RESUMO
Phytochemicals, plant-derived compounds, are the major components of traditional medicinal plants. Some phytochemicals have restricted applications, due to low bioavailability and less efficacy. However, their medicinal properties can be enhanced by converting them into value-added products for different bioactivities like anti-oxidant, neuroprotective, anti-obesity, anti-neuroinflammatory, anti-microbial, anti-cancer and anti-inflammatory. Microbial transformation is one such process that is generally more specific and makes it possible to modify a compound without making any unwanted alterations in the molecule. This has led to the efficient production of value-added products with important pharmacological properties and the discovery of new active compounds. The present review assimilates the existing knowledge of the microbial transformation of some phytochemicals like eugenol, curcumin, ursolic acid, cinnamaldehyde, piperine, ß-carotene, ß-sitosterol, and quercetin to value-added products for their application in food, fragrances, and pharmaceutical industries.
RESUMO
In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small, focused library of derivatives. We assessed their anticancer activity against various cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, silicon-tethered compound B-4a demonstrated the highest potency against breast cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (CDK-2 and CDK-4) and their associated cyclins (cyclin-B1, cyclin-D1), inducing apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.
Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , Colchicina , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Colchicina/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Descoberta de Drogas , Feminino , Apoptose/efeitos dos fármacos , Reação de Cicloadição , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacosRESUMO
Ultraviolet-B (UV-B) irradiation has been reported to cause oxidative stress and inflammation-mediated skin photo-damage. Furthermore, mitochondrial dynamics have been implicated to play a critical role in these processes. For the first time, we describe in this study how UVB-induced aberrant mitochondrial dynamics and inflammation interact in primary human dermal fibroblasts (HDFs). Our findings demonstrated that UV-B irradiation induced -impairment in mitochondrial dynamics by increasing mitochondrial fragmentation in HDFs. Imbalanced mitochondrial dynamics lead to the activation of NFкB and pro-inflammatory cytokines. The current study further aimed to investigate the protective effect of Naringenin (a naturally occurring flavonoid isolated from Sea buckthorn fruit pulp) against UV-B-induced mitochondrial fragmentation and inflammation in HDFs and Balb/c mice. Although Naringenin has been shown to have anti-inflammatory and antioxidant potential, its effects and mechanisms of action on UVB-induced inflammation remained unclear. We observed that Naringenin restored the UV-B-induced imbalance in mitochondrial fission and fusion in HDFs. It also inhibited the phosphorylation of NFкB and reduced the generation of pro-inflammatory cytokines. Naringenin also alleviated UV-B-induced oxidative stress by scavenging the reactive oxygen species and up-regulating the cellular antioxidant enzymes (Catalase and Nrf2). Topical application of Naringenin to the dorsal skin of Balb/c mice exposed to UV-B radiation prevented mitochondrial fragmentation and progression of inflammatory responses. Naringenin treatment prevented neutrophil infiltration and epidermal thickening in mice's skin. These findings provide an understanding for further research into impaired mitochondrial dynamics as a therapeutic target for UV-B-induced inflammation. Our findings imply that Naringenin could be developed as a therapeutic remedy against UVB-induced inflammation.
Assuntos
Fibroblastos , Flavanonas , Hippophae , Inflamação , Camundongos Endogâmicos BALB C , Dinâmica Mitocondrial , Extratos Vegetais , Pele , Raios Ultravioleta , Animais , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/uso terapêutico , Raios Ultravioleta/efeitos adversos , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Camundongos , Pele/efeitos da radiação , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Hippophae/química , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos da radiação , Extratos Vegetais/farmacologia , Extratos Vegetais/química , NF-kappa B/metabolismo , Citocinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacosRESUMO
Koenimbine (1), a carbazole alkaloid isolated from Murraya koenigii, belongs to the Rutaceae family. Various pharmacological effects such as anti-diabetic, melanogenesis inhibition, anti-diarrheal, anti-cancer, and anti-inflammatory properties of koenimbine have already been reported. In the current study, we investigated the anti-inflammatory role of koenimbine (1) and its novel semi-synthetic derivative 8-methoxy-3,3,5-trimethylpyrano[3,2-a] carbazole-11(3H)-yl) (3-(trifluoromethyl) phenyl) methanone (1G) in both in vitro and in vivo biological systems. Our results demonstrated that the anti-inflammatory activity of 1G significantly lowered the production of NO, pro-inflammatory cytokines (IL-6, TNF-α & IL-1ß), LTB4 following LPS stimulation in RAW 264.7 macrophages. Furthermore, 1G significantly attenuated the expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner and also decreased the production of reactive oxygen species (ROS) in LPS-activated RAW 264.7 cells. In addition, the oral administration of 1G reduced the inflammatory response in carrageenan-induced paw edema in BALB/C mice. Moreover, it effectively reduced NO, IL-6, IL-1ß & TNF-α levels, liver markers (AST, ALT), and kidney markers (BUN, CRE, and Urea). Also, 1G reverted the infiltration of inflammatory cells and tissue damage in lungs, liver and kidney enhanced the survival rate in LPS-challenged mice. 1G blocks NF-κB p65 from translocating into the nucleus and activating inflammatory gene transcription. These results illustrated that 1G suppresses the inflammatory effects both in-vitro and in-vivo studies via downregulating the nuclear factor kappa-B (NF-κB) signaling pathway. In conclusion, our results demonstrate that semi-synthetic derivative 1G can effectively attenuate the inflammatory response via NF-κB and MAPK signaling pathways; suggesting 1G is a potential novel anti-inflammatory drug candidate in treating inflammatory disorders.
Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos BALB C , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carbazóis , Células RAW 264.7 , Ciclo-Oxigenase 2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismoRESUMO
The Rosa L. genus is a significant plant family in the Rosaceae group, consisting of around 200 species, primarily shrubs. In India, it has 37 species, most located in the Western Himalayan region of Jammu and Kashmir and Himachal Pradesh. Roses are highly regarded for their beauty and growth and are popular worldwide for their nutritional, therapeutic, ornamental, and cosmetic value. The rose hips are utilized in creating various food and drink items, such as jams, jellies, teas, and alcoholic beverages. The Rosa species has various pharmacological activities, including anti-inflammatory, antidiabetic, hepatoprotective, antimicrobial, anti-proliferative/anticancer, anti-arthritic, neurological, and anti-obesity activity. This review aims to provide an in- -depth overview of the phytochemistry and pharmacology of the Rosa species in India, focusing on Rosa indica L., which has significant potential for future chemical and biological research.
RESUMO
Natural products possess unique and broader intricacies in the chemical space and have been essential for drug discovery. The crucial factor for drug discovery success is not the size of the library but rather its structural diversity. Although reports on the number of new structurally diverse natural products (NPs) have declined recently, researchers follow the next logical step: synthesizing natural product hybrids and their analogues using the most potent tool, diversity-oriented synthesis (DOS). Here, we use weed Parthenium hysterophorus as a source of parthenin for synthesis of novel dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione natural product hybrids of parthenin via chemo-, regio-, and stereoselective azomethine ylide cycloaddition. All synthesized compounds were characterized through a detailed analysis of one-dimensional (1D) and two-dimensional (2D) NMR and HRMS data, and the stereochemistries of the compounds were confirmed by X-ray diffraction analysis. All compounds were evaluated for their cytotoxicity against four cell lines (HCT-116, A549, Mia-Paca-2, and MCF-7), and compound 6 inhibited the HCT-116 cells with an IC50 of 5.0 ± 0.08 µM.
RESUMO
ß- boswellic acid, a pentacyclic triterpene derived from Boswellia serrata is extensively known for its anti-inflammatory potential. BA-25 (3-α-o-acetoxy-4ß-amino-11-oxo-24-norurs-12-ene) is an amino analogue of ß-boswellic acid that has shown anti-inflammatory potential in LPS-induced macrophages and animal models. The present study aims at investigation of the combination of BA-25 with the conventional gold standard DMARD methotrexate (MTX) for its anti-inflammatory and anti-arthritic potential using in vitro and in vivo experimental models. The anti-inflammatory potential of MTX versus the combination (BA-25 + MTX) was investigated for inhibition of NO, ROS and pro-inflammatory cytokines including TNF-α and IL-6 using ELISA in LPS-stimulated RAW-264.7 cells. The results demonstrated significant reduction in NO, ROS, TNF- α and IL-6 production with the combination treatment in comparison to MTX alone. The cytokine inhibition potential of the combination was further validated in-vivo using balb/c wherein the combination restored LPS-induced increase in pro-inflammatory cytokines. The toxicological aspect of the in vivo doses of the combination was also investigated in mice after dosing for 28 days wherein the results suggested no significant change in the hematological parameters and serum biochemical parameters in the combination versus the vehicle group. The effect of BA-25 was also investigated on MTX-induced increase in liver function tests and the expression of Bax and blc2. The results demonstrated decrease in the production of liver enzymes with BA-25 administration along with downregulating the expression of apoptotic protein Bax while increasing the expression of anti-apoptotic protein Bcl2. Furthermore, pharmacokinetic studies of BA-25 were conducted in Balb/c mice wherein the compound showed rapid absorption, high volume of distribution and a t1/2 of 13.08. Finally the anti-arthritic effect of the combination of MTX + BA-25 vs MTX alone was investigated using CIA model in DBA/1 mice wherein the treatment with the combination resulted in significant reduction in paw inflammation, IL-6 and IL-1ß levels. Furthermore, the western blot analysis demonstrated considerable decrease in the expression of p-NF-κB p65 and p-IκB in the ankle-joint tissue of the CIA mice treated with the combination therapy. The results insinuated increased anti-inflammatory and anti-arthritic potential of the combination of MTX with BA-25 as evident from in to vitro and in-vivo studies.
Assuntos
Artrite Experimental , Artrite Reumatoide , Camundongos , Animais , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Interleucina-6 , Lipopolissacarídeos/efeitos adversos , Espécies Reativas de Oxigênio , Proteína X Associada a bcl-2/uso terapêutico , Artrite Experimental/metabolismo , Camundongos Endogâmicos DBA , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Chemoresistance is one of the leading causes of the failure of chemotherapy. Overexpression of P-glycoprotein (P-gp) in cancer cells is one of the most important contributing factors toward the development of chemoresistance. This study was designed to synthesize the derivatives of dihydronaphthyl and to evaluate the P-gp inhibition activity of these compounds. Among all the compounds, PGP-41 showed the most potent P-gp inhibition activity in colorectal adenocarcinoma LS-180 cells. This compound showed potent P-gp inhibition activity in chemoresistant ovarian cell line NCI/ADR-RES. Paclitaxel is one of the first lines of drugs for treating ovarian cancer and is a substrate of P-gp; therefore, NCI/ADR-RES cells are highly resistant to treatment with paclitaxel. Based on this information, we evaluated PGP-41 to overcome the paclitaxel resistance of NCI/ADR-RES cells. PGP-41 was able to sensitize the NCI/ADR-RES cells to the treatment of paclitaxel, which was evident by the reduced IC50 value of paclitaxel from 6.64 µM to 0.12 µM. The sensitization of NCI/ADR-RES cells by PGP-41 was comparable to that of elacridar and Zosuquidar. Further studies revealed that the PGP-41 exerts its effect by downregulating the expression of P-gp. Reduction of P-gp activity leads to the accumulation of higher intracellular concentration of paclitaxel, and thus allowing it to interact with its targets, which further helps in its increased efficacy. Paclitaxel was able to arrest the sensitized NCI/ADR-RES cells into G2M phase, which ultimately led to the induction of apoptotic proteins and the death of cancer cells. Being a different scaffold from zosuquidar and elacridar, further studies are required to develop PGP-41 into a potential drug to overcome chemoresistance in cancer cells.
Assuntos
Alcaloides , Paclitaxel , Paclitaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Alcaloides/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATPRESUMO
ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate ß-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPß. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPß is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.
RESUMO
Host inflammatory responses are key to protection against injury; however, persistent inflammation is detrimental and contributes to morbidity and mortality. Herein, we demonstrated the anti-inflammatory role of Arteannuin-B (1) and its new spirocyclic-2-isoxazoline derivative JR-9 and their side effects in acute inflammatory condition in vivo using LPS-induced cytokines assay, carrageenan-induced paw edema, acetic acid-induced writhing and tail immersion. The results show that the spirocyclic-2-isoxazoline derivative is a potent anti-inflammatory agent with minimal cell toxicity as compared to Arteannuin-B. In addition, the efficacies of these compounds were also validated by flow cytometric, computational, and histopathological analysis. Our results show that the anti-inflammatory response of JR-9 significantly reduces the ability of mouse macrophages to produce NO, TNF-α, and IL-6 following LPS stimulation. Therefore, JR-9 is a prospective candidate for the development of anti-inflammatory drugs and its molecular mechanism is likely related to the regulation of NF-κB and MAPK signaling pathway.
Assuntos
Lipopolissacarídeos , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Regulação para Baixo , Camundongos Endogâmicos BALB C , Macrófagos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Inflammation involves a dynamic network that is highly regulated by signals that initiate the inflammation process as well as signals that downregulate it. However, an imbalance between the two leads to tissue damage. Throughout the world, inflammatory disease becomes common in the aging society. The drugs which are used clinically have serious side effects. Natural products or compounds derived from natural products show diversity in structure and play an important role in drug discovery and development. OBJECTIVE: Oreganum Vulgare is used in traditional medicine for various ailments including respiratory and rheumatic disorders, severe cold, suppression of tumors. The current study aims to evaluate the anti-inflammatory potential by evaluating various in vitro parameters. METHODS: Inflammation-induced in macrophages via LPS is the most accepted model for evaluating the antiinflammatory activity of various plant extracts and lead compounds. RESULTS: The extracts (OVEE, OVEAF) as well as the isolated compound(OVRA)of Oreganum Vulgare inhibit the pro-inflammatory cytokines (IL-6 and TNF-α) and NO without affecting cell viability. CONCLUSION: Our study established that the leaf extracts of Oreganum vulgare L. exhibit anti-inflammatory activity and thus confirm its importance in traditional medicine.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Origanum/química , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/química , Cinamatos/metabolismo , Citocinas/metabolismo , Depsídeos/química , Depsídeos/metabolismo , Dexametasona/química , Dexametasona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Interleucina-1beta/química , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Células RAW 264.7 , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismo , Ácido RosmarínicoRESUMO
Bakuchiol (BAK) has been reported to have a diverse pharmacological property as an antibiotic, anti-cancer, anti-hypolipidemic, anti-inflammatory and anti-convulsant agent. This study aimed to elucidate the immunomodulation and anti-inflammatory mechanism of bakuchiol using lipopolysaccharide stimulated RAW 264.7 macrophages and various animal models. The present study has shown that BAK significantly suppressed the pro-inflammatory cytokine expression in a dose-dependent manner and its oral administration significantly decreased delayed hypersensitivity responses as compared to control group. The assessment of immunomodulatory activity was carried out by the testing Hemagglutinating antibody (HA) titer, delayed type hypersensitivity (DTH) responses and phagocytic index by carbon clearance test. On the other hand, it showed significant decrease in circulating antibody titer and carbon clearance assay in a concentration-dependent manner. BAK has significantly potentiated the cellular immunity as well as humoral immunity by facilitating the footpad thickness responses in sheep RBCs in sensitized mice by significantly decreasing circulating antibody titer. Molecular studies revealed that BAK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. The responses were statistically significant as compared with the control (*p < 0.05, **p < 0.01).
Assuntos
Anti-Inflamatórios/farmacologia , Rejeição de Enxerto/prevenção & controle , Hipersensibilidade Tardia/prevenção & controle , Imunossupressores/farmacologia , Inflamação/prevenção & controle , Macrófagos/efeitos dos fármacos , Fenóis/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Hipersensibilidade Tardia/imunologia , Hipersensibilidade Tardia/metabolismo , Imunidade Humoral/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fagocitose/efeitos dos fármacos , Fosforilação , Células RAW 264.7 , Ovinos , Transdução de Sinais , Transplante de PeleAssuntos
Glucosídeos/farmacologia , Hepatite Alcoólica/tratamento farmacológico , Lamiaceae/química , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Etanol/toxicidade , Feminino , Glucosídeos/isolamento & purificação , Glucosídeos/uso terapêutico , Células Hep G2 , Hepatite Alcoólica/patologia , Humanos , Proteínas I-kappa B/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , NF-kappa B/metabolismo , Fenóis/isolamento & purificação , Fenóis/uso terapêutico , Folhas de Planta/química , Ratos , Ratos Wistar , Testes de Toxicidade Aguda , Resultado do TratamentoRESUMO
Kaempferol-3-O-ß-d-glucuronide (K3G) having various pharmacological effects was explored for its anti-inflammatory effect in LPS induced RAW 264.7 cells and mice model. K3G significantly inhibited various pro-inflammatory mediators like IL-1ß, NO, PGE2, and LTB4. It upregulated the secretion of anti-inflammatory cytokine IL-10. K3G is found to reduce inflammation when studied for parameters like phagocytic index, carrageenan induced paw edema in mice and organ weight. It reduced inflammation in a dose dependent manner both in-vitro and in-vivo. Further molecular insights into the study reveal that K3G blocks the phosphorylation of NF-kB which is key regulator of inflammation, thereby exhibiting anti-inflammatory potential. Hence, this study permits further investigation to develop K3G as anti-inflammatory drug.
Assuntos
Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Glucuronatos/uso terapêutico , Quempferóis/uso terapêutico , Macrófagos/fisiologia , Animais , Carragenina , Dinoprostona/metabolismo , Edema/induzido quimicamente , Feminino , Glucuronatos/química , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Quempferóis/química , Leucotrieno B4/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7 , Transdução de Sinais , Regulação para CimaRESUMO
Hentriacontane, has various pharmacological effects including anti-inflammatory, antitumor and antimicrobial activities. Its anti-inflammatory potential has been demonstrated in peritoneal macrophages. However detailed studies on other models elucidating the mechanistic description of the mode of action has not been done. Hence, the aim of the present study is to evaluate the anti-inflammatory potential of hentriacontane both in-vivo (Balb/c mice) and in-vitro (RAW 264.7 cells). Cytokine inhibition of both pro-inflammatory (TNF-α, IL-6, MCP-1 and IL-1ß) and anti-inflammatory (IL-10) cytokines was studied in RAW 264.7 cells and Balb/c mice. Suppressive potential of hentriacontane on NO, PGE2, LTB4 and on LPS induced translocation of NF-κB in RAW 264.7 cells was studied. Further investigations on the effect of hentriacontane on phagocytic index, carrageenan induced paw oedema in mice and on organ weight were done. It was found that hentriacontane significantly reduced all the parameters of inflammation in the experiments under study at all the concentrations, 10µM, 5µM and 1µM (in-vitro) and 5mg/kg, 2mg/kg and 1mg/kg (in-vivo). The highest concentration used in the two models presented the most significant results. The results indicate that hentriacontane is a potent suppressor of inflammatory cytokines and other mediators. Moreover it also has regulatory effect on NF-κB. Hence, hentriacontane is a potential candidate for investigations to develop anti-inflammatory drug.
Assuntos
Anti-Inflamatórios/farmacologia , Hidrocarbonetos/farmacologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Células RAW 264.7RESUMO
A new library of 20 compounds from α-santonin was synthesized and tested against Con-A induced T-cell proliferation and LPS-induced B-cell proliferation via MTT assay. The study resulted in the identification of potent immunosuppressant molecules, which were further screened along with α-santonin for Tumor Necrosis Factor Alpha (TNF-α) inhibitory activity. One of the molecules (7) at 10 µM showed equipotency to that of dexamethasone (1 µM conc.) used as a standard. Structure activity relationships of the synthesized compounds along with our earlier reported α-santonin derivatives have been studied. Inferences from the modifications carried out at all the three sites of α-santonin have been elaborated. Computational study of the active compounds shows TNF-α protein as its preferable target rather than Inosine Monophosphate Dehydrogenase (IMPDH).
Assuntos
Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Santonina/síntese química , Santonina/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , IMP Desidrogenase/química , IMP Desidrogenase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Santonina/química , Santonina/metabolismo , Relação Estrutura-Atividade , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In our present study, four new, designated as murrayakonine A-D (), along with 18 known carbazole alkaloids were isolated from CHCl3 : MeOH (1 : 1) crude extracts of the stems and leaves of Murraya koenigii (Linn.) Spreng. The structures of the all isolated compounds were characterized by analysis of HR-ESI-MS and NMR (1D and 2D spectroscopy) results, and comparison of their data with the literature data. For the first time, all the isolates were evaluated for their anti-inflammatory activities, using both in vitro and in vivo experiments, against the key inflammatory mediators TNF-α and IL-6. The new compound murrayakonine A (), O-methylmurrayamine A () and murrayanine () were proven to be the most active, efficiently inhibiting TNF-α and IL-6 release in a dose-dependent manner and showing decreased LPS induced TNF-α and IL-6 production in human PBMCs [corrected]. Furthermore, all the isolates were screened for their antimicrobial potential, and the compounds girinimbine () (IC50 3.4 µM) and 1-hydroxy-7-methoxy-8-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carbaldehyde () (IC50 10.9 µM) displayed potent inhibitory effects against Bacillus cereus. Furthermore, compounds murrayamine J () (IC50 11.7 µM) and koenimbine () (IC50 17.0 µM) were active against Staphylococcus aureus. However, none of the compounds were found to be active against Escherichia coli or Candida albicans.
Assuntos
Alcaloides/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacologia , Murraya/química , Alcaloides/síntese química , Alcaloides/química , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Bacillus cereus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Carbazóis/síntese química , Carbazóis/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating ß-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear ß-catenin and augmented its cytoplasmic pool as evidenced by reducing ß-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3ß (by Akt) to promote ß-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear ß-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear ß-catenin level suggesting Par-4 mediated ß-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total ß-catenin and decreased expression of phospho-ß-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and ß-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated ß-catenin signaling by 3-AWA induced Par-4 protein.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias/tratamento farmacológico , Vitanolídeos/agonistas , beta Catenina/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Plantas Medicinais/química , Transdução de Sinais/efeitos dos fármacosRESUMO
A library of boswellic acid analogues were synthesized and tested for their anti-inflammatory potential on key inflammatory mediators, TNF-α and IL-6. The study led to the identification of lead compounds showing significant inhibition of the cytokines, TNF-α and IL-6 both in vitro and in vivo.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6/antagonistas & inibidores , Triterpenos/química , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Humanos , Interleucina-6/imunologia , Camundongos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells. METHODS: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts. RESULTS: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone. CONCLUSION: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.