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1.
Life Sci ; 258: 118213, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768583

RESUMO

AIMS: Intermittent cyclic tension stimulation(ICMT) was shown to promote degeneration of endplate chondrocytes and induce autophagy. However, enhancing autophagy can alleviate degeneration partly. Studies have shown that curcumin can induce autophagy and protect chondrocytes, we speculated that regulation of autophagy by curcumin might be an effective method to improve the stress resistance of endplate cartilage. In this study, human cervical endplate cartilage specimens were collected, and expression of autophagy markers was detected and compared. MAIN METHODS: Human cervical endplate chondrocytes were cultured to establish a tension-induced degeneration model, for which changes of functional metabolism and autophagy levels were detected under different tension loading conditions. Changes in functional metabolism of endplate chondrocytes were observed under high-intensity tension loading in the presence of inhibitors, inducers, and curcumin to regulate the autophagy level of cells. In addition, a rat model of lumbar instability was established to observe the degeneration of lumbar disc after curcumin administration. KEY FINDINGS: Through a series of experiments, we found that low-intensity tension stimulation can maintain a stable phenotype of endplate chondrocytes, but high-intensity tension stimulation has a negative effect. Moreover, with increasing tension intensity, the degree of degeneration of endplate chondrocytes was gradually aggravated and the level of autophagy increased. Besides, curcumin upregulated autophagy, inhibited apoptosis, and reduced phenotype loss of endplate chondrocytes induced by high-intensity tension loading, thereby relieving intervertebral disc degeneration induced by mechanical imbalance. SIGNIFICANCE: Curcumin mediated autophagy and enhanced the adaptability of endplate chondrocytes to high-intensity tension load, thereby relieving intervertebral disc degeneration.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Autofagia/efeitos dos fármacos , Cartilagem/efeitos dos fármacos , Curcumina/uso terapêutico , Degeneração do Disco Intervertebral/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Autofagia/fisiologia , Cartilagem/patologia , Curcumina/farmacologia , Feminino , Degeneração do Disco Intervertebral/patologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Masculino , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 259: 118293, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822714

RESUMO

AIMS: Liver fibrosis is an inflammatory and fibrogenic process that occurs following chronic liver damage. TGFß1 is the key inducer of fibrosis. MiR-21 and miR-122 are two miRNAs that their expression changes during fibrosis. In the present study, we investigate the effects of curcumin, quercetin, and atorvastatin on the expression levels of miR-21 and miR-122 and evaluated their correlation with TGFß1 expression in bile duct ligation (BDL)-induced fibrotic rats. MATERIALS AND METHODS: Thirty two adult male Wistar rats were divided into 8 groups (n = 8 for each): Sham, Sham + curcumin (100 mg/kg/day), Sham + quercetin (30 mg/kg/day), Sham + atorvastatin (15 mg/kg/day), BDL, BDL + curcumin, BDL + quercetin, BDL + atorvastatin and treated for four weeks via oral gavage. The expression of miR-21, miR-122, and TGFß1 was evaluated via RT-qPCR. KEY FINDINGS: The expression levels of TGFß1 and miR-21 were significantly increased in the BDL group compared to the Sham group (P < 0.05), but the expression of miR-122 was significantly decreased in the BDL group compared to the Sham group (P < 0.05). Curcumin, quercetin, and atorvastatin treatment lead to down-regulation of miR-21 and TGFß1 and up-regulation of miR-122 in the BDL groups. There was no significant difference between these drugs in altering gene expression and all had the same effects. Moreover, a direct significant correlation was observed between mir-21 and TGFß1 and an inverse significant correlation between mir-122 and TGFß1 expression. SIGNIFICANCE: In summary, targeting these molecular pathways may partially prevent the progression of liver fibrosis.


Assuntos
Atorvastatina/farmacologia , Curcumina/farmacologia , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
3.
Parasitol Res ; 119(9): 2991-3003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32748038

RESUMO

Visceral leishmaniasis (VL, also known as kala-azar) is a vector borne disease caused by obligate intracellular protozoan parasite Leishmania donovani. To overcome the limitations of currently available drugs for VL, molecular target-based study is a promising tool to develop new drugs to treat this neglected tropical disease. One such target we recently identified from L. donovani (Ld) genome (WGS, clinical Indian isolate; BHU 1220, AVPQ01000001) is a small GTP-binding protein, Rab6 protein. We now report a specific inhibitor of the GTPase activity of Rab6 protein of L. donovani (LdRab6) without restricting host enzyme activity. First, to understand the nature of LdRab6 protein, we generated recombinant LdRab6 mutant proteins (rLdRab6) by systematically introducing deletion (two cysteine residues at C-terminal) and mutations [single amino acid substitutions in the conserved region of GTP (Q84L)/GDP(T38N) coding sequence]. The GTPase activity of rLdRab6:GTP and rLdRab6:GDP locked mutant proteins showed ~ 8-fold and ~ 1.5-fold decreases in enzyme activity, respectively, compared to the wild type enzyme activity. The mutant protein rLdRab6:ΔC inhibited the GTPase activity. Sequence alignment analysis of Rab6 protein of L. donovani with Homo sapiens showed identical amino acids in the G conserved region (GTP/GDP-binding sites) but it differed in the C-terminal region. We then evaluated the inhibitory activity of trans-dibenzalacetone (DBA, a synthetic analog of curcumin with strong antileishmanial activity reported earlier by us) in the GTPase activity of LdRab6 protein. Comparative molecular docking analysis of DBA and specific inhibitors of Rab proteins (Lovastatin, BFA, Zoledronate, and NE10790) indicated that DBA had optimum binding affinity with LdRab6 protein. This was further confirmed by the GTPase activity of DBA-treated LdRab6 which showed a basal GTP level significantly lower than that of the wild-type rLdRab6. The results confirm that DBA inhibits the GTPase activity of LdRab6 protein from L. donovani (LdRab6), a potential target for its antileishmanial effect.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Pentanonas/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas rab de Ligação ao GTP/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Curcumina/farmacologia , Humanos , Leishmania donovani/química , Leishmania donovani/enzimologia , Leishmania donovani/genética , Leishmaniose Visceral/tratamento farmacológico , Simulação de Acoplamento Molecular , Pentanonas/química , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Alinhamento de Sequência , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
4.
Toxicon ; 185: 97-103, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622693

RESUMO

Mycotoxins are toxic secondary metabolites produced by fungus which cause worldwide concern regarding food and feed safety. Ochratoxin A (OTA), fumonisin B1 (FB1) and deoxynivalenol (DON) are some of the main mycotoxins and oxidative stress is the main mechanism of toxicity. Thereby, this study investigates the in vitro cytoprotective effects of curcumin (CUR) and silymarin (SIL) - known for their strong antioxidant activity - in PK-15 cells exposed to OTA, FB1 and DON. Pretreatment with CUR and SIL enhanced the viability of cells exposed to the mycotoxins (P < 0.001) and attenuated reactive oxygen species (ROS) formation by DON (P < 0.01), partially reduced ROS formation by FB1 (P < 0.001), but not OTA. CUR significantly decreased apoptosis in cells exposed to DON (P < 0.01) but was not able to prevent apoptosis in cells exposed to OTA and FB1. Whereas SIL was able to prevent apoptosis in PK-15 cells exposed to FB1 and DON (P < 0.01) but was not able to decrease apoptosis in cells exposed to OTA. In summary, these data indicate that curcumin and silymarin are able to provide cytoprotection against toxicity induced by OTA, FB1 and DON in PK-15 cells.


Assuntos
Curcumina/farmacologia , Micotoxinas/toxicidade , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Apoptose , Sobrevivência Celular , Fumonisinas/toxicidade , Fungos , Ocratoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Tricotecenos/toxicidade
5.
Life Sci ; 256: 118016, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603817

RESUMO

AIMS: Ischemia/reperfusion (I/R) is one of the most important causes of acute kidney injury (AKI), a clinical syndrome with kidney dysfunction and high mortality rates. New diagnostic biomarkers need to be defined to better illuminate the pathophysiology of AKI. For the first time, we aim to investigate the protective effects of Curcumin which is known for its antioxidant and anti-inflammatory properties and 12/15 lipoxygenase inhibitor LOXblock-1 on I/R induced AKI by modulating inflammatory processes, oxidative stress, apoptosis and semaphorin-plexin pathway. MAIN METHODS: The rats were divided into five groups, with eight animals per group: Sham, I/R, I/R + DMSO (1%, i.p.), I/R + Curcumin (100 mg/kg, i.p.), I/R + LOXblock-1 (2 µg/kg, i.p.). KEY FINDINGS: The renal function biomarkers (BUN, CREA and UA) in serum were significantly increased in the I/R group. The inflammatory (TNF-α, IL-6 and MCP-1), apoptotic (CYCS and CASP3) and oxidative stress parameters (MDA, MPO, TAS and TOS) measured by ELISA were significantly increased in the I/R group. In histopathological analysis, it was observed that I/R caused serious damage to kidney tissue. SEMA3A was found to increase both serum level and mRNA expression in I/R group. It was observed that curcumin and LOXblock-1 reduce inflammatory processes, oxidative stress and apoptosis via the semaphorin-plexin pathway by both measurements and histopathological analysis. Curcumin was proved more effective than LOXblock-1 with its antioxidant feature in I/R injury. SIGNIFICANCE: The current study reveals the protective effects of Curcumin and LOXblock-1 on acute kidney injury by suppressing SEMA3A as a new biomarker.


Assuntos
Lesão Renal Aguda/prevenção & controle , Curcumina/farmacologia , Inflamação/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Curcumina/administração & dosagem , Inibidores de Lipoxigenase/administração & dosagem , Inibidores de Lipoxigenase/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Semaforina-3A/sangue , Semaforinas/metabolismo
6.
Life Sci ; 257: 117658, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621921

RESUMO

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.


Assuntos
Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Citomegalovirus/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Life Sci ; 257: 118091, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668325

RESUMO

AIM: Inflammatory and oxidative microenvironment at diabetic' wound site hinder the therapeutic efficacy of cell-based therapies in diabetic patients. The purpose of this study is to explore the competence of curcumin preconditioned human adipose derived cells (hASCs) in combination with platelet rich plasma (PRP) for the repair of wounds in diabetic rats. MAIN METHODS: The cytoprotective effect of curcumin preconditioning for hASCs against hyperglycemic stress was evaluated through analysis of cell morphology, viability, cytotoxicity, senescence, and scratch wound healing assays. Subsequently, the healing capacity of curcumin preconditioned hASCs (Cur-hASCs) added to PRP was examined in excisional wounded diabetic rat model. Healed skin biopsies were excised to analyze gene and protein expression of wound healing markers by qPCR and western blotting. Histopathological changes were observed through hematoxylin and eosin staining. KEY FINDINGS: We found that Cur-hASCs counteract the glucose stress much better than non-preconditioned hASCs by maintaining their cellular morphology and viability as well as metabolic potential. Further in vivo results revealed that, Cur-hASCs co-injected with PRP resulted in faster wound closure, improved fibroblast proliferation, increased neovascularization, marked reduction in inflammatory cells, and compact extracellular matrix with completely covered thick epithelium. Moreover, Cur-hASCs + PRP treatment significantly improved the expression of key healing markers such as pro-angiogenic (Vegf), dermal matrix deposition (Col1α1), cell migration (bFgf) and cell proliferation (Pcna) at wound site. SIGNIFICANCE: Our findings propose a combinatorial therapy (Cur-hASCs + PRP) as a novel modality to improve the efficacy of hASCs-based therapy for diabetic wounds.


Assuntos
Curcumina/farmacologia , Diabetes Mellitus Experimental/terapia , Plasma Rico em Plaquetas , Transplante de Células-Tronco/métodos , Cicatrização/fisiologia , Tecido Adiposo/citologia , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Terapia Combinada , Diabetes Mellitus Experimental/complicações , Feminino , Glucose/metabolismo , Humanos , Ratos , Ratos Wistar
8.
Life Sci ; 257: 118051, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634426

RESUMO

AIMS: Chemotherapy is an effective therapeutic modality which is commonly used for battling various cancers. However, several side effects induced by chemotherapeutic drugs would limit their clinical use. The present systematic review aims to evaluate the role of curcumin/curcuminoids co-administration during gastric cancer chemotherapy. METHODS: This systematic review was done according to PRISMA guidelines and a full systematic search in the electronic databases up to May 2020 using search terms in the titles and abstracts for the identification of relevant literature. 279 articles were found in electronic databases and 175 articles screened by title and abstract. Finally, 13 articles were included in this systematic review according to our inclusion and exclusion criteria. KEY FINDINGS: The findings indicated that gastric cancer chemotherapy induces cytotoxicity effects in various ways including a decrease of cell viability, colony formation, metastasis, tumor growth, and weight, as well as elevation of apoptosis pathway, oxidative stress pathway compared to the control group. Co-administration of curcumin/curcuminoids with chemotherapy synergistically increased the effects of anti-cancer chemotherapy compared to the group solo treated with chemotherapeutic agents. Also, in chemoresistance gastric cancer cells, co-administration of curcumin reduced chemoresistance mainly through the reduction of NF-κB activation and elevation of apoptosis. SIGNIFICANCE: According to the findings, the use of curcumin/curcuminoids during gastric cancer chemotherapy has chemosensitizing effects, and also it can reduce chemoresistance in gastric cancer.


Assuntos
Curcumina/uso terapêutico , Diarileptanoides/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/metabolismo , Curcumina/farmacologia , Diarileptanoides/metabolismo , Diarileptanoides/farmacologia , Tratamento Farmacológico/métodos , Humanos
9.
Int J Nanomedicine ; 15: 3649-3667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547020

RESUMO

Introduction: The polyphenolic spice and food coloring ingredient curcumin has beneficial effects in a broad variety of inflammatory diseases. Amongst them, curcumin has been shown to attenuate microglia reaction and prevent from glial scar formation in spinal cord and brain injuries. Methods: We developed a protocol for the efficient encapsulation of curcumin as a model for anti-inflammatory drugs yielding long-term stable, non-toxic liposomes with favorable physicochemical properties. Subsequently, we evaluate the effects of liposomal curcumin in experimental models for neuroinflammation and reactive astrogliosis. Results: We could show that liposomal curcumin can efficiently reduce the reactivity of human microglia and astrocytes and preserve tissue integrity of murine organotypic cortex slices. Discussion and Perspective: In perspective, we want to administer this curcumin formulation in brain implant coatings to prevent neuroinflammation and glial scar formation as foreign body responses of the brain towards implanted materials.


Assuntos
Encéfalo/patologia , Curcumina/uso terapêutico , Gliose/tratamento farmacológico , Inflamação/tratamento farmacológico , Neuroglia/patologia , Animais , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Encéfalo/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Lipossomos , Camundongos , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , Neuroglia/efeitos dos fármacos
10.
Aquat Toxicol ; 224: 105516, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485495

RESUMO

Summer outbreaks of the hepatobiliary syndrome in fish impose a heavy burden on aquaculture in China. Curcumin is a polyphenol with antioxidant activity that has been used to protect the health of fish livers, but the mechanism underlying its protective effect is unclear. In this study, an in vitro model of hepatocyte oxidative damage in Oreochromis niloticus was established using H2O2. Treatment with 5 mM H2O2 for 2.5 h markedly reduced cell viability and antioxidant activity and elevated lactate dehydrogenase (LDH) activity, indicating conditions that can be used to establish an oxidative stress model. Under H2O2 stress, curcumin pretreatment significantly maintained cell viability, reduced malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. RNA-seq results showed that acute H2O2 treatment resulted in minor changes in gene expression, whereas curcumin changed the expression profile and affected cytochrome P450 (Cyp 450), glutathione (GSH) metabolism, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Several critical antioxidant defense signaling pathways were identified, and altered expression was confirmed by q-PCR. These results indicate that curcumin might upregulate PPAR expression by increasing Cyp2J2 expression. Further experiments showed that curcumin can upregulate the Nrf2-Keap1 signaling pathway at the transcriptional level, and this upregulation can induce downstream defense genes, including glutamate cysteine ligase catalytic subunit(GCLC) and glutamate cysteine ligase modifier subunit (GCLM), and thereby promote GSH synthesis and the expression of related antioxidases. This study might shed light on the effects of curcumin on the prevention and alleviation of liver diseases in fish.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tilápia/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Células Cultivadas , Curcumina/metabolismo , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Hepatócitos/metabolismo , Peróxido de Hidrogênio/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tilápia/genética , Poluentes Químicos da Água/toxicidade
11.
Phytomedicine ; 75: 153238, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32507349

RESUMO

BACKGROUND: The NLRP3 inflammasome formation and following cytokine secretion is a crucial step in innate immune responses. Internal and external factors may trigger inflammasome activation and result in inflammatory cytokine secretion. Inflammasome formation and activity play critical roles in several disease pathologies such as cardiovascular, metabolic, renal, digestive, and CNS diseases. Underlying pathways are not yet clear, but phytochemicals as alternative therapies have been extensively used for suppression of inflammatory responses. PURPOSE: In this review, we aimed to summarize in vivo and in vitro effects on NLRP3 inflammasome activation of selected phytochemicals. METHOD: Three phytochemicals; Sulforaphane, Curcumin, and Resveratrol were selected, and studies were reviewed to clarify their intracellular signaling mechanism in NLRP3 inflammasome activity. PubMed and Scopus databases are used for the search. For sulforaphane, 8 articles, for curcumin, 25 articles, and for resveratrol, 41 articles were included in the review. CONCLUSION: In vitro and in vivo studies pointed out that the selected phytochemicals have inhibitory properties on NLRP3 inflammasome activity. However, neither the mechanism is clear, nor the study designs and doses are standardized.


Assuntos
Curcumina/farmacologia , Inflamassomos/efeitos dos fármacos , Isotiocianatos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Fitoquímicos/uso terapêutico , Resveratrol/farmacologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
AAPS PharmSciTech ; 21(5): 171, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529560

RESUMO

Modifications to the surface chemistry, charge, and hydrophilicity/hydrophobicity of nanoparticles are applicable approaches to the alterations of the in vivo fate of intravenously administered nano-sized drug carriers. The objective of this study is to investigate the in vitro and in vivo antitumor efficacies of curcumin PLGA nanoparticles in relation to their surface structural modification via self-assembling coating with unique fungal hydrophobin. The hydophobin-coated curcumin PLGA nanoparticles (HPB PLGA NPs) were obtained by simply soaking curcumin-loaded PLGA nanoparticles (PLGA NPs) in aqueous fungal hydrophobin solution. The in vitro drug release behavior of the HPB PLGA NPS was also tested. The cytotoxicity and cellular uptake of these nanoparticles were determined in HepG2, A549, and Hela cell lines using MTT assay method and CLSM observation. The in vivo antitumor activity was evaluated in Hela tumor xenografted mice model. Compared with the PLGA NPs, the size and zeta potential of the nanoparticles were changed after hydrophobin coating, whereas similar in vitro release pattern was observed. The pharmacodynamics study showed prolonged blood retention of both nano-formulations than that of free curcumin, but no significant difference between the hydrophobin coated and uncoated nanoparticles. It was found that HPB PLGA NPs had increased cytotoxicities, higher cellular uptake, and improved antitumor efficacy. Surface modification of nanoparticles via self-assembling of hydrophobin is a convenient and promising method of changing particle surface physiochemical properties and antitumor performances. Further investigations, especially on tissue distribution, were needed to assess the potential application of the hydrophobin self-assembling coating in nano-drug delivery carriers.


Assuntos
Antineoplásicos/química , Curcumina/química , Fungos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Células A549 , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Curcumina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Células HeLa , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Life Sci ; 256: 118003, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32589998

RESUMO

INTRODUCTION AND AIMS: Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder affecting females. Mechanisms underlying PCOS complicated pathology remain largely unknown, making current treatment only symptomatic. Increasing reports suggest impaired PI3K/AKT/mTOR pathway and tumor necrosis factor-α (TNF-α) levels are involved in cellular proliferation and metabolism-related disorders. However, rare data explored their role in PCOS. Hence, this study investigated TNF-α and pancreatic PI3K/AKT/mTOR levels in PCOS animal model and evaluated their effects on developed pancreatic deficits. Secondly; we explored the impact of nanocurcumin as powerful anti-inflammatory supplement against these developed pancreatic pathologies. METHODS: PCOS was induced in rats using letrozole. Nanocurcumin was formulated to increase solubility and bioavailability of curcumin. Transmission electron microscopy (TEM), zeta potential and Infra-red spectroscopy (FT-IR) were used for characterization. Nanocurcumin was orally ingested for 15 days. FINDINGS: PCOS group exhibited significant disturbance in sex hormones, oxidative stress markers, and TNF-α levels as determined by immunoassay. Western blotting revealed significant reduction of PI3K/AKT/mTOR levels leading to impaired insulin sensitivity, decreased ß cells function and mass as confirmed by HOMA assessments and immunohistochemistry. Nanocurcumin significantly improved oxidative markers, glucose indices and TNF-α levels. It reinstated PI3K/AKT/mTOR levels, alleviated insulin resistance, and retained islets integrity consequently restoring normal sex hormonal levels. SIGNIFICANCE: To the best of our knowledge, the study is the first to report pancreatic role of PI3K/AKT/mTOR and TNF-α in PCOS and the first to demonstrate nanocurcumin promising potential against PCOS-related pancreatic molecular and histological pathologies that can indeed offer better control of the disease.


Assuntos
Curcumina/farmacologia , Resistência à Insulina , Nanopartículas , Pâncreas/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Curcumina/administração & dosagem , Modelos Animais de Doenças , Feminino , Pâncreas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Mol Immunol ; 124: 109-116, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32554101

RESUMO

Disordered collagen production by fibroblasts in response to tissue injury contributes to pulmonary fibrosis (PF). Therefore, elimination of collagen deposition has becoming a potential target in PF treatment which despite standard anti-fibrosis regiment still remains challenge. Curcumin and curcumol are regarded as the main active components extraction from the rhizomes of Curcuma zedoaria, which is widely used for inhibition the proliferation of multiple cells. However, the molecular basis for the function of curcumin and curcumol in limiting fibrogenesis still unknown. In this study, we have investigated the effects of curcumin and curcumol in the fibroblast overproliferation model human lung fibroblast (HLF) inducing by TGF-ß1. The growth-inhibitory effects of the components wasn't observed from 8 to 64 µg/ml. Administration of curcumin or curcumol significantly diminished the level of hydroxyproline hydroxyproline and α-smooth muscle actin (α-SMA), also the collagen Ⅰ (Col-Ⅰ) and collagen Ⅲ (Col-Ⅲ) deposition were reduced in the HLF. Furthermore, related to the collagen synthesis proteins including N-terminal pro-peptide for Type Ⅰ collagen (PⅠNP), N-terminal pro-peptide for Type Ⅲ collagen (PⅢNP) and prolyl-hydroxylase (PHD) were degraded gracefully at dose-dependent manner. Autophagy as the scavenger was crippled in TGF-ß1-fibroblast overproliferation HLF, conversely the increased autophagosomes have been spotted in cytoplasm under transmission electron microscope which is consistent with up-regulation of Beclin1 and ATG7 after treatment with curcumin or curcumol in this study. Additionally, blocking autophagy by inhibitor chloroquine (CQ) caused collagen deposition, providing further evidence regard to autophagy activation capacity of curcumin and curcumol. Our findings provide a detailed understanding that the function of curcumin and curcumol on decreasing collagen deposition mediating by autophagy mechanism, which may also inspire the further research on PF at different perspectives.


Assuntos
Autofagia/efeitos dos fármacos , Colágeno/efeitos dos fármacos , Curcumina/farmacologia , Fibroblastos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células Cultivadas , Curcuma , Humanos , Extratos Vegetais/farmacologia , Fibrose Pulmonar/patologia
15.
Ecotoxicol Environ Saf ; 200: 110756, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464442

RESUMO

Arsenic is a recognized highly toxic contaminant, responsible for numerous human diseases and affecting many millions of people in different parts of the world. Contrarily, curcumin is a natural dietary polyphenolic compound and the main active ingredient in turmeric. Recently it has drawn great attention due to its diverse biological activities, strong antioxidant properties and therapeutic potential against many human ailments. In this study, we aimed to explore the protective effects and the regulatory role of curcumin on arsenic-induced toxicity and gain insights into biomolecular mechanism/s. Arsenic (10 µM) treatment in PC12 cells for 24 h induced cytotoxicity by decreasing cell viability and intracellular glutathione level and increasing lactate dehydrogenase activity and DNA fragmentation. In addition, arsenic caused apoptotic cell death in PC12 cells, which were confirmed from flow cytometry results. Moreover, arsenic (10 µM) treatment significantly down-regulated the inhibition factors of autophagy/apoptosis; mTOR, Akt, Nrf2, ERK1, Bcl-x, Xiap protein expressions, up-regulated the enhanced factors of autophagy/apoptosis; ULK, LC3, p53, Bax, cytochrome c, caspase 9, cleaved caspase 3 proteins and eventually caused autophagic and apoptotic cell death. However, curcumin (2.5 µM) pretreatment with arsenic (10 µM) effectively saves PC12 cells against arsenic-induced cytotoxicity through increasing cell viability, intracellular GSH level and boosting the antioxidant defense system, and limiting the LDH activity and DNA damage. Furthermore, pretreatment of curcumin with arsenic expressively alleviated arsenic-induced toxicity and cell death by reversing the expressions of proteins; mTOR, Akt, Nrf2, ERK1, Bcl-x, Xiap, ULK, LC3, p53, Bax, cytochrome c, caspase 9 and cleaved caspase 3. Our findings indicated that curcumin showed antioxidant properties through the Nrf2 antioxidant signaling pathway and alleviates arsenic-triggered toxicity in PC12 cells by regulating autophagy/apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Arsênico/toxicidade , Autofagia/efeitos dos fármacos , Curcumina/farmacologia , Poluentes Ambientais/toxicidade , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos
16.
Prostate ; 80(10): 742-752, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32449811

RESUMO

BACKGROUND: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells. METHODS: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism. RESULTS: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. CONCLUSIONS: We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.


Assuntos
Docetaxel/efeitos adversos , Células Matadoras Naturais/efeitos dos fármacos , Lectinas Tipo C/imunologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/terapia , Receptores Androgênicos/imunologia , Receptores de Superfície Celular/imunologia , Antagonistas de Receptores de Andrógenos/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Técnicas de Cocultura , Terapia Combinada , Curcumina/análogos & derivados , Curcumina/farmacologia , Docetaxel/uso terapêutico , Células HEK293 , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/biossíntese , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/biossíntese , Regulação para Cima/efeitos dos fármacos
17.
Int J Nanomedicine ; 15: 2699-2715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368050

RESUMO

Purpose: Current direct-acting antiviral agents for treatment of hepatitis C virus genotype 4a (HCV-4a) have been reported to cause adverse effects, and therefore less toxic antivirals are needed. This study investigated the role of curcumin chitosan (CuCs) nanocomposite as a potential anti-HCV-4a agent in human hepatoma cells Huh7. Methods: Docking of curcumin and CuCs nanocomposite and binding energy calculations were carried out. Chitosan nanoparticles (CsNPs) and CuCs nanocomposite were prepared with an ionic gelation method and characterized with TEM, zeta size and potential, and HPLC to calculate encapsulation efficiency. Cytotoxicity studies were performed on Huh7 cells using MTT assay and confirmed with cellular and molecular assays. Anti-HCV-4a activity was determined using real-time PCR and Western blot. Results: The strength of binding interactions between protein ligand complexes gave scores with NS3 protease, NS5A polymerase, and NS5B polymerase of -124.91, -159.02, and -129.16, for curcumin respectively, and -68.51, -54.52, and -157.63 for CuCs nanocomposite, respectively. CuCs nanocomposite was prepared at sizes 29-39.5 nm and charges of 33 mV. HPLC detected 4% of curcumin encapsulated into CsNPs. IC50 was 8 µg/mL for curcumin and 25 µg/mL for the nanocomposite on Huh7 but was 25.8 µg/mL and 34 µg/mL on WISH cells. CsNPs had no cytotoxic effect on tested cell lines. Apoptotic genes' expression revealed the caspase-dependent pathway mechanism. CsNPs and CuCs nanocomposite demonstrated 100% inhibition of viral entry and replication, which was confirmed with HCV core protein expression. Conclusion: CuCs nanocomposite inhibited HCV-4a entry and replication compared to curcumin alone, suggesting its potential role as an effective therapeutic agent.


Assuntos
Antivirais/farmacologia , Curcumina/farmacologia , Hepacivirus/efeitos dos fármacos , Nanopartículas/química , Antivirais/química , Linhagem Celular , Quitosana/química , Curcumina/administração & dosagem , Curcumina/química , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Humanos , Neoplasias Hepáticas/virologia , Nanopartículas/uso terapêutico , Proteínas do Core Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
Int J Nanomedicine ; 15: 3099-3120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431504

RESUMO

Curcumin, a yellow-colored polyphenol extracted from the rhizome of turmeric root, is commonly used as a spice and nutritional supplement. It exhibits many pharmacological activities such as anti-inflammatory, anti-bacterial, anti-cancer, anti-Alzheimer, and anti-fungal. However, the therapeutic application of curcumin is limited by its extremely low solubility in aqueous buffer, instability in body fluids, and rapid metabolism. Nano delivery system has shown excellent potential to improve the solubility, biocompatibility and therapeutic effect of curcumin. In this review, we focus on the recent development of nano encapsulated curcumin and its potential for biomedical applications.


Assuntos
Curcumina/administração & dosagem , Curcumina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Curcumina/química , Humanos , Lipossomos/química , Solubilidade
19.
Int J Nanomedicine ; 15: 2987-2998, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431497

RESUMO

Background: Emerging cancer therapy requires highly sensitive diagnosis in combination with cancer-targeting therapy. In this study, a self-assembled pH-sensitive curcumin (Cur)-loaded nanoparticle of 99mTc radiolabeled hyaluronan-cholesteryl hemisuccinate conjugates (HA-CHEMS) and D-a-tocopheryl polyethylene glycol succinate (TPGS) was prepared for breast cancer synergistic theranostics. Materials and Methods: The synthesized amphiphilic HA-CHEMS conjugates and TPGS self-assembled into Cur-loaded nanoparticles (HA-CHEMS-Cur-TPGS NPs) in an aqueous environment. The physicochemical properties of HA-CHEMS-Cur-TPGS NPs were characterized by transmission electron microscopy (TEM) and dynamic lighter scattering (DLS). The in vitro cytotoxicity of HA-CHEMS-Cur-TPGS NPs against breast cancer cells was evaluated by using the methyl thiazolyl tetrazolium (MTT) assay. Moreover, the in vivo animal experiments of HA-CHEMS-Cur-TPGS NPs including SPECT/CT imaging biodistribution and antitumor efficiency were investigated in 4T1 tumor-bearing BALB/c mice; furthermore, pharmacokinetics were investigated in healthy mice. Results: HA-CHEMS-Cur-TPGS NPs exhibited high curcumin loading, uniform particle size distribution, and excellent stability in vitro. In the cytotoxicity assay, HA-CHEMS-Cur-TPGS NPs showed remarkably higher cytotoxicity to 4T1 cells with an IC50 value at 38 µg/mL, compared with free curcumin (77 µg/mL). Moreover, HA-CHEMS-Cur-TPGS NPs could be effectively and stably radiolabeled with 99mTc. The SPECT images showed that 99mTc-HA-CHEMS-Cur-TPGS NPs could target the 4T1 tumor up to 4.85±0.24%ID/g at 4 h post-injection in BALB/c mice. More importantly, the in vivo antitumor efficacy studies showed that HA-CHEMS-Cur-TPGS NPs greatly inhibited the tumor growth without resulting in obvious toxicities to major organs. Conclusion: The results indicated that HA-CHEMS-Cur-TPGS NPs with stable 99mTc labeling and high curcumin-loading capacity hold great potential for breast cancer synergistic theranostics.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Curcumina/uso terapêutico , Ácido Hialurônico/química , Nanopartículas/química , Tecnécio/química , Nanomedicina Teranóstica , alfa-Tocoferol/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Curcumina/farmacocinética , Curcumina/farmacologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Tecidual/efeitos dos fármacos
20.
Life Sci ; 256: 117840, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32450173

RESUMO

AIMS: Platelet production improvement can resolve concerns about the limitations of external platelet supply and platelet transfusion in thrombocytopenia patients. To this end, scientists encourage to induce the generation of megakaryocyte and platelet. Curcumin is a safe ingredient of turmeric that affects various cellular pathways. The effect of this component on platelet production has not been yet reported. MAIN METHODS: Our in vitro experiments include the investigation of the effects of nanocurcumin on megakaryocytes production from K562 cells and hematopoietic stem cells via megakaryocyte markers expression, DNA content, ROS, and morphologic analysis, and CFC assay. The regulatory functions of MAPKs pathways were also determined. In the in vivo study tissue distribution of nanocurcumin was determined and two treatment schedules were used to evaluate the capability of nanocurcumin to prevent the occurrence of Busulfan-induced thrombocytopenia in the mouse model. KEY FINDING: In vitro evidences demonstrated that nanocurcumin can induce MK production from K562 cells and hematopoietic stem cells. Inhibition of ERK1/2 and JNK pathways arrested this activity. In vivo experiments showed the uptake of nanocurcumin by tissues in mice. Administration of nanocurcumin could preserve bone marrow integrity and increase of the number of circulating platelets in the Busulfan-treated mice models. SIGNIFICANCE: Our results have demonstrated that nanocurcumin administration can be useful for the improvement of megakaryocytes and platelet generation in vitro. This component may be exerting these beneficial effects on megakaryopoiesis by modulating ERK1/2 and JNK pathways. As well as nanocurcumin has the potential to prevent thrombocytopenia in chemotherapy threated mice.


Assuntos
Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Megacariócitos/efeitos dos fármacos , Nanoestruturas , Trombocitopenia/prevenção & controle , Animais , Antineoplásicos Alquilantes/toxicidade , Plaquetas/metabolismo , Bussulfano/toxicidade , Curcumina/administração & dosagem , Curcumina/farmacocinética , Feminino , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células K562 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Megacariócitos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Trombocitopenia/induzido quimicamente , Distribuição Tecidual
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