RESUMO
Phoenix dactylifera L. (date palm) is the most significant member of the palm family (Arecaceae), particularly in the Middle East and Arab World. It is a valuable source of both primary and secondary metabolites including sugars, amino acids, phenolic acids, flavonoids, proanthocyanidins, carotenoids, phytosterols, terpenes and sphingolipids, besides vitamins and minerals. Besides, it possesses a wide array of pharmacologic activities viz. immunomodulatory, antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, anti-mutagenic and anti-cancer activities, in addition to its positive effects on male and female fertility. Further research is still required to deeply understand its clinical implications, especially concerning women's health. Moreover, there are other Phoenix species that still need to be investigated to learn more about their undiscovered phytochemical components and biological activities.
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Phoeniceae , Compostos Fitoquímicos , Saúde da Mulher , Humanos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Phoeniceae/química , Feminino , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificaçãoRESUMO
Erythrina bidwillii Lindl., Leguminosae, constitutes a valuable crop for horticulture and medicine; however, it is rarely investigated. Menopause is a crucial transitional period in women's health. Women worldwide consider the use of phytoestrogens as a safe hormone replacement therapy to alleviate detrimental menopausal symptoms. Thus, the discovery of novel phytoestrogens is highly demanded. The present study aimed to investigate, for the first time, the metabolomic profile and the estrogenic potential of E. bidwillii Lindl. leaf. Ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry and gas chromatography-mass spectrometry metabolite profiling revealed the prevalence of alkaloids, flavonoids, isoflavonoids and fatty acids. Additionally, five erythrinan alkaloids, cristanine A (1), 8-oxoerythraline (2), (+)-erythrinine (3), (+)-erythraline (4) and 8-oxoerythrinine (5), along with the isoflavonoid genistin (6), were isolated. Erythrina bidwillii leaf extract exhibited significant in vivo estrogenic, anti-osteoporotic, anti-hyperlipidemic, hepatoprotective, and nephroprotective activities, utilizing ovariectomized rat model. Moreover, ethyl acetate and hexane fractions possessed significant in vitro estrogeic potential on MCF-7 cell lines. An in silico study of the isolated metabolites revealed that (+)-erythrinine (3) and 8-oxoerythrinine (5) exhibited the highest affinity for ERα and ERß, respectively, modeling them as potential estrogenic lead metabolites. Therefore, E. bidwillii leaf could be employed as promising hormone replacement therapy for postmenopausal women after thorough clinical trials.
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Alcaloides , Erythrina , Feminino , Humanos , Ratos , Animais , Fitoestrógenos/química , Erythrina/química , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células MCF-7RESUMO
The aim of the current study is to preserve the emulsomal vesicles against the harsh condition of gastrointestinal tract (GIT), after oral administration, employing tripolyphosphate (TPP)-crosslinked chitosan as a protective coating layer. Rutin was used as a model drug with evaluation of anti-hyperlipidemic activity in rats. The rutin loaded unmodified emulsomes were prepared using tripalmitin and soybean phosphatidylcholine (SPC), by thin film method. Drug loading for the prepared formulations ranged between 6.80 and 15.50 %. The selected formulation (RT-Emuls-6) comprised tripalmitin and SPC, molar ratio 1:1, and exhibited particle size (PS) and zeta potential (ZP) of 150.40 nm and -35.35 mV, respectively. RT-Emuls-6 was then modified by coating with either solely chitosan (RT-Emuls-6-Ch) or TPP-crosslinked chitosan (RT-Emuls-6-Ch-TPP-1). The latter exhibited PS and ZP values of 269.60 nm and 37.17 mV, respectively. Transmission electron microscopy of RT-Emuls-6-Ch-TPP-1 showed a dense pale greyish layer of a coating layer of chitosan crosslinked with TPP surrounding SPC bilayers. Fourier transform infrared spectroscopy analysis along with X-ray powder diffraction confirmed cross-linking between chitosan and TPP. Stability study in the simulated GIT fluids revealed that the order of rutin retained percentage was RT-Emuls-6-Ch-TPP-1 > RT-Emuls-6-Ch > RT-Emuls-6 (80.02, 50.66 and 44.41 %, respectively for simulated gastric fluid and 63.50, 55.66 and 24.00 %, respectively for simulated intestinal fluid, after 2 h incubation). Anti-hyperlipidemic activity of rutin loaded emulsomes was evaluated, after oral administration, in a high fat diet-induced hyperlipidemia in rats. The order of activity was as follows: RT-Emuls-6-Ch-TPP-1 > RT-Emuls-6-Ch > RT-Emuls-6 > free rutin. These findings revealed the potential of TPP-crosslinked chitosan as a protective coating layer for enhancing the stability of emulsomes against the harsh condition of GIT. RT-Emuls-6-Ch-TPP-1 had a potent anti-hyperlipidemic activity via regulation of lipids, oxidative stress, irisin and uncoupling protein 1.
Assuntos
Quitosana , Nanopartículas , Ratos , Animais , Quitosana/química , Preparações Farmacêuticas , Rutina , Polifosfatos/química , Administração Oral , Tamanho da Partícula , Nanopartículas/químicaRESUMO
AIM: Aging is the leading risk factor for diminishing lung function, as well as injury and lung disorder. The target of our research was to examine the potential protective effect of naringin and the possible role of SIRT1 in mice with D-galactose-induced lung aging, by evaluating its effects on antioxidant systems, mitochondrial biogenesis, autophagy, and apoptosis, by referring to the potential involvement of Nrf2/NQO1, LKB1/AMPK/PGC-1α, FOXO1, and P53/caspase-3 signaling. MATERIAL AND METHODS: The mice were randomly sorted into 5 groups (10 each): 1st: normal group received subcutaneous normal saline and intragastric distilled water, 2nd: naringin 300â¯mg/kg orally, 3rd: D-galactose (200â¯mg/kg/day) was administered subcutaneously into mice for eight weeks, to accelerate aging, 4th & 5th: oral naringin (150, 300â¯mg/kg) was given daily concurrently with D-galactose injection for 8â¯weeks. KEY FINDING: In silico investigation revealed that naringin substantially stimulates the SIRT1 and AMPK molecules. At the molecular level, our findings indicated that treatment with naringin stimulated the mitochondrial biogenesis pathway through regulation of the LKB1/AMPK/PGC-1α signals and upregulated FOXO1-mediated autophagy. Furthermore, naringin exhibited antioxidant properties by activating the Nrf2/NQO1 pathway and inhibiting MDA and AGEs levels. In addition, Naringin ameliorated alveolar spaces destruction and bronchial wall thickening, as well as alleviated P53/caspase-3 apoptosis signaling. SIGNIFICANCE: Naringin exerts protective effects against D-galactose-induced lung aging and enhances longevity by activating SIRT1. SIRT1 regulates various aging-related molecular pathways via restoring pro-oxidant/antioxidant homeostasis, activation of mitochondrial biogenesis, modulating of autophagy and inhibition of apoptosis.
Assuntos
Antioxidantes , Galactose , Camundongos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Galactose/farmacologia , Caspase 3/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Envelhecimento/metabolismo , Mitocôndrias/metabolismo , Pulmão/metabolismoRESUMO
BACKGROUND: Carbohydrates are known as the main natural products of life activities. RESULTS: Streptomyces rochie strain OF1 isolated from a mangrove tree produced exopolysaccharide S5 (EPSS5) (14.2 gl-1) containing uronic acid 21.98% sulfate content of 11.65 mg/ml, and a viscosity of 1.35 mm2/s. while total hexose amine content was 24.72%. The high performance liquid chromatography (HPLC) analysis of mono sugars revealed that EPS was composed of manouronic acid, glucuronic acid, xylose, and fructose at a molar ratio of 1.0:0.5:1.0:2.0, respectively. It showed that the whole antioxidant activity was 92.06%. It showed antibacterial activity against Staphylococcus aureus, and E. coli, MRSA and Klebsiella pneumoniae. But, EPSS5 displayed low antifungal activity against Candida albicans. While no antifungal activity has been detected against Aspergillus niger. EPSS5 has antibiofilm action that is noticeable toward S. aureus with an inhibition ratio of biofilm up to 50%. Effect of EPS on serum levels of TNF-α and COX2 by 2 fold and 1.9 fold of EPS reduced serum levels of Tumor necrosis factor-α (TNF-α) by 38%, 12%, 49%, and Cyclooxygenase-2 (COX2) by 61%, 34%, and 62%, respectively. By affected of EPSS5 on arthritis in rats stimulated by carrageenan. CONCLUSIONS: Administration of EPS ameliorated carrageen-induced elevation in inflammatory mediators; TNF-α/COX and suppressed the expressions of metalloproteinase 9 (MMP9) by 68%, 86%, and 75% correspondingly in comparison to the group of carrageenans. Then again, therapy involving a high dose only reduced MMP9 level by 57%, compared to free drug suggesting that EPSS5 is a good inhibitor of the MMP9, as it brought MMP9 back to normal levels via the signaling pathway.
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AIMS: Osteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans. MATERIALS AND METHODS: Thirty-two rats were divided into four groups (n = 8). The 1st group received saline and included the normal-control rats. Groups 2-4 received intra-articular injections of MIA (3 mg/50 µL) in the rats' knee joints to induce OA. Group 2 included the MIA-control rats. Groups 3 and 4 received intra-articular MIA followed by a 14-day oral eplerenone (50 and 100 mg/kg); respectively. KEY FINDINGS: Intra-articular injection of MIA in rats' knee joints caused significant inflammation and pain, elevation of Akt and ERK gene expression in knee joints along with significant alterations in the histological pictures of knee joints and OARSI scores. RANKL/OPG Axis was significantly disrupted. SIGNIFICANCE: Eplerenone treatment produced a significant improvement in motor coordination and spontaneous locomotor activity in rats and modulated the key inflammatory mediators in OA (TNF-α, NF-κß, and IL-6). Eplerenone also suppressed the qRT-PCR gene expression of Akt and ERK in knee joint tissues and improved the histological pictures and OARSI scores of knee joints of treated rats. Eplerenone caused a decline in RANKL concentration accompanied by a rise in OPG concentration thus modulating the RANKL/OPG Axis. Consequently, eplerenone is a candidate for OA therapy due to its potential anti-inflammatory effects.
Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Humanos , Ratos , Animais , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Ácido Iodoacético/toxicidade , Eplerenona/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dor/metabolismo , Cartilagem Articular/patologiaRESUMO
Background and purpose: Kidney diseases impose significant global health challenges. Potassium dichromate (PD) is a heavy metal frequently associated with nephrotoxicity. PD prompts oxidative and inflammatory injuries in renal tissues. L-carnitine is a naturally-occurring amino acid commonly used as a supplement. Experimental approach: Forty rats were randomly allocated into 5 groups. Group 1 (normal) received only saline. Nephrotoxicity was induced in the remaining groups by PD (15 mg/kg; i.p). Group 2 served as a nephrotoxic group. Groups 3-5 received L-carnitine (25, 50, and 100 mg/kg; p.o.), respectively for 4 weeks. Findings/Results: PD administration resulted in elevated serum creatinine and blood urea nitrogen accompanied by diminished reduced glutathione and elevated malondialdehyde, tumor necrosis factor-alpha, and transforming growth factor-beta renal tissue contents relative to normal rats. PD also produced apoptotic histopathological injuries and down-regulated PI3K/Akt signaling pathway; signifying ongoing apoptosis. In the current work, L-carnitine use in the selected dose levels resulted in improvement of all the aforementioned serum, renal tissue, and histological parameters relative to nephrotoxic rats. L-carnitine up-regulated PI3K/Akt signaling pathway that was down-regulated post PD use. Conclusion and implications: Collectively, the study highlighted that the possible mechanisms beyond the beneficial effects of L-carnitine are mainly through its antioxidant as well as anti-inflammatory actions. L- carnitine significantly abrogated apoptosis via up-regulation of PI3K/Akt signaling pathway and signified restoration of normal renal cell proliferation and functionality.
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The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κß signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1ß, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-ß1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-ß1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-ß1 /FAK/α-SMA.
Assuntos
Actinas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Óleo de Farelo de Arroz/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismo , Albuminas/metabolismo , Animais , Becaplermina/metabolismo , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Globulinas/metabolismo , Glutationa/metabolismo , Hidroxiprolina/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Óleo de Farelo de Arroz/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tioacetamida , Transaminases/sangue , Transaminases/metabolismoRESUMO
The historic DHP nucleus was serendipitously discovered by Arthur Hantzsch about 130 years ago and is still considered a hidden treasure for various pharmacological activities. Twenty-one DHP analogues were synthesized using the expedient one pot Hantzsch synthesis for screening as anticancer agents. Initially, the in vitro anti-proliferative single dose against a panel of 18 cancer cell lines showed that compounds 11b and 8f were the superlative candidates regarding their antitumor effect (GI% mean = 66.40% and 50.42%, correspondingly) compared to cisplatin (GI% mean = 65.58%) and doxorubicin (GI% mean = 74.56%). Remarkably, compound 11b showed a remarkable MDA-MB-468 anticancer activity (GI%=80.81%), higher than cisplatin (64.44%) and doxorubicin (76.72%), as well as strong antitumor activity against lung cancer A549 (GI%= 83.02%), more powerful than both cisplatin and doxorubicin. Compound 11b exhibited an exceptional anticancer activity against lung cancer cell line (A549) as its GI50 in nanomolar was (540 nM) with a 9-fold increase greater than cisplatin (GI50 = 4.93 µM) and with a selectivity index = 131 to cancer cells over normal cells. Further mechanistic investigations proved that DHPs anticipate simultaneously TOPI and RTKs (VEGFR-2, HER-2 and BTK) which can stimulate BAX/BAK and the executioner caspases via rtPCR studies.
Assuntos
Antineoplásicos/farmacologia , Di-Hidropiridinas/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The present study aims to formulate all-trans retinoic acid (ATRA) loaded chitosan/tripolyphosphate lipid hybrid nanoparticles (CTLHNs) for enhancing its solubility and oral delivery. This is to improve ATRA therapeutic effect on diabetic nephropathy (DN). CTLHNs were prepared by o/w homogenization, employing stearic acid, to form lipid nanoparticles coated with chitosan that is stabilized against acidic pH via sodium tripolyphosphate crosslinking. Chitosan coated (F7) and naked lipid nanoparticles (F6) were also prepared for comparison with CTLHNs. In vitro characterization for the prepared formulations was performed comprising entrapment efficiency, particle size, zeta potential, transmission electron microscopy, FT-IR spectroscopy and x-ray diffraction. Stability of chitosan coat in GI fluid revealed that CTLHNs were more stable than F7. In vitro release indicated an enhanced release of ATRA from the developed formulations. In vitro mucoadhesion study proved a notable mucoadhesive property for CTLHNs. In DN rat model, serum levels of creatinine and urea were elevated, over expression of tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were observed. In addition, adenosine monophosphate activated protein kinase (AMPK) and liver kinase B1 (LKB1) expressions were decreased in DN rats. Treatment with free ATRA and the selected formulations led to a significant amelioration of DN by reducing of creatinine, urea, TNF-α, ICAM-1, GM-CSF, VEGF levels as well as elevating AMPK and LKB1 levels. The order of activity was: CTLHNs > F7 > F6 > free ATRA, as proved by histopathological examination.
Assuntos
Quitosana , Diabetes Mellitus , Nefropatias Diabéticas , Nanopartículas , Animais , Nefropatias Diabéticas/tratamento farmacológico , Portadores de Fármacos , Lipídeos , Tamanho da Partícula , Polifosfatos , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Tretinoína , Fator A de Crescimento do Endotélio VascularRESUMO
Although Malpighia glabra Linn. fruits are well studied for their nutritional and medicinal prominence; little attention has been given to the leaves. Our study intends to investigate the leaves metabolic profile using Q-TOF LC/MS/MS (Quadrupole-Time-of-Flight-Liquid-Chromatography-Mass-Spectrometry), and to explore their in vivo hepatoprotective activity in rats using CCL4 -induced hepatic damage model and silymarin as standard. Fifty metabolites were characterized, belonging to different classes; coumarins (capensine, daphnoretin, and scopoletin), flavonoids (mainly quercetin and apigenin glycosides), phenolic acids (cinnamic acid and quinic acid derivatives) and amino acids (adenosine, homoisoleucine, and phenylalanine).These compounds are detected in the leaves for the first time. The hepatoprotective activity at three doses (200, 400, and 800 mg/kg) was investigated. The dose of 800 mg/Kg showed the highest hepatoprotective effect as it reduced the elevated serum levels of ALT, AST, NO, and TNF-α liver content by 26, 24, 23, and 42%, respectively, it also remarkably increased the serum level of catalase by 102%. All the tested doses showed higher reduction in serum level of TNF-α compared to silymarin which suggests their strong anti-inflammatory potential. M. glabra leaves are revealed to be a rich source of secondary metabolites and proved to possess significant hepatoprotective potential. PRACTICAL APPLICATIONS: The performed analyses in this study shows the richness of Malpighia glabra Linn. leaves in a plethora of beneficial and safe phytochemicals which are well-known to have a pivotal role in protection against different diseases including liver disorders. The carried-out investigations were done using Q-TOF LC/MS/MS analysis which is a reliable technique for the determination, characterization and identification of bioactive metabolites; in addition to evaluation of the hepatoprotective effect of the leaves. Therefore, this study may emphasize that Malpighia glabra Linn. leaves may have the same nutritional and medicinal importance as its fruits, and they could be incorporated into pharmaceuticals and foods instead of discarding them.
Assuntos
Malpighiaceae , Animais , Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Espectrometria de Massas em TandemRESUMO
Colorectal cancer is one of the primary causes of cancer-related mortality worldwide. The tumor microenvironment contains growth factors; inflammatory chemokines, matrix metalloproteinases, and pro-oxidants leading to cancer development and progression. Phytochemicals have been used as the main source of anti-cancer agents. Accordingly, the effect of two natural flavonoids (Chrysin and Daidzein) was investigated on the level of amphiregulin (AREG), chemokine ligand (CXCL1), and matrix metalloproteinase-9 (MMP-9) in 1, 2-dimethylhydrazine dihydrochloride (DMH) induced colorectal cancer. Rats were injected by DMH (40 mg/kg/week S.C.) for 16 weeks concomitantly with 2% dextran sodium sulfate (DSS) in drinking water for three cycles. Rats were orally treated with chrysin (125 and 250 mg/kg) and daidzein (5 and10 mg/kg) three times/week for the last 8 weeks. DMH + DSS group showed a significant (P < 0.05) increase in the levels of AREG (2386 ± 18 vs 1377 ± 10 pg/ml), CXCL1 (18 ± 0.9 vs 6 ± 0.83
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Anfirregulina/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Quimiocina CXCL1/metabolismo , Colo/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Flavonoides/farmacologia , Isoflavonas/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , 1,2-Dimetilidrazina , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/enzimologia , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Citocromo P-450 CYP2E1/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de SinaisRESUMO
Colchicine is a drug from the past with a bright shining future. It has gained much attention nowadays due to the newly explored therapeutic avenues that were opened by its application in serious ailments. Colchicine has been recently observed as a potential treatment for osteoarthritis (OA). OA is a widespread joint degenerative disease that causes extensive pain and disability. Colchicine has been discovered to affect bone turnover and to reduce different cytokines like interleukin 6 (IL6). Colchicine oral administration has several limitations including extensive first-pass effect, poor bioavailability, and severe GIT side effects. The transdermal route circumvents these limitations. However, colchicine transdermal delivery is challenging owing to its high aqueous solubility and hence poor skin permeation. In this study, novel colchicine transdermal delivery systems were developed to conquer such obstacles. Cellulose-based patches were primed, where mesoporous silica nanoparticles (MSNs) were prepared and used as colchicine encapsulators. The free colchicine or the encapsulated drug was embedded into self-healing hydrogel. The hydrogel was prepared by reacting carboxyethyl chitosan and oxidized pullulan. These composites were used to treat cotton fabric to produce easily applicable and extended-release transdermal patches. Nitrogen adsorption-desorption isotherms, DLS, TEM, and SEM were used to estimate surface area, pore-volume, size, zeta potential, and morphology of MSNs. The hydrogel was characterized using FTIR and TEM. The prepared cotton patch was tested for fabric stiffness. Ex vivo drug permeation study through isolated rat skin was conducted. In comparison to free drug aqueous solution, the patches revealed enhanced drug flux and amplified permeated drug levels which were sustained all over 24 h. Skin permeation was further validated via confocal laser microscopy using fluorescein. The therapeutic investigation of colchicine formulated patches in mono-iodoacetate (MIA)-induced rat osteoarthritis model depicted improved locomotor activity, glutathione blood level, and remarkable decline in levels of malondialdehyde, nitric oxide, TNF-α, and COX-2. Histopathology of rats knee joint supported the OA protective effect of the developed patches, The obtained results revealed significant potentiality of the developed colchicine mesoporous silica nanoparticles/hydrogel patches in the offering, efficient safe and patient convenient formulation for OA management.
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Colchicina/administração & dosagem , Hidrogéis/química , Nanopartículas Metálicas/química , Osteoartrite/tratamento farmacológico , Dióxido de Silício/química , Pele/efeitos dos fármacos , Administração Cutânea , Administração Oral , Animais , Celulose/química , Fibra de Algodão , Ciclo-Oxigenase 2/metabolismo , Sistemas de Liberação de Medicamentos , Incidência , Cinética , Masculino , Microscopia Confocal , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nitrogênio/química , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Têxteis , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and vomiting (CINV) through the buccal route. CINV comprises bothersome side effects accompanying cytotoxic drugs administration in cancer patients. Meclizine was loaded in chitosan-pectin nanoparticles which were further incorporated within a buccal film. Different formulations were prepared based on a 21.31 full factorial study using Design Expert®8. The optimum formulation possessed favorable characters regarding its particle size (129 nm), entrapment efficiency (90%) and release profile. Moreover, its permeation efficiency through sheep buccal mucosa was assessed via Franz cell diffusion and confocal laser microscopy methods. Enhanced permeation was achieved compared with the free drug form. In-vivo performance was assessed using cyclophosphamide induced emesis. The proposed formulation exerted significant relief of the measured responses (reduced body weight and motor coordination, elevated emesis, anorexia, proinflammatory mediators and neurotransmitters that were also associated with scattered degenerated neurons and glial cells). The developed formulation ameliorated all behavioral, biochemical and histopathological changes induced by cyclophosphamide. The obtained data were promising suggesting that our bioadhesive formulation can offer an auspicious medication for treating distressing symptoms associated with chemotherapy for cancer patients.
Assuntos
Antieméticos/farmacologia , Quitosana/química , Meclizina/farmacologia , Nanopartículas/química , Pectinas/química , Vômito/tratamento farmacológico , Administração Bucal , Animais , Antieméticos/administração & dosagem , Antieméticos/farmacocinética , Antineoplásicos/efeitos adversos , Química Farmacêutica/métodos , Ciclofosfamida/efeitos adversos , Citocinas/biossíntese , Preparações de Ação Retardada , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Mediadores da Inflamação/metabolismo , Masculino , Meclizina/administração & dosagem , Meclizina/farmacocinética , Microscopia Eletrônica de Transmissão , Neurotransmissores/metabolismo , Absorção pela Mucosa Oral/fisiologia , Ratos , Ratos Wistar , Ovinos , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à Tração , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Abnormal activation of protein kinase B (PKB) is associated with many cancers. This makes inhibition of PKB signaling pathway a promising strategy for cancer therapy. Lactoferrin (Lf) has been reported for its inhibition of tumor growth and metastasis, however, the mechanism is not completely understood. Its anti-hepatocarcinogenic activity has not taken the deserved recognition despite the additional advantages of Lf as an antiviral against hepatitis C virus, the main cause of hepatocellular carcinoma (HCC), and as a targeting ligand for delivering chemotherapeutics to hepatoma cells. METHODS: This study evaluated the anti-hepatocarcinogenic effect of Lf, and the role of PKB in this effect using diethylnitrosamine (DENA)-induced HCC rat model, and a primary cell culture prepared from the induced hepatic lesions (DENA-HCC cell culture). RESULTS: Up-regulation of activated PKB in the hepatocytes of rats with DENA-induced HCC was observed, as measured biochemically in the liver homogenate, and localized immunohistochemically. This was accompanied by increment of hepatocytes proliferation, and expression of vascular endothelial growth factor and endothelial nitric oxide synthase. Involvement of PKB in DENA-induced HCC was confirmed by the observed decrease in cell proliferation in DENA-HCC cell culture that was treated with PKB inhibitor. In Lf-treated rats, a dose-dependent chemopreventive effect was observed, with decreased expression and activation of PKB, amelioration of the other DENA-induced alterations, and stimulation of apoptosis. In vitro, Lf blocked PKB activator-induced cell proliferation. CONCLUSION: These findings support the chemopreventive activity of Lf against HCC, and suggest regulation of PKB-pathway as a potential mechanism underlying this effect.
Assuntos
Anticarcinógenos/farmacologia , Lactoferrina/farmacologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Fígado/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Proliferação de Células/efeitos dos fármacos , Quimioprevenção , Dietilnitrosamina , Fígado/enzimologia , Fígado/patologia , Testes de Função Hepática , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Tadalafila/farmacologia , Tioacetamida/farmacologia , Actinas/metabolismo , Animais , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Hidroxiprolina/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Transaminases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Depression is very common in asthmatic patients and may increases risk for morbidity and mortality. The present work aimed to investigate the protective effect of fluoxetine, on behavioral and biochemical changes, associated with ovalbumin (OVA) - induced bronchial asthma and depression in rats. Rats were sensitized with intraperitoneal administration of OVA plus aluminum hydroxide for 3 consecutive days then at day 11 followed by OVA intranasal challenge at days 19, 20, 21. Rats were either pretreated with dexamethasone, fluoxetine10mg/kg or fluoxetine 20â¯mg/kg. At the end of the experiment, various tests were performed, including open field, forced swimming and respiratory function tests. Blood was drawn for serum IgE detection. Finally, rats were euthanized, brain-derived neurotrophic factor (BDNF) was estimated in bronchoalveolar lavage (BAL) fluid and lung content of reduced glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α) and interleukin 4 (IL-4) were determined. Histopathological study was also performed. The results showed that fluoxetine significantly ameliorated OVA- induced biochemical and behavioral changes. Fluoxetine may protect against OVA-induced asthma and depression in rats. This effect may be mediated at least in part by its antioxidant, anti-inflammatory and immunosuppressant effect.
Assuntos
Asma/prevenção & controle , Depressão/prevenção & controle , Fluoxetina/uso terapêutico , Ovalbumina/imunologia , Animais , Asma/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/análise , Dexametasona/uso terapêutico , Imunoglobulina E/sangue , Interleucina-4/análise , Masculino , Estresse Oxidativo , Pico do Fluxo Expiratório/efeitos dos fármacos , RatosRESUMO
The objective of this study was to innovate an effective oral sustained release hepatoprotective formula for - the water soluble drug - caffeine. Caffeine is rapidly absorbed and eliminated which dictates frequent administration to achieve adequate therapeutic effect. A w/o Pickering emulsion incorporating caffeine in the internal phase was primed. It contained wheat germ oil and was stabilized by synthesized magnesium oxide nanoparticles (MgO NPs). Components selection was based on their antioxidant, hepatoprotective and anticarcinogenic effects. The MgO NPs were prepared via sol-gel method, and then were characterized using X-ray diffractometry, transmission electron microscopy, contact angle and cytotoxicity. The Pickering emulsion formula stabilized by MgO NPs (F1) was compared to another stabilized by conventional MgO particles (F2). Both were evaluated regarding droplet size, stability and caffeine release. F1 was stable against phase separation for a 2â¯months period. Its droplets mean size was 665.9⯱â¯90â¯nm. F1 afforded sustained release for caffeine that reached 70% within 48â¯h that followed zero order kinetics. 100â¯ppm of F1 showed nearly 36% growth inhibition of hepatocellular carcinoma (HEPG2). In vivo and histopathalogical evaluations were conducted on CCl4 intoxicated rats. Biochemical analysis for liver enzymes - (ALT and AST), oxidative stress biomarkers and the inflammation marker (protein kinase C) - revealed that the selected formula elicited significant hepatoprotection. This formula acted as an economical approach to multiple therapy and afforded safe effective sustained level for caffeine.
Assuntos
Cafeína/administração & dosagem , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Fígado/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Administração Oral , Animais , Cafeína/química , Cafeína/farmacologia , Cafeína/uso terapêutico , Intoxicação por Tetracloreto de Carbono/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Emulsões , Células Hep G2 , Humanos , Fígado/patologia , Óxido de Magnésio/administração & dosagem , Óxido de Magnésio/química , Óxido de Magnésio/farmacologia , Óxido de Magnésio/uso terapêutico , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/uso terapêutico , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Óleos de Plantas/uso terapêutico , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Wistar , ReologiaRESUMO
BACKGROUND: Bronchial asthma is a true ascending clinical problem. Angiotensin II is now accused to be potentially implicated in its pathogenesis, being a potent pro-inflammatory mediator with remodeling effects. OBJECTIVE: This study aims to evaluate the possible protective effect of telmisartan, an angiotensin II receptor blocker, on experimentally-induced bronchial asthma. METHODS: Animals were divided into 5 groups; a normal control group, an asthma control group, a reference treatment group, receiving dexamethasone, and two treatment groups, receiving telmisartan in two dose levels. Bronchial asthma was induced by intraperitoneal sensitization followed by intranasal challenge with ovalbumin (OVA). Test agents were administered prior to each intranasal OVA challenge. Lung function tests, namely tidal volume (TV) and peak expiratory flow rate (PEF) were assessed 1h after the last challenge. One day after the last challenge, absolute eosinophil counts (AEC) in blood and bronchoalveolar lavage fluids (BALF) were assessed. Serum immunoglobulin E (IgE) as well as BALF total nitrate/nitrite (NOx) were assessed. Oxidative and inflammatory biomarkers, namely lung tissue superoxide dismutase (SOD), glutathione reduced (GSH), tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5), were also assessed, in addition to histopathological study. RESULTS: Telmisartan administration in both doses significantly improved TV, PEF, AEC, IgE, NOx, GSH, SOD, TNF-α and IL-5 values compared to asthma control values. Histopathological study strongly supported the results of biochemical estimations, particularly regarding airway remodeling. CONCLUSION: These results suggest that telmisartan may have potential protecting effects against experimental bronchial asthma, probably due to its bronchodilator, antioxidant and anti-inflammatory effects.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Asma/prevenção & controle , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Ovalbumina/toxicidade , Inibidores de Serina Proteinase/toxicidade , Animais , Asma/patologia , Biomarcadores , Líquido da Lavagem Broncoalveolar/química , Imunização , Masculino , Pico do Fluxo Expiratório/efeitos dos fármacos , Ratos , Ratos Wistar , Testes de Função Respiratória , Telmisartan , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Calcium influx, inflammatory infiltration, cytokine production, immunoglobulin E activation and oxidative stress play coordinated roles in bronchial asthma pathogenesis. We aim to assess the protective effect of cinnarizine against experimentally induced bronchial asthma. METHODS: Bronchial asthma was induced by ovalbumin sensitization and challenge. Rats were allocated into a normal control, an asthma control, a dexamethasone (standard) treatment, and 2 cinnarizine treatment groups. The respiratory functions tidal volume (TV) and peak expiratory flow rate (PEFR), the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5) in lung tissue, the allergic immunoglobulin IgE in serum, the absolute eosinophil count (AEC) in bronchoalveolar lavage fluid (BALF), as well as the oxidative and nitrosative markers glutathione reduced (GSH) and superoxide dismutase (SOD) in lung tissue and nitric oxide end products (NOx) in BALF were assessed, followed by a histopathological study. RESULTS: Cinnarizine administration significantly restored TV, PEFR, TNF-α, IL-5, IgE, AEC, GSH, SOD and NOx values back to normal levels, and significantly decreased perivascular and peribronchiolar inflammatory scores. CONCLUSION: Cinnarizine may protect against experimental bronchial asthma. Suppressant effect of cinnarizine on pro-inflammatory cytokines release, IgE antibody production, eosinophil infiltration as well as oxidative and nitrosative stress may explain its anti-asthmatic potential.