RESUMO
In the current study, a series of new pyrrolizine-5-carboxamide derivatives (5-8, 9a-d, 10a-d, 11a,b and 12a,b) were developed, synthesized and evaluated in terms of in vitro COX-2 enzyme inhibition. The in vivo anti-inflammatory evaluation was conducted on the most selective compounds (9a,b,d, 10b,c and 11a,b). For the most active five compounds (9a, 10b,c and 11a,b), ulcerogenic liability, histopathological examinations, physicochemical properties study and antioxidant activity were investigated. Also, nitric oxide donor activity was evaluated for compounds (6, 7, 10a-d and 12a,b), while, compounds (10c,d and 12a,b) showed a high significant result relative to the normal control. According to the findings of this study, 2,3-dihydro-1H-pyrrolizine-5-carboxamide (9a) demonstrated high antioxidant (highest beta-carotene concentration (10.825 µg/ml)) and anti-inflammatory activity (EIP = 63.6 %) with lower ulcerogenicity (ulcer index 13.67), presenting it as a promising candidate for treating inflammatory diseases which are complicated by oxidative tissue damage. Furthermore, MOE software tools docking software was used to carry out the in silico studies. Docking study for the most active compounds showed that all compounds made three to four H-bond interactions in COX-2 active site adopting excellent docking scores.
Assuntos
Antioxidantes , Inibidores de Ciclo-Oxigenase 2 , Humanos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Úlcera , Pirróis/química , Pirróis/farmacologiaRESUMO
Benign prostatic hyperplasia (BPH) is one of the most prevalent clinical disorders in the elderly. Probenecid (Prob) is a well-known FDA-approved therapy for gout owing to its uricosuric effect. The present study evaluated the use of Prob for BPH as a COX-2 inhibitor. Prob (100 and 200 mg/kg) was intraperitoneally injected into male Wistar rats daily for 3 weeks. In the second week, testosterone (3 mg/kg) was subcutaneously injected to induce BPH. Compared with BPH-induced rats, Prob treatment reduced prostate weight and index and improved histopathological architecture. The protease activity of ADAM-17/TACE and its ligands (TGF-α and TNF-α) were regulated by prob, which in turn abolished EGFR phosphorylation, and several inflammatory mediators (COX-2, PGE2, NF-κB (p65), and IL-6) were suppressed. By reducing the nuclear import of extracellular regulated kinase protein 1/2 (ERK1/2), Prob helped re-establish the usual equilibrium between antiapoptotic proteins like Bcl-2 and cyclin D1 and proapoptotic proteins like Bax. All of these data point to Prob as a promising treatment for BPH because of its ability to inhibit COX-2-syntheiszed PGE2 and control the ADAM-17/TGF-α-induced EGFR/ERK1/2 signaling cascade. These findings might help to repurpose Prob for the treatment of BPH.
Assuntos
Hiperplasia Prostática , Testosterona , Humanos , Ratos , Masculino , Animais , Idoso , Testosterona/efeitos adversos , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Probenecid/efeitos adversos , Dinoprostona/metabolismo , Fator de Crescimento Transformador alfa/efeitos adversos , Fator de Crescimento Transformador alfa/metabolismo , Proteína ADAM17/metabolismo , Ciclo-Oxigenase 2/metabolismo , Sistema de Sinalização das MAP Quinases , Ratos Sprague-Dawley , Ratos Wistar , Receptores ErbB/metabolismoRESUMO
Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 µM and 0.143 ± 0.008 µM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 µM and 0.067 ± 0.004 µM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.
Assuntos
Antineoplásicos , Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Melanoma , Feminino , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Lapatinib/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
OBJECTIVE AND DESIGN: Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis. MATERIALS OR SUBJECTS: Adult male Wistar rats were used. TREATMENT: Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH. METHODS: Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey's multiple comparison test. RESULTS: Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR-ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects. CONCLUSION: COX-2 stimulates the ERK1/2 pathway via PGE2-ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.
Assuntos
Hiperplasia Prostática , Testosterona , Animais , Masculino , Ratos , Proteína ADAM17/metabolismo , Celecoxib/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Receptores ErbB/metabolismo , Hiperplasia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Hiperplasia Prostática/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Testosterona/efeitos adversos , Fator de Crescimento Transformador alfa/efeitos adversos , Fator de Crescimento Transformador alfa/metabolismoRESUMO
A novel series of indole-based compounds was designed, synthesised, and evaluated as anti-Alzheimer's and anti-neuroinflammatory agents. The designed compounds were in vitro evaluated for their AChE and BuChE inhibitory activities. The obtained results revealed that compound 3c had higher selectivity for AChE than BuChE, while, 4a, 4b, and 4d showed selectivity for BuChE over AChE. Compounds 5b, 6b, 7c, and 10b exerted dual AChE/BuChE inhibitory activities at nanomolar range. Compounds 5b and 6b had the ability to inhibit the self-induced Aß amyloid aggregation. Different anti-inflammatory mediators (NO, COX-2, IL-1ß, and TNF-α) were assessed for compounds 5b and 6b. Cytotoxic effect of 5b and 6b against human neuroblastoma (SH-SY5Y) and normal hepatic (THLE2) cell lines was screened in vitro. Molecular docking study inside rhAChE and hBuChE active sites, drug-likeness, and ADMET prediction were performed.
Assuntos
Doença de Alzheimer , Neuroblastoma , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Humanos , Indóis/farmacologia , Inflamação/tratamento farmacológico , Ligantes , Simulação de Acoplamento Molecular , Neuroblastoma/tratamento farmacológico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfaRESUMO
Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via recombinant enzyme assays to explore their anti-inflammatory activities and cardiovascular safety profiles. Comprehensively, the structures of the synthesized compounds were established via spectral and elemental analyses, followed by the assessment of both their in vitro COX inhibitory and in vivo anti-inflammatory activities. The most active compounds as COX inhibitors were further evaluated for their in vitro 5-LOX and sEH inhibitory activities, alongside with their in vivo analgesic and ulcerogenic effects. Compounds 6d and 11f showed excellent inhibitory activities against both COX-2 and sEH (COX-2 IC50â¯=â¯0.043 and 0.048⯵M; sEH IC50â¯=â¯83.58 and 83.52⯵M, respectively). Moreover, the compounds demonstrated promising results as anti-inflammatory and analgesic agents with considerable ED50 values and gastric safety profiles. Remarkably, the most active COX inhibitors 6d and 11f possessed improved cardiovascular safety profiles, if compared to celecoxib, as shown by the laboratory evaluation of both essential cardiac biochemical parameters (troponin-1, prostacyclin, tumor necrosis factor-α, lactate dehydrogenase, reduced glutathione and creatine kinase-M) and histopathological studies. On the other hand, docking simulations confirmed that the newly synthesized compounds displayed sufficient structural features required for binding to the target COX-2 and sEH enzymes. Also, in silico ADME studies prediction and drug-like properties of the compounds revealed favorable oral bioavailability results. Collectively, the present work could be featured as a promising future approach towards novel selective COX-2 inhibitors with declined cardiovascular risks.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Pirazóis/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
New indomethacin analogs 4a-g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against cyclooxygenase 2 (COX-2; IC50 value range: 0.09-0.4 µÐ) as compared with celecoxib (IC50 = 0.89 µÐ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX-2 selectivity index (SI range = 4.07-6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti-inflammatory activity with edema inhibition (79.36-88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti-inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX-2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Carragenina , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Formaldeído , Humanos , Indometacina/síntese química , Indometacina/química , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Cinarizina/farmacologia , Animais , Asma/induzido quimicamente , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Dexametasona/uso terapêutico , Interleucina-5/sangue , Pulmão/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ovalbumina/imunologia , Estresse Oxidativo/efeitos dos fármacos , Pico do Fluxo Expiratório , Ratos , Espécies Reativas de Nitrogênio/metabolismo , Volume de Ventilação Pulmonar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Torsion of the spermatic cord is a hazardous and common urologic issue. The current work evaluates the possible protective effect of pregabalin (PGB) and xanthenone (XAN) in testicular ischemia/reperfusion injury induced by testicular torsion/detorsion in rats. MATERIALS AND METHODS: Seven groups of adult male Wistar albino rats were allocated randomly into seven groups, namely, sham control, torsion/detorsion (T/D), PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups. Serum cholesterol and testosterone levels were determined. Also, the levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-ÒB), angiotensin (Ang) II, Ang-(1-7), and angiotensin-converting enzyme2 (ACE2) were assessed in testicular tissue. Immunohistochemical analysis of heme oxygenase-1 (HO-1) and caspase-3 was performed. Finally, the histopathological examination of the testicular tissues was performed. RESULTS: The PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups showed a significant decrease in serum cholesterol, MDA, NO, TNF-α, NF-ÒB, and Ang-II levels coupled with a significant increase in both testosterone and ACE2 expression. Furthermore, all test groups showed a significant improvement in the histopathological picture with a reduction in caspase-3 and an increase in HO-1 immunoexpression in testicular tissue. CONCLUSION: PGB and XAN may have promising effects on preventing testicular T/D injury through antioxidant, anti-inflammatory, and antiapoptotic actions.
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Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors.
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Lung carcinoma is one of the most prevalent and deadly neoplasia worldwide. Numerous synthetic medications have been used in the treatment of cancer. However, there are several drawbacks, such as side effects and inefficiency. The current study focused on the potential anti-cancer effectiveness of tangeretin, an antioxidant flavonoid, on lung cancer induced experimentally in BALB/c mice and explored the involvement of NF-κB/ICAM-1, JAK/STAT-3, and caspase-3 signaling in its anti-cancer effect. BALB/c mice were injected with urethane (1.5 mg/kg) twice; on the first day and on the 60th day of the experiment, then treated with 200 mg/kg tangeretin orally once daily for the last 4 weeks of the experiment. Compared with urethane group, tangeretin normalized oxidative stress markers; MDA, GSH, and SOD activity. Moreover, it had an anti-inflammatory effect by decreasing lung MPO activity, ICAM-1, IL-6, NF-ÒB, and TNF-α expressions. Interestingly, tangeretin decreased cancer metastasis by reducing p-JAK, JAK, p-STAT-3, and STAT-3 protein expression levels. Furthermore, it increased the apoptotic marker, caspase-3, indicating enhanced apoptosis of cancer cells. Finally, histopathology confirmed the anti-cancer effect of tangeretin. In conclusion, tangeretin could have a promising effect in counteracting lung cancer via modulation of NF-κB/ICAM-1, JAK/STAT-3, and caspase-3 signaling.
Assuntos
Neoplasias Pulmonares , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Caspase 3 , Uretana , Molécula 1 de Adesão Intercelular , Camundongos Endogâmicos BALB C , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , ApoptoseRESUMO
Rebamipide is a quinolone derivative that has been commonly used for the treatment of gastric and duodenal ulcers. However, the molecular mechanisms of rebamipide against acetic acid-evoked colitis have not been adequately examined. Hence, the current study aimed to investigate the ameliorative effect of rebamipide in a rat model of acetic acid-evoked ulcerative colitis and the linked mechanisms pertaining to SIRT1/FoxO3a/Nrf2 and PI3K/AKT pathways. Herein, colitis was induced by the intrarectal administration of 3% acetic acid solution in saline (v/v) while rebamipide was administered by oral gavage (100 mg/kg/day) for seven days before the colonic insult. The colonic injury was examined by macroscopical and microscopical examination. The current findings demonstrated that rebamipide significantly improved the colonic injury by lowering the colonic disease activity index and macroscopic mucosal injury score. Moreover, it mitigated the histopathological aberrations and microscopical damage score. The favorable outcomes of rebamipide were driven by combating inflammation evidenced by dampening the colonic expression of NF-κBp65 and the pro-inflammatory markers CRP, TNF-α, and IL-6. In the same context, rebamipide curtailed the colonic pro-inflammatory PI3K/AKT pathway as seen by downregulating the immunostaining of PI3K and p-AKT(Ser473) signals. In tandem, rebamipide combated the colonic pro-oxidant events and augmented the antioxidant milieu by significantly diminishing the colonic TBARS and replenishing GSH, SOD, GST, GPx, and CAT. In the same regard, rebamipide stimulated the colonic upstream SIRT1/FoxO3a/Nrf2 axis by upregulating the expression of SIRT1, FoxO3a, and Nrf2, alongside downregulating Keap-1 gene expression. These antioxidant actions were accompanied by upregulation of the protein expression of the cytoprotective signal PPAR-γ in the colons of rats. In conclusion, the present findings suggest that the promising ameliorative features of rebamipide against experimental colitis were driven by combating the colonic inflammatory and oxidative responses. In perspective, augmentation of colonic SIRT1/FoxO3a/Nrf2 and inhibition of PI3K/AKT pathways were engaged in the observed favorable outcomes.
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Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a-q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a-q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC50 = 0.02-17.02 µM). The cytotoxicity of 7a-q was also assessed against normal MRC5 cells (IC50 = 0.47-13.46 µM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 µM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 µM). On the other hand, compounds 7a-q inhibited the activity of COX-2 (IC50 = 0.42-29.11 µM) compared to celecoxib (IC50 = 0.86 µM). In addition, 7c, 7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Ratos , Camundongos , Humanos , Animais , Feminino , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Tubulina (Proteína)/metabolismo , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2/metabolismo , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
AIMS: The use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals. MATERIALS AND METHODS: The intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later. RESULTS: Herein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1ß, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1-7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis. CONCLUSIONS: Perindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enteropatias/tratamento farmacológico , Perindopril/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Enteropatias/induzido quimicamente , Intestinos/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Metotrexato , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Perindopril/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression through the classic ACE/Ang-II/AT1 axis and its antagonist, ACE2/Ang-(1-7)/Mas axis which exerts an important role in the kidney. The present study evaluates the protective effects of the angiotensin-converting enzyme 2 (ACE2) activator; xanthenone; against experimental nephrotoxicity induced by gentamicin. Rats were divided into 4 groups, normal control, xanthenone (2 mg/kg, s.c), gentamicin (100 mg/kg, i.p. for one week) and xanthenone + gentamicin groups. Blood urea nitrogen (BUN) and serum creatinine levels were measured. The kidney tissues were used for estimating glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB, Angiotensin II (AngII), and Ang-(1-7). In addition, histopathological examination and Western blot analysis of ACE2 expression were done. Xanthenone significantly restored serum levels of BUN and creatinine. Xanthenone exerted significant antioxidant effect as revealed by increased GSH content and SOD activity together with reduced MDA content. It exerted anti-inflammatory effect by significant reduction in TNF-α, NF-κB and IL-6 expression compared to gentamicin group. Xanthenone increased Ang-(1-7) and ACE2 expression while significantly decreased Ang-II expression. Histopathologically, xanthenone markedly counteracted gentamicin-induced renal aberrations. Activation of ACE2/Ang-(1-7) by xanthenone produced significant antioxidant and anti-inflammatory effects that counteracted gentamicin-induced nephrotoxicity.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Gentamicinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Xantonas/farmacologia , Injúria Renal Aguda/prevenção & controle , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Western Blotting , Interleucinas/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Herein we describe our efforts to develop novel anti-inflammatory/analgesic agents devoid of known cardiovascular drawbacks. In doing so, two 1,5-diarylpyrazole series of urea linked (9a-f) and amide linked (11a-f) compounds were synthesized and evaluated in vitro as dual COX-2/sEH inhibitors using recombinant enzyme assays. The in vivo anti-inflammatory and analgesic activities were then examined using reported animal models. Compounds 9b and 9c showed the highest inhibitory activities against both COX-2 and sEH (IC50 of COX-2â¯=â¯1.85 and 1.24⯵M; sEHâ¯=â¯0.55 and 0.40â¯nM, respectively), besides showing the best activity as anti-inflammatory agents. Interestingly, the cardiovascular profile of the two compounds 9b and 9c was evaluated through measuring some biochemical parameters such as prostacyclin (PGI2), lactate dehydrogenase (LDH), troponin-1 (Tn-1), tumor necrosis factor- α (TNF-α), creatine kinase-M (CK-M) and reduced glutathione (GSH) in addition to a histo-pathological study to investigate the changes in the heart muscle. The results confirmed that compounds 9b and 9c have a more favorable cardio-profile than celecoxib with much less cardiovascular risks associated with the common selective COX-2 inhibitors. Finally, the current work provided a promising approach that can be optimized to serve as a lead project to overcome the cardiovascular toxicity related to the traditional selective COX-2 inhibitors.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Fatores de Risco de Doenças Cardíacas , Pirazóis/química , Pirazóis/farmacologia , Ureia/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Biomarcadores/metabolismo , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Epóxido Hidrolases/química , Humanos , Fatores de Risco , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.