregnant rats were divided into three groups and administered 20 or 200 µg/kg/day of DEHP or corn oil vehicle control via oral gavage from gestation days 0-20. Male rat offspring were euthanized on postnatal day 84, and blood and liver specimens were collected for analysis. We observed fibrotic changes in the livers of the exposed groups, accompanied by the proliferation and activation of hepatic stellate cells and upregulated expression of TGF-B and collagen 1A1. Additionally, an inflammatory response, characterized by increased macrophage infiltration and elevated levels of pro-inflammatory cytokines, was evident. Third, hepatic and serum triglyceride and serum cholesterol were notably increased, along with upregulated expression of lipid metabolism-related proteins, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and diacylglycerol O-acyltransferase 1, particularly in the low-dose group. These results suggest that prenatal exposure to DEHP can disrupt lipid metabolism, resulting in hepatic lipid accumulation in the offspring. This exposure may also induce an inflammatory response that contributes to the development of liver fibrosis. Thus, even at relatively low doses, such exposure can precipitate latent liver damage in offspring.
Assuntos
Dietilexilftalato , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Ratos , Animais , Masculino , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos Sprague-Dawley , Fígado/metabolismo , LipídeosRESUMO
During respiration, particulate matter with a diameter of 2.5 µm or less (PM2.5) suspended in the atmosphere enters the terminal alveoli and blood. PM2.5 particles can attach to toxic substances, resulting in health problems. Limited information is available regarding the effects of prenatal exposure to water-soluble PM2.5 (WS-PM2.5) and water-insoluble PM2.5 (WI-PM2.5) on male reproduction. In addition, whether exposure to these particles has transgenerational effects remains unknown. We investigated whether prenatal exposure to WS-PM2.5 and WI-PM2.5 disrupts sperm function in generations F1, F2, and F3 of male mice. Pregnant BALB/c mice were treated using intratracheal instillation on gestation days 7, 11, and 15 with 10 mg of a water extract or insoluble PM2.5. On postnatal day 105, epididymal sperm count, motility, morphology, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, the sperm chromatin DNA fragmentation index (DFI), and testicular DNA methyltransferase (Dnmt) levels were evaluated in all generations. Whole-genome bisulfite sequencing was used to analyze the DNA methylation status of generation F3. According to the results, exposure to WS-PM2.5 affected sperm morphology, ROS production, and mean DFI in generation F1; ROS production and mean DFI in generation F2; and sperm morphology and MMP in generation F3. Similarly, exposure to WI-PM2.5 affected sperm morphology, ROS production, mean DFI, %DFI, and Dnmt1 expression in generation F1; sperm morphology, MMP, and ROS production in generation F2; and sperm morphology, ROS, and %DFI in generation F3. Two hypermethylated genes, PRR16 and TJP2, were observed in the WS-PM2.5 and WI-PM2.5 groups, two hypomethylated genes, NFATC1 and APOA5, were observed in the WS-PM2.5 group, and two hypomethylated genes, ZFP945 and GSE1, were observed in the WI-PM2.5 group. Hence, prenatal exposure to PM2.5 resulted in transgenerational epigenetic effects, which may explain certain phenotypic changes in male reproduction.
Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Camundongos , Masculino , Animais , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taiwan , Sêmen , Espermatozoides , Material Particulado/metabolismo , Água/metabolismoRESUMO
BACKGROUND: Fine particulate matter (particulate matter with aerodynamic diameter of â¦2.5 µm, PM2.5) exposure cause adverse health effects, including lung inflammation. Through intra-tracheal instillation of PM2.5 components, the study aimed to evaluate the inflammatory and proliferative effects on mice liver. PM2.5 samples were collected near an industrial complex at southern Taiwan. Mice were exposed to water extracts or insoluble particles by intra-tracheal instillation. Male C57BL/6 mice were divided into five groups: control, low dose insoluble particle exposure (LP), high dose insoluble particle exposure (HP), low dose water extract exposure (LW), and high dose water extract exposure (HW). Biochemical analysis, western blotting, histological examination, and immunohistochemistry were employed to evaluate the results. RESULT: Enrichment factor (EF) of metallic elements showed that the EFs of trace elements (Ti, V, Ni, Zn, Pb, Cr, and Cu) in PM2.5 were above 10. Hematoxylin and Eosin (H&E) staining of the liver tissue showed inflammatory infiltration in particle exposure group; hepatocyte ballooning degeneration and karyomegaly were seen in the water extract exposure group. Upregulation of inflammatory signaling, p65 and p50, and caspase-3 (an important effector involved in apoptosis) positive hepatocytes was significantly increased in the HP group, followed by an elevation in protein levels of growth arrest and DNA damage-inducible protein 153 (GADD153). Increased protein expression of proliferating cell nuclear antigen (PCNA) was noted in the LW and HW groups. An increase in phosphorylation of regulators of cell proliferation, Akt and extracellular signal-regulated kinase (ERK) 1/2, were detected in the LW and HW groups. CONCLUSION: The present study shows that the insoluble particle composition of PM2.5 induced inflammatory signaling and cytokines upregulation in the liver, accompanied with inflammatory cell and macrophage infiltration and an abnormal liver function. Exposure of water extract to PM2.5 induced signals of upregulated cellular proliferation, elevated markers of cell proliferation in liver, hepatocyte ballooning degeneration and karyomegaly.
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Type II collagen is an important component of cartilage; however, little is known about its effect on skin wound healing. In this study, type II collagen was extracted from the cartilage of Acipenser baerii and its effect on in vitro and in vivo wound healing was compared to type I collagen derived from tilapia skin. Sturgeon cartilage collagen (SCC) was composed of α1 chains and with a thermal denaturation (Td) at 22.5 and melting temperature (Tm) at 72.5 °C. Coating SCC potentiated proliferation, migration, and invasion of human dermal fibroblast adult (HDFa) cells. Furthermore, SCC upregulated the gene expression of extracellular matrix (ECM) components (col Iα1, col IIIα1, elastin, and Has2) and epithelial-mesenchymal transition (EMT) molecules (N-cadherin, Snail, and MMP-1) in HDFa. Pretreatment with Akt and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated the HDFa invasion caused by SCC. In mice, the application of SCC on dorsal wounds effectively facilitated wound healing as evidenced by 40-59% wound contraction, whereas the untreated wounds were 18%. We observed that SCC reduced inflammation, promoted granulation, tissue formation, and ECM deposition, as well as re-epithelialization in skin wounds. In addition, SCC markedly upregulated the production of growth factors in the dermis, and dermal and subcutaneous white adipose tissue; in contrast, the administration of tilapia skin collagen (TSC) characterized by typical type I collagen was mainly expressed in the epidermis. Collectively, these findings indicate SCC accelerated wound healing by targeting fibroblast in vitro and in vivo.
Assuntos
Colágeno Tipo II/farmacologia , Fibroblastos/efeitos dos fármacos , Peixes , Pele/efeitos dos fármacos , Cicatrização , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratinócitos/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismoRESUMO
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/ß-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.
Assuntos
Autofagia/efeitos dos fármacos , Benzo(a)pireno/administração & dosagem , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/prevenção & controle , Sulfato de Dextrana/administração & dosagem , Flavonas/farmacologia , Animais , Carcinógenos Ambientais/efeitos adversos , Colite/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mutagênicos/efeitos adversosRESUMO
Macrophages can polarize into two different states (M1 and M2), which play contrasting roles during pathogenesis or tissue damage. M1 polarized macrophages produce pro-inflammatory cytokines and mediators resulting in inflammation, while M2 macrophages have an anti-inflammatory effect. Secretion of appropriate cytokines and chemokines from macrophages can lead to the modification of the microenvironment for bridging innate and adaptive immune responses. Increasing evidence suggests that polarized macrophages are pivotal for disease progression, and the regulation of macrophage polarization may provide a new approach in therapeutic treatment of inflammation-related diseases, including cancer, obesity and metabolic diseases, fibrosis in organs, brain damage and neuron injuries, and colorectal disease. Polarized macrophages affect the microenvironment by secreting cytokines and chemokines while cytokines or mediators that are produced by resident cells or tissues may also influence macrophages behavior. The interplay of macrophages and other cells can affect disease progression, and therefore, understanding the activation of macrophages and the interaction between polarized macrophages and disease progression is imperative prior to taking therapeutic or preventive actions. Manipulation of macrophages can be an entry point for disease improvement, but the mechanism and potential must be understood. In this review, some advanced studies regarding the role of macrophages in different diseases, potential mechanisms involved, and intervention of drugs or phytochemicals, which are effective on macrophage polarization, will be discussed.
Assuntos
Inflamação/complicações , Inflamação/prevenção & controle , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Animais , Polaridade Celular/efeitos dos fármacos , Citocinas/imunologia , Humanos , Inflamação/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Compostos Fitoquímicos/uso terapêuticoRESUMO
The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling.
Assuntos
Tecido Adiposo , Dieta Hiperlipídica , Glucose , Hiperglicemia , Inflamação , Fígado , Macrófagos , Obesidade , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Glucose/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Células RAW 264.7 , Camundongos Obesos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Liver fibrosis occurs due to injury or inflammation, which results in the excessive production of collagen and the formation of fibrotic scar tissue that impairs liver function. Despite the limited treatment options available, freshwater clams may hold promise in the treatment of liver fibrosis. In this study, we demonstrated the effects of ethanol extract of freshwater clam (FCE), ethyl acetate extract of FCE (EA-FCE), and trans-2-nonadecyl-4-(hydroxymethyl)-1,3-dioxolane (TNHD) on liver fibrosis induced by dimethylnitrosamine (DMN). Administration of FCE and TNHD alleviated liver injury, including tissue damage, necrosis, inflammation scores, fibrosis scores, serum enzymes, and triglyceride levels. Furthermore, we analyzed the expression of fibrosis-related proteins, such as α-smooth muscle actin (α-SMA) and transforming growth factor (TGF-ß), as well as the hydroxyproline content, which decreased after treatment with FCE and TNHD. Animal experiments revealed that FCE and TNHD can reduce liver fibrosis by inhibiting cytokines that activate stellate cells and decreasing extracellular matrix (ECM) secretion. Cell experiments have shown that TNHD inhibits the MAPK/Smad signaling pathway and TGF-ß1 activation, resulting in a reduction in the expression of fibrosis-related proteins. Therefore, freshwater clam extracts, particularly TNHD, may have potential therapeutic and preventive effects for the amelioration of liver fibrosis.
Assuntos
Bivalves , Dimetilnitrosamina , Dioxolanos , Animais , Dimetilnitrosamina/toxicidade , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Bivalves/genética , InflamaçãoRESUMO
BACKGROUND: Exposure to fine particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) is associated with adverse health effects. This study aimed to evaluate the toxic effects of the constituents of PM2.5 on mouse kidneys. METHODS: We collected PM2.5 near an industrial complex located in southern Kaohsiung, Taiwan, that was divided into water extract and insoluble particles. Male C57BL/6 mice were divided into five groups: control, low- and high-dose insoluble particle exposure, and low- and high-dose water extract exposure. Biochemical analysis, Western blot analysis, histological examination, and immunohistochemistry were performed to evaluate the impact of PM2.5 constituents on mice kidneys. RESULTS: PM2.5 was collected from January 1, 2021, to February 8, 2021, from an industrial complex in Kaohsiung, Taiwan. Metallic element analysis showed that Pb, Ni, V, and Ti were non-essential metals with enrichment factors >10. Polycyclic aromatic hydrocarbon and nitrate polycyclic aromatic hydrocarbon analyses revealed that the toxic equivalents are, in the order, benzo(a)pyrene (BaP), indeno(1,2,3-cd) pyrene (IP), dibenzo(a,h)anthracene (DBA), and benzo(b)fluoranthene (BbF), which are potential carcinogens. Both water extract and insoluble particle exposure induced inflammatory cytokine upregulation, inflammatory cell infiltration, antioxidant activity downregulation, and elevation of kidney injury molecule 1 (KIM-1) level in mouse kidneys. A dose-dependent effect of PM2.5 water extract and insoluble particle exposure on angiotensin converter enzyme 2 downregulation in mouse kidneys was observed. CONCLUSION: We found that water-soluble extract and insoluble particles of PM2.5 could induce oxidative stress and inflammatory reactions, influence the regulation of renin-angiotensin system (RAS), and lead to kidney injury marker level elevation in mouse kidneys. The lowest-observed-adverse-effect level for renal toxicity in mice was 40 µg water-soluble extract/insoluble particle inhalation per week, which was approximately equal to the ambient PM2.5 concentration of 44 µg/m3 for mice.
Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Angiotensinas/análise , Animais , Antioxidantes/análise , Benzo(a)pireno/análise , Carcinógenos/análise , Citocinas/análise , Rim/química , Chumbo/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nitratos/análise , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Água/análiseRESUMO
Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic ß-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.
Assuntos
Adiponectina/metabolismo , Curcumina/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Fitoterapia , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/uso terapêutico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina , Regulação para Cima/efeitos dos fármacosRESUMO
Gold nanoparticles (AuNPs) are biocompatible nanomaterials with potential application in the food industry. The safety of AuNPs oral consumption remains inconclusive, and information on possible long-term toxicity is limited. The current study aimed to evaluate the subchronic oral toxicity of AuNPs in male and female Institute of Cancer Research (ICR) mice. Citrate-coated spherical AuNPs with 53 nm diameters were prepared and orally administered to the mice. No mortality or clinical abnormalities were observed following daily administration of AuNPs at the dosages of 0.2, 2, and 20 mg/kg for 90 days. There was no significant difference in body weight or the relative organs' weights between the control and AuNPs-treated mice. No gross abnormalities or histopathological changes were observed except that the male mice treated with high dose (20 mg/kg AuNPs) showed minor infiltration in the kidneys, and female mice showed a reduced A/G ratio and elevated platelet indices. Overall, the 90-day long-term oral consumption of AuNPs did not cause significant toxicity in mice.
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Decabromodiphenyl ether (BDE-209), a congener of polybrominated diphenyl ethers, is a commonly used brominated flame retardant and a known endocrine disrupting chemical (EDC). Knowledge about the effects of prenatal BDE-209 exposure on male reproduction and whether transgenerational effects occur in subsequent generations are scant. Therefore, in this study, we tested the hypothesis that prenatal exposure to BDE-209 disrupted sperm function in the F1, F2, and F3 generations of male rats. Pregnant Sprague-Dawley rats were treated by gavage from gestation day 0 to birth with 5 mg BDE-209/kg/day. This treatment was based on the lowest-observed-adverse-effect level for DNA damage to sperm in male offspring. On postnatal day 84 for all generations, epididymal sperm counts, motility, morphology, reactive oxygen species generation, sperm chromatin DNA structure integrity, testicular DNA content in spermatogenesis, and serum testosterone levels were assessed. DNA methyltransferase (Dnmts) mRNA expression and methyl-CpG binding domain sequencing were also examined to analyze DNA methylation status in the F3 generation. In the F1 generation, prenatal exposure to BDE-209 disrupted body weight, decreased anogenital distance (AGD), sperm count, and motility; and increased bent tail rates of sperm. In the F2 generation, exposure to BDE-209 decreased AGD, sperm count, normal morphology rates, Dnmt1 expression, and increased Dnmt3a expression. In the F3 generation, BDE-209 exposure decreased AGD and normal sperm morphology, disrupted testicular elongated spermatid and round spermatid rates, reduced serum testosterone levels, and inhibited the mRNA expression of Dnmt1 and Dnmt3b. Compared with the control group, there existed 215 differentially hyper-methylated and 83 hypo-methylated genes in the BDE-209 group. BDE-209 is an EDC to disrupt the male reproduction from F1 to F3. BDE-209-induced changes in sperm function and hyper- or hypo-DNA methylation in the F3 generation might therefore explain the possible mechanism underlying BDE-209-mediated epigenetic transgenerational effects on the male reproductive system.
Assuntos
Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Animais , DNA , Disruptores Endócrinos/farmacologia , Feminino , Genitália Masculina , Éteres Difenil Halogenados/toxicidade , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Reprodução , Espermatogênese , TestosteronaRESUMO
In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.
Assuntos
Antineoplásicos/uso terapêutico , Curcumina/análogos & derivados , Neoplasias/tratamento farmacológico , Curcumina/uso terapêutico , HumanosRESUMO
High blood glucose in diabetic patients often causes cardiovascular diseases (CVDs) that threats to human life. Curcumin (Cur) is known as an antioxidant agent, possesses anti-inflammatory activity, and prevents CVDs. However, the clinical application of curcumin was limited due to its low bioavailability. This study aimed to investigate the ameliorative effects of chitosan-encapsulated curcumin (CEC) on heart and kidney damages in streptozotocin-induced type-1 diabetes C57BL/6 mice model. The results showed that Cur- and CEC-treatments downregulated the blood sugar and total cholesterol level as well as enhanced insulin secretion. However, blood pressure, triglycerides content, and very low-density lipoprotein-cholesterol content were not changed. Histochemistry analysis revealed that both curcumin and chitosan-encapsulated curcumin ameliorated cell hypertrophy and nucleus enlargement in the left ventricular of heart and reduced fibrosis in the kidney, especially after the chitosan-encapsulated curcumin treatment. Our study suggested that chitosan can effectively enhance the protective effect of curcumin on the heart and kidney damages in type-1 diabetes mice model.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Quitosana/química , Curcumina/administração & dosagem , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Cardiomiopatias Diabéticas/patologia , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , EstreptozocinaRESUMO
Adipocyte-macrophage interaction in obesity can cause adipose tissue inflammation and contribute to insulin resistance. Here, we investigated the effect of SlimTrym®-a formulated product containing citrus polymethoxyflavones (PMFs), green tea extract, and lychee polyphenols-on 3T3-L1 adipocyte differentiation and obesity-induced inflammation. SlimTrym® inhibited mitotic clonal expansion (MCE) of 3T3-L1 adipocytes by inducing G1 cell cycle arrest via upregulation of p21 and p53. SlimTrym® attenuated adipogenic differentiation by downregulating adipogenic factors, such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), and upregulating AMP-activated protein kinase (AMPK). Pretreatment with compound C significantly reduced SlimTrym®-mediated suppression of lipid accumulation. SlimTrym® reduced the expression of pro-inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1ß and IL-6, in co-cultured 3T3-L1 adipocytes and RAW264.7 macrophages. C57BL/6 mice administered with SlimTrym® for 16 weeks showed markedly reduced high-fat diet (HFD)-induced infiltration of monocytes/macrophages in adipose tissue; however, the level of M2 macrophage markers (CD163 and IL-10) was increased. Taken together, these findings indicate that SlimTrym® exerts both anti-adipogenic and anti-inflammatory effects, and can potentially treat obesity and adipose tissue inflammation.
Assuntos
Camellia sinensis/química , Citrus/química , Flavonas/administração & dosagem , Litchi/química , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/imunologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/imunologia , Frutas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , Obesidade/fisiopatologia , PPAR gama/genética , PPAR gama/imunologiaRESUMO
We reported previously that 3',4'-didemethylnobiletin (DDMN) is the major metabolite of nobiletin in mouse urine. In this study, we examined DDMN's molecular mechanism of action and its anti-inflammatory and antitumor properties. We demonstrated that topical application of DDMN effectively inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated transcription of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and ornithine decarboxylase (ODC) messenger RNA and protein expression in mouse skin. Pretreatment with DDMN has resulted in the reduction of TPA-induced nuclear translocation of the nuclear factor-kappa B (NF-kappaB) subunit. DDMN also reduced DNA binding by blocking phosphorylation of inhibitor kappaB (IkappaB) alpha and p65 and caused subsequent degradation of IkappaBalpha. DDMN inhibited TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription 3. Moreover, DDMN suppressed TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and activator protien-1. We also found that DDMN significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, DDMN significantly inhibited 7,12-dimethylbenz[a]anthracene/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. Presented data for the first time reveal that DDMN is an effective antitumor agent that functions by downregulating inflammatory iNOS, COX-2 and ODC gene expression in mouse skin. It is suggested that DDMN is a novel functional agent capable of preventing inflammation-associated tumorigenesis.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Flavonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Benzo(a)Antracenos/toxicidade , Western Blotting , Testes de Carcinogenicidade , Ciclo-Oxigenase 2/efeitos dos fármacos , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Flavonas/metabolismo , Flavonas/urina , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Camundongos , NF-kappa B/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Ornitina Descarboxilase/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/induzido quimicamente , Fator de Transcrição AP-1/efeitos dos fármacosRESUMO
Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. Here we report that 3,5,4'-trimethoxystilbene (MR-3), the permethylated derivative of R-3 was more potent against the growth of human cancer cells (HT-29, PC-3, COLO 205) with estimated IC(50) values of 81.31,42.71, and 6.25 microM, respectively. We further observed that MR-3 induced apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of MR-3-induced apoptosis, preceding cytochrome-c release, caspase activation, and DNA fragmentation. Significant therapeutic effects were demonstrated in vivo by treating severe combined immune deficiency (SCID) mice bearing COLO 205 tumor xenografts with MR-3 (50 mg/kg ip). Assays on DNA fragmentation and caspase activation were performed and demonstrated that apoptosis occurred in tumor tissues treated with MR-3. The appearance of apoptotic cells, as shown by Hematoxylin and Eosin (H&E) staining, and an increase in p21 and decrease in proliferating cell nuclear antigen (PCNA) protein by immuno-histochemistry were observed in tumor tissues under MR-3 treatment. Our study identifies the novel mechanisms of the antitumor effects of MR-3 and indicates that these results may have significant applications for cancer chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adenocarcinoma/patologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Fragmentação do DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Concentração Inibidora 50 , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Antígeno Nuclear de Célula em Proliferação/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/químicaRESUMO
Obesity is a current global epidemic that has led to a marked increase in metabolic diseases. However, its treatment remains a challenge. Obesity is a multifactorial disease, which involves the dysfunction of neuropeptides, hormones, and inflammatory adipokines from the brain, gut, and adipose tissue. An understanding of the mechanisms and signal interactions in the crosstalk between organs and tissue in the coordination of whole-body energy metabolism would be helpful to provide therapeutic and putative approaches to the treatment and prevention of obesity and related complications. Resveratrol and pterostilbene are well-known stilbenes that provide various potential benefits to human health. In particular, their potential anti-obesity effects have been proven in numerous cell culture and animal studies. Both compounds act to regulate energy intake, adipocyte life cycle and function, white adipose tissue (WAT) inflammation, energy expenditure, and gut microbiota by targeting multiple molecules and signaling pathways as an intervention for obesity. Although the efficacy of both compounds in humans requires further investigation with respect to their oral bioavailability, promising scientific findings have highlighted their potential as candidates for the treatment of obesity and the improvement of obesity-related metabolic diseases. © 2018 BioFactors, 44(1):50-60, 2018.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Metabolismo Energético/efeitos dos fármacos , Obesidade/dietoterapia , Estilbenos/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipocinas/genética , Adipocinas/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Dieta Hiperlipídica , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica , Humanos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Resveratrol , Transdução de Sinais , Termogênese/efeitos dos fármacosRESUMO
Diet-induced obesity is strongly associated with nonalcoholic fatty-liver disease (NAFLD) and insulin resistance. We aimed to investigate the in vivo therapeutic value of tetrahydrocurcumin (THC) intervention in high-fat-diet (HFD)-induced obesity and hepatic steatosis. C57BL/6 mice were fed an HFD for 10 weeks, and then they received 20 or 100 mg/kg THC along with the HFD for another 10 weeks. Mice fed an HFD for 20 weeks experienced obesity, hepatic steatosis, hyperlipidemia, and insulin resistance. Tetrahydrocurcumin (THC) intervention for 10 weeks significantly reduced adiposity (epididymal-fat weights of 6.6 ± 0.4 g for the HFD-only group and 5.3 ± 0.8 and 5.6 ± 0.7 g for the HFD with 20 mg/kg THC and HFD with 100 mg/kg THC groups, respectively; p < 0.05) via downregulation of adipogenic factors. Inflammatory macrophage infiltration and polarization were decreased by THC in mouse epididymal adipose tissues. In the liver, THC markedly alleviated steatosis by approximately 28-37% ( p < 0.05) via the downregulation of lipogenesis, the activation of AMP-activated protein kinase (AMPK), and the increase of fatty acid oxidation. Elevated blood glucose and insulin resistance were also improved by THC, which might be caused by regulation of the hepatic insulin signaling cascade, gene transcription involved in glucose metabolism, and reduced macrophage infiltration in the liver and adipose tissue. Our results demonstrated the beneficial effects of THC-mediated intervention against obesity and NAFLD as well as other metabolic syndromes, revealing a novel therapeutic use of THC in obese populations.
Assuntos
Curcumina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Curcumina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in ß-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 ß (GSK3ß), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).