RESUMO
The aim of this study was to examine the impact of Resveratrol nanoparticles on migration/invasion capacity of renal cell carcinoma (RCC) cells and its mechanism. Human RCC cells were exposed to dimethyl sulfoxide or gradient concentrations of Resveratrol nanoparticles respectively, and U0126 were also added in some experiments. We examined renal cell viability by MTT assay, and wound healing test and Transwell assays were used detect invasion and migration capability of RCC cells. We used Western blotting assay to analyze the protein levels in extracellular signal-regulated kinase (ERK) signaling. We also detected the enzymatic capacity of matrix metalloproteinase 2 (MMP-2) in cells by gelatin enzymatic profiling. Resveratrol nanoparticles treatment significantly suppressed cell viability to migrate and invade RCC cells in a dose-dependent manner. Also, notably were reduced MMP-2 activity and expression, and elevated TIMP-2 level were observed in RCC cells exposed with Resveratrol nanoparticles. Further, Resveratrol nanoparticles treatment significantly decreased only the expression of p-ERK1/2, but not p-p38 and p-JNK. Moreover, U0126, which is the ERK inhibitor, exerted similar role as Resveratrol nanoparticles did. Of note was that, combined use of U0126 and Resveratrol nanoparticles displayed a more intense suppression of MMP-2 activity and expression, and also the viability to migrate and invade the RCC cells, compared with Resveratrol nanoparticles treatment alone. The Resveratrol nanoparticles inhibited RCC cells migration and invasion by regulating MMP2 expression and ERK pathways.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz , Nanopartículas , Resveratrol , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Inibidores de Metaloproteinases de Matriz/farmacologia , Nanopartículas/administração & dosagem , Invasividade Neoplásica , Resveratrol/administração & dosagem , Resveratrol/farmacologiaRESUMO
BACKGROUND: Elastin degradation has been established as one of the driving factors of emphysema. Elastin-derived peptides (EDPs) are shown to act as a chemoattractant for monocytes. Effectively shielding elastin from elastolytic damage and regenerating lost elastin are two important steps in improving the mechanical function of damaged lungs. Pentagalloyl glucose (PGG) has been shown to preserve elastin in vascular tissues from elastolytic damage in vivo and aid in elastin deposition in vitro. METHODS: We created emphysema by elastase inhalation challenge in mice. Albumin nanoparticles loaded with PGG, conjugated with elastin antibody, were delivered to target degraded elastin in lungs. We investigated matrix metalloproteinase-12 activity and lung damage by measuring dynamic compliance and tidal volume changes. RESULTS: Ex-vivo experiments demonstrated elastin preservation in PGG treated samples compared to controls. Inhaled nanoparticles conjugated with elastin antibody retained for extended periods in lungs. Further, mice treated with PGG nanoparticles showed a significant suppression of MMP-12 activity measured in the lungs. We observed suppression of emphysema in terms of dynamic lung compliance and tidal volume change compared to the control group. The histological examination further confirmed elastin preservation in the lungs. CONCLUSION: These results demonstrate successful targeted delivery of nanoparticles loaded with PGG to inhibit MMP-12 activity and preserve elastin in the lungs. Such targeted PGG therapy has potential therapeutic use in the management of emphysema.
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Sistemas de Liberação de Medicamentos/métodos , Elastina/metabolismo , Taninos Hidrolisáveis/administração & dosagem , Metaloproteinase 12 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Enfisema Pulmonar/metabolismo , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/patologia , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologiaRESUMO
Purpose. To overcome the insufficiency of conventional photodynamic therapy (PDT) for treating metastatic melanoma, the combination of smart nanoparticles and PDT with immunotherapy was used to achieve a higher efficiency by accumulating more photosensitizers in tumor areas and triggering stronger immune responses against tumors after PDT.Methods. In this study, we designed a nanoliposome co-encapsulation of chlorin E6 (Ce6) and SB-3CT to realize significant antitumoral proliferation and metastasis efficacy after laser irradiation in A375 cells. The morphology, size distribution, and loading efficiency of Ce6-SB3CT@Liposome (Lip-SC) were characterized. The reactive oxygen species (ROS) generation and cytotoxicity were evaluated in A375 cells, and the mechanisms of natural killer (NK) cell-mediated killing were assessed.Results. Lip-SC showed good stability and was well-dispersed with a diameter of approximately 140 nm in phosphate-buffered saline. The nanoliposomes could accumulate in tumor areas and induce apoptosis in cancer cells upon 660 nm light irradiation, which could trigger an immune response and induce the expression of NK group 2 member D (NKG2D) ligands. The subsequently released SB-3CT could further activate NK cells effectively and strengthen the immune system by inhibiting the shedding of soluble NKG2D ligands.Discussion. Taken together, the synergistic effects of SB-3CT on nanoliposomes for Ce6-mediated PDT were analyzed in detail to provide a new platform for future anti-melanoma treatment.
Assuntos
Clorofilídeos/administração & dosagem , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Melanoma/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fotoquimioterapia/métodos , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Clorofilídeos/química , Clorofilídeos/farmacologia , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/metabolismo , Lipossomos , Masculino , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Melanoma/metabolismo , Camundongos , Nanopartículas , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/OBJECTIVE: Systemic inflammation and oxidative stress (OS) are associated with breast cancer. CoQ10 as an adjuvant treatment with conventional anti-cancer chemotherapy has been demonstrated to help in the inflammatory process and OS. This systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to evaluate the efficacy of CoQ10 supplementation on levels of inflammatory markers, OS parameters, and matrix metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) in patients with breast cancer. METHODS: A systematic literature search was carried out using electronic databases, including PubMed, Web of Science, Scopus, Google Scholar, and Embase, up to December 2020 to identify eligible RCTs evaluating the effect of CoQ10 supplementation on OS biomarkers, inflammatory cytokines, and MMPs/TIMPs. From 827 potential reports, 5 eligible studies consisting of 9 trials were finally included in the current meta-analysis. Quality assessment and heterogeneity tests of the selected trials were performed using the PRISMA checklist protocol and the I2 statistic, respectively. Fixed and random-effects models were assessed based on the heterogeneity tests, and pooled data were determined as the standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Our meta-analysis of the pooled findings for inflammatory biomarkers of OS and MMPs showed that CoQ10 supplementation (100 mg/day for 45-90 days) significantly decreased the levels of VEGF [SMD: - 1.88, 95% CI: (- 2. 62 to - 1.13); I2 = 93.1%, p < 0.001], IL-8 [SMD: - 2.24, 95% CI: (- 2.68 to - 1.8); I2 = 79.6%, p = 0.001], MMP-2 [SMD: - 1.49, 95% CI: (- 1.85 to - 1.14); I2 = 76.3%, p = 0.005] and MMP-9 [SMD: - 1.58, 95% CI: (- 1.97 to - 1.19); I2 = 79.6%, p = 0.002], but no significant difference was observed between CoQ10 supplementation and control group on TNF-α [SMD: - 2.30, 95% CI: (- 2.50 to - 2.11); I2 = 21.8%, p = 0.280], IL-6 [SMD: - 1.56, 95% CI: (- 1.73 to - 1.39); I2 = 0.0%, p = 0.683], IL-1ß [SMD: - 3.34, 95% CI: (- 3.58 to - 3.11); I2 = 0.0%, p = 0.561], catalase (CAT) [SMD: 1.40, 95% CI: (1.15 to 1.65); I2 = 0.0%, p = 0.598], superoxide dismutase (SOD) [SMD: 2.42, 95% CI: (2.12 to 2.71); I2 = 0.0%, p = 0.986], glutathione peroxidase (GPx) [SMD: 2.80, 95% CI: (2.49 to 3.11); I2 = 0.0%, p = 0.543]], glutathione (GSH) [SMD: 4.71, 95% CI: (4.26 to 5.16); I2 = 6.1%, p = 0.302] and thiobarbituric acid reactive substances (TBARS) [SMD: - 3.20, 95% CI: (- 3.53 to - 2.86); I2 = 29.7%, p = 0.233]. CONCLUSION: Overall, the findings showed that CoQ10 supplementation reduced some of the important markers of inflammation and MMPs in patients with breast cancer. However, further studies with controlled trials for other types of cancer are needed to better understand and confirm the effect of CoQ10 on tumor therapy.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ubiquinona/análogos & derivados , Neoplasias da Mama/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Metaloproteinases da Matriz/metabolismo , Estresse Oxidativo/fisiologia , Inibidores Teciduais de Metaloproteinases/antagonistas & inibidores , Inibidores Teciduais de Metaloproteinases/metabolismo , Resultado do Tratamento , Ubiquinona/administração & dosagemRESUMO
BACKGROUND: The objective of the present study was co-delivery of venlafaxin (VEN) and doxycycline (DOX), a matrix metalloproteinase inhibitor drug, for alleviating inflammation and neuropathy in diabetic foot ulcer (DFU). METHODS: Bacterial cellulose nanofiber sheets (BCNS) were loaded with DOX and VEN and categorized by their loading efficiency, release profiles and ex vivo permeation throughrat skin. The optimized nanofibers were used in patients with DFU to compare with the standard wound care regimen during a 12-week trial. Wound area was measured every 2 weeks. Biochemical parameters and microscopic studies of the skin were examined prior and at the end of the treatment. The Michigan Neuropathy Screening Instrument (MNSI) questionnaire was utilized to assess diabetic neuropathy. RESULTS: The optimum formulation showed loading efficiency of 37.8 ± 1.6% for DOX and 48 ± 1.9% for VEN. Rat skin permeation was 40% for DOX after 7-29 h and 83% for VEN during 105 h. Patients treated with BCNS showed no significant difference in their biochemical parameters before and after intervention. The ulcer size showed faster reduction after 12 weeks in the treatment group compared to the control group. The abnormal responses in the MNSI questionnaire decreased and pain-free walking distance increased significantly in the treatment group compared with the control group (p < 0.001). Microscopic studies of the skin after using nanofibers showed a large number of polymorphonuclear chronic inflammatory cells and formation of new capillary beds. CONCLUSIONS: The BCNS loaded with DOX and VEN may expedite healing and reduce neuropathy in the DFU of diabetic patients.
Assuntos
Celulose/administração & dosagem , Pé Diabético/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Metaloproteinases da Matriz/metabolismo , Nanofibras/administração & dosagem , Cloridrato de Venlafaxina/administração & dosagem , Idoso , Animais , Doxiciclina/administração & dosagem , Feminino , Humanos , Masculino , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are proteases with different biological and pathological activities, and many have been linked to several diseases. Targeting individual MMPs may offer a safer therapeutic potential for several diseases. We assessed the safety, tolerability, and pharmacokinetics of FP-025, a novel, highly selective oral matrix metalloproteinase-12 inhibitor, in healthy subjects. METHODS: Two randomized, double-blind, placebo-controlled studies were conducted. Study I was a first-in-man study, evaluating eight single ascending doses (SADs) (50-800 mg) in two formulations: i.e., neat FP-025 in capsule (API-in-Capsule) and in an amorphous solid dispersion (ASD-in-Capsule) formulation. In Study II, three multiple ascending doses (MADs) (100, 200, and 400 mg, twice daily) of FP-025 (ASD-in-Capsule) were administered for 8 days, including a food-effect evaluation. RESULTS: Ninety-six subjects were dosed. Both formulations were well tolerated with one adverse event (AE) reported in the 800 mg API-in-Capsule SAD group and seven AEs throughout the MAD groups. The exposure to FP-025 was low with the API-in-Capsule formulation; it increased dose-dependently with the ASD-in-Capsule formulation, with which exposure to FP-025 increased in a greater-than-dose-proportional manner at lower doses (≤ 100 mg) but less proportionally at higher doses. The elimination half-life (t1/2) was between 6 (Study I) and 8 h (Study II). Accumulation of FP-025 was approximately 1.7-fold in the MAD study. Food intake delayed the rate of absorption, but without effect in the extent of absorption or bioavailability. CONCLUSION: FP-025 was well tolerated and showed a favorable pharmacokinetic profile following ASD-in-Capsule dosing. Efficacy studies in target patient populations, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, are warranted. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov : NCT02238834 (Study I); NCT03304964 (Study II). Trial registration date: Study I was registered on 12 September 2014 while study II was registered on 9 October 2017.
Assuntos
Metaloproteinase 12 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Inibidores de Metaloproteinases de Matriz/efeitos adversos , Inibidores de Metaloproteinases de Matriz/farmacocinética , Adulto JovemRESUMO
INTRODUCTION Vitamin D-deficiency is known to cause nerve conduction impairments, cancer and chronic diseases, as well as the pathogenesis of osteoarthritis. Our goal with this study is to evaluate the cartilage healing by applying intraarticular 1α, 25 (OH) 2D3 at different doses in rats with normal vitamin D levels and metabolism, which we made focal chondral damage model in the knee joint. MATERIAL AND METHODS 35 male Sprague-Dawley rats aged 20-24 weeks were used in our study. Both knees of rats were cartilage defected surgically on day 0. Joint injections performed at 06:00 am on 0th and 2nd days and after second injection others performed on days 9-16 and 23 following a weekly period. RESULTS In the fourth week, hematoxylin eosin staining measurements showed statistically significant difference according to the groups (p < 0.01) Metalloproteinase-13 (MMP-13) in histological staining for evaluating cartilage healing and healing levels showed statistically significant differences between the groups at first week and fourth week (p < 0.05). DISCUSSION Vitamin D, which affects many tissues through its receptors, is believed to be chondroprotective and neuroprotective by decreasing the expression of MMP in cartilage fibroblast, macrophage, lymphocyte through its intracellular receptors. To the best of our knowledge, this is the first study known to be intraarticular use of 1α, 25-dihydroxyvitamin D3. Our study has been found to be safe and successful in terms of weight, systemic PTH and 1α, 25-dihydroxyvitamin D3 levels in rats during treatment as well as better healing of cartilage damage. Key words: vitamin D3 receptor, articular cartilage, orthopedics, nerve conduction.
Assuntos
Calcitriol/administração & dosagem , Cartilagem Articular/efeitos dos fármacos , Membro Posterior/lesões , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Cartilagem Articular/lesões , Modelos Animais de Doenças , Injeções Intra-Articulares , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The objective of the present study was the fabrication of a wound dressing membrane based on RGD modified polybutylene adipate-co-terephthalate (PBAT)/gelatin nanofibrous structures loaded with doxycycline (DOX). This type of nanofiber for wound healing has not been reported so far and is quite novel. PBAT and gelatin nanofibers were separately electrospun using double needles electrospinning setup. Electrospinning variables were optimized to obtain bead-free thin nanofibers. The amount of drug loaded and release were measured in different concentrations of DOX and PBAT. MMPs inhibition was studied by polyacrylamide gel-zymography. Then, surface of the nanofibers was modified with RGD peptide, and their antimicrobial effect was investigated on Staphylococcus aureus and Pseudomonas aeruginosa. Effect of developed nanofibrous membranes on L929 fibroblast cells proliferation, adhesion and closure of excised wounds in rat were also studied. PBAT/gelatin nanofibrous structures with average fiber diameter of 75-529 nm were developed successfully. Drug release study revealed that about 65% of DOX was released from the optimized formulation (P17D1.6) after 20 h. The developed DOX loaded membrane inhibited the MMPs activity and showed no cytotoxicity. RGD surface-modified PBAT/gelatin nanofibers significantly improved the wound closure and histopathological results (re-epithelialization, collagen deposition, and angiogenesis) in rats compared to the control groups. Overall, RGD immobilized PBAT/gelatin nanofibrous membrane may have a potential application for wound healing.
Assuntos
Doxiciclina/administração & dosagem , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Nanofibras , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Bandagens , Linhagem Celular , Doxiciclina/farmacologia , Liberação Controlada de Fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Gelatina/química , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Oligopeptídeos/química , Poliésteres/química , Pseudomonas aeruginosa/efeitos dos fármacos , Ratos , Ratos Wistar , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND: Realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types. We previously showed that realgar nanoparticles (nano-realgar) had significant antileukemia, anti-lung cancer and anti-liver cancer effects. In addition, the anti-tumor effects of nanorealgar were significantly better than those of ordinary realgar. OBJECTIVE: To explore the inhibitory effects and molecular mechanisms of nano-realgar on the migration, invasion and metastasis of mouse breast cancer cells. METHODS: Wound-healing migration assays and Transwell invasion assays were carried out to determine the effects of nano-realgar on breast cancer cell (4T1) migration and invasion. The expression levels of matrix metalloproteinase (MMP)-2 and -9 were measured by Western blot. A murine breast cancer metastasis model was established, administered nano-realgar for 32 days and monitored for tumor growth and metastasis by an in vivo optical imaging system. Finally, living imaging and hematoxylin and eosin (HE) staining were used to measure the morphology and pathology of lung and liver cancer cell metastases, respectively. Angiogenesis was assessed by CD34 immunohistochemistry. RESULTS: Nano-realgar significantly inhibited the migration and invasion of breast cancer 4T1 cells and the expression of MMP-2 and -9. Meanwhile, nano-realgar effectively suppressed the abilities of tumor growth, metastasis and angiogenesis in the murine breast cancer metastasis model in a time- and dosedependent manner. CONCLUSION: Nano-realgar significantly inhibited migration and invasion of mouse breast cancer cells in vitro as well as pulmonary and hepatic metastasis in vivo, which may be closely correlated with the downexpression of MMP-2 and -9 and suppression of tumor neovascularization.
Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Nanopartículas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Sulfetos/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Neovascularização Patológica/metabolismo , CicatrizaçãoRESUMO
BACKGROUND: The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound. METHODS: Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPßCD was studied using the DSC, FTIR and XRPD. RESULTS: The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures. CONCLUSION: In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.
Assuntos
Doxiciclina/administração & dosagem , Excipientes/química , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Estomatite Aftosa/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Adesividade , Administração através da Mucosa , Química Farmacêutica , Doxiciclina/química , Doxiciclina/farmacocinética , Estabilidade de Medicamentos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Metaloproteinases da Matriz/metabolismo , Mucosa Bucal/química , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/imunologia , Mucosa Bucal/metabolismo , Oxirredução , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Estomatite Aftosa/imunologia , Estomatite Aftosa/patologia , Água/químicaRESUMO
The mechanisms of secondary brain injury after traumatic brain injury (TBI) are complex and are the result of multiple factors. Protecting the blood-brain barrier (BBB) and ameliorating cerebral edema are two key factors for improving the prognosis of TBI patients. The BBB is regulated by the hedgehog pathway through Scube2 and Shh protein. Matrix metalloproteinase-9 (MMP-9) influences the transport system and enzyme system of vascular endothelial cells, possibly via the hedgehog pathway. The present study aimed to investigate the role and mechanism of MMP-9 in TBI via the hedgehog pathway. Eighty male Sprague-Dawley rats were used to establish a murine model of TBI. Subsequently, the effect of SB-3CT-a specific inhibitor of MMP-9-was assessed via Western blotting, real-time PCR, immunofluorescence, apoptotic assays, and neurological scoring. The results showed that, compared with those of the sham-operation group, the mRNA and protein levels of MMP-9 were significantly increased after TBI, while the expressions of Scube2 and Shh were decreased. Application of SB-3CT at 24 h after TBI significantly reduced neuronal apoptosis and BBB permeability, while increasing expressions of Scube2 and Shh. In conclusion, these findings demonstrate an influence of TBI-induced MMP-9 upregulation in the induction of post-traumatic nerve and BBB injury, which may be partially mediated by Scube2 and Shh via the hedgehog pathway.
Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/metabolismo , Proteínas Hedgehog/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Masculino , Inibidores de Metaloproteinases de Matriz/administração & dosagem , RNA Mensageiro , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sulfonas/administração & dosagemRESUMO
Global prevalence of the severe periodontitis is at the alarming stage and its association with the systemic complications is highly evident which cannot be neglected. An insight into the pathophysiology of the periodontitis reveals that the promising amelioration could only be envisaged with the 4-D/multi-pronged approach of combining antibiotic along with the host modulating agents. The complications of the disease itself suggest that the use of antibiotic alone is not able to cater the symptoms completely. There is a need of other host modulatory agents too, such as Cyclo-oxygenase -II (COX II) enzyme inhibitors, Matrix metalloproteinase's (MMPs) inhibitors and osteo-integrating agents. Also, there is an unmet need of singular treatment modality through which all these agents can be sequentially and directly delivered into the periodontal cavity. The current hypothesis takes it a step forward wherein an antibiotic is combined with other three host modulatory agents in a singular drug delivery system. The encapsulation of multiple therapeutic agents with controlled release would therefore allow for reduced drug dose thus minimizing side effects; contributing to enhanced patient compliance and treatment efficacy. Hence this approach can be presented as a 4-D/multi-pronged approach for circumvention of periodontitis.
Assuntos
Antibacterianos/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Periodontite/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/administração & dosagem , Celecoxib/uso terapêutico , Terapia Combinada , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacocinética , Doxiciclina/administração & dosagem , Doxiciclina/uso terapêutico , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Durapatita/administração & dosagem , Durapatita/uso terapêutico , Gengiva/fisiologia , Humanos , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Inibidores de Metaloproteinases de Matriz/farmacocinética , Minociclina/administração & dosagem , Minociclina/uso terapêutico , Modelos Biológicos , Osseointegração/efeitos dos fármacos , Periodontia/métodos , Periodontite/cirurgia , Regeneração , Transtornos Relacionados ao Uso de SubstânciasRESUMO
A drug and gene co-delivery system with chemotherapeutic sensibilization was prepared and used for nasopharyngeal carcinoma therapy. For this purpose, the graphene oxide (GO) was conjugated with the redox hyperbranched poly(amido amine) (HPAA) and then the targeting molecule, transferrin (Tf), was also conjugated. The obtained Tf-HPAA-GO could co-deliver docetaxel (DOC) and MMP-9 shRNA plasmid (pMMP-9) effectively and showed the targeting effect to HNE-1 cells. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency. Besides that, Tf-HPAA-GO/DOC also showed the chemotherapeutic sensibilization effect, the formulation containing HPAA segments showed much higher cytotoxicity than free DOC. Benefiting from the sensibilization effect and DOC/pMMP-9 co-delivery strategy, this Tf-HPAA-GO/DOC/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. This strategy provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization, and targeting into one single platform, which showed a promising application in cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Grafite/administração & dosagem , Metaloproteinase 9 da Matriz/genética , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Transferrina/administração & dosagem , Células 3T3 , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética , Glutationa/metabolismo , Grafite/química , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismoRESUMO
Platelet-rich plasma (PRP) and broad-spectrum matrix metalloproteinase inhibitors (MMPIs) have been used as therapeutic options for tendinopathy. However, mixed results have been reported regarding their efficacy. We posited that the combination of these two treatment strategies would be more beneficial for healing tendons than each treatment alone. Rat tail tendons were harvested and cultured without mechanical stress for 0, 4, or 10 days. Single and combination treatment with PRP and MMPIs with either broad- or narrow-spectrum (MMP-13 selective), was administered to 4-day stress-deprived (SD) tendons, an ex vivo model for moderate tendinopathy. This treatment was applied to the damaged tendons over 6 days. At the end of their culture time, the tendons were subjected to traction testing and pathohistology, immunohistochemistry, and viability assays. The results showed better histological features for the PRP + narrow-spectrum MMPI group compared with all individual treatment modalities. Moreover, higher fiber density, more elongated nucleus shape, smaller space between fibers, and a trend toward higher mechanical strength were noted for PRP + narrow-spectrum MMPI group compared with 10-day SD tendons. This study shows that the combination of PRP + narrow-spectrum MMPI is a potentially effective treatment approach for tendinopathy. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1838-1847, 2019.
Assuntos
Inibidores de Metaloproteinases de Matriz/administração & dosagem , Plasma Rico em Plaquetas , Tendinopatia/tratamento farmacológico , Tendões/efeitos dos fármacos , Tendões/patologia , Animais , Sobrevivência Celular , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse MecânicoRESUMO
Matrine is a natural compound derived from Radix Sophora flavescens which is a commonly used Chinese herb. Herein, we report that matrine may inhibit lung metastasis in liver cancer in mice. Invasion chamber assay, scratch-wound assay and orthotopic liver tumor implantation mice were introduced to investigate the potential pharmacological effects of matrine on human hepatocellular carcinoma (HCC). Our results showed that matrine at non-toxic dose could significantly suppress PLC/PRF/5 and MHCC97L cells migration and invasion. Furthermore, matrine treatment (5â¯mg/kg/day) significantly decreased lung metastasis in orthotopic HCC mouse models. Quantitative polymerase chain reaction, gelatin zymography and immunoblotting assay indicated that matrine could inhibit the activity of matrix metalloproteinase-9 without down-regulating its protein expression in HCC. The docking approach, site-directed mutagenesis, and surface plasmon resonance were applied to identify residues involved in matrine binding in matrix metalloproteinase-9. The biophysical and cell-based assays showed that Pro415, Arg424 residue might contribute to the binding affinity of matrine on matrix metalloproteinase-9 activity. In conclusion, matrine might be a promising anti-cancer agent for inhibiting HCC metastasis.
Assuntos
Alcaloides/farmacologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/secundário , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Quinolizinas/farmacologia , Alcaloides/administração & dosagem , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Camundongos , Quinolizinas/administração & dosagem , MatrinasRESUMO
The study was aimed to evaluate the effectiveness of rosmarinic acid (RA) loaded ethosomes (ETHs) and liposomes (LPs) when subjected to the transdermal application. RA-loaded ETHs and LPs were prepared, optimised, and characterised. The ex vivo permeation studies of formulations using mouse abdominal skin were performed. Antioxidant activities and the inhibitory effects of formulations on collagenase and elastase enzymes were measured. Optimised ethosomal formulation (F3) was showed nanometric size range (138 ± 1.11 nm) and greatest entrapment (55 ± 1.80%), was selected for further transdermal permeation studies. Skin permeation profile of the nanoformulations analysed by HPLC revealed an enhanced permeation of ETHs. Transdermal flux of ETHs was found to be higher than RA solution and LPs. Enzyme inhibitions of ETHs were the significant difference found between ETHs and LPs (p < 0.05). ETHs were found to be more effective and successful than LPs. Results suggest that ETHs are more effective than LPs for transdermal delivery of RA.
Assuntos
Antioxidantes/administração & dosagem , Cinamatos/administração & dosagem , Depsídeos/administração & dosagem , Portadores de Fármacos/química , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Administração Cutânea , Animais , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Linhagem Celular , Cinamatos/farmacocinética , Cinamatos/farmacologia , Colagenases/metabolismo , Depsídeos/farmacocinética , Depsídeos/farmacologia , Lipossomos/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Absorção Cutânea , Envelhecimento da Pele/efeitos dos fármacos , Ácido RosmarínicoRESUMO
A Disintegrin and Metalloproteinase (ADAM) is a family of proteolytic enzymes that possess sheddase function and regulate shedding of membrane-bound proteins, growth factors, cytokines, ligands and receptors. Typically, ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and a characteristic transmembrane domain. Most ADAMs are activated by proprotein convertases, but can also be regulated by G-protein coupled receptor agonists, Ca2+ ionophores and protein kinase C activators. A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) is a family of secreted enzymes closely related to ADAMs. Like ADAMs, ADAMTS members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but they lack a transmembrane domain and instead have characteristic thrombospondin motifs. Activated ADAMs perform several functions and participate in multiple cardiovascular processes including vascular smooth muscle cell proliferation and migration, angiogenesis, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs may also be involved in pathological conditions and cardiovascular diseases such as atherosclerosis, hypertension, aneurysm, coronary artery disease, myocardial infarction and heart failure. Like ADAMs, ADAMTS have a wide-spectrum role in vascular biology and cardiovascular pathophysiology. ADAMs and ADAMTS activity is naturally controlled by endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs), and their activity can also be suppressed by synthetic small molecule inhibitors. ADAMs and ADAMTS can serve as important diagnostic biomarkers and potential therapeutic targets for cardiovascular disorders. Natural and synthetic inhibitors of ADAMs and ADAMTS could be potential therapeutic tools for the management of cardiovascular diseases.
Assuntos
Proteínas ADAM/metabolismo , Desintegrinas/metabolismo , Endotélio Vascular/metabolismo , Trombospondinas/metabolismo , Doenças Vasculares/metabolismo , Proteínas ADAM/antagonistas & inibidores , Motivos de Aminoácidos/efeitos dos fármacos , Motivos de Aminoácidos/fisiologia , Animais , Desintegrinas/antagonistas & inibidores , Endotélio Vascular/efeitos dos fármacos , Humanos , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Trombospondinas/antagonistas & inibidores , Doenças Vasculares/tratamento farmacológicoRESUMO
There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-ß & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-ß as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.
Assuntos
Caspase 3/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neuralgia/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/administração & dosagem , Ligadura , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Neuralgia/genética , Neuralgia/patologia , Propionatos/administração & dosagem , Ratos , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/lesões , Tiofenos/administração & dosagemRESUMO
Wound management in diabetic patient is of an extreme clinical and social concern. The delayed and impaired healing makes it more critical for research focus. The research on impaired healing process is proceeding hastily evident by new therapeutic approaches other than conventional such as single growth factor, dual growth factor, skin substitutes, cytokine stimulators, cytokine inhibitors, matrix metalloproteinase inhibitors, gene and stem cell therapy, extracellular matrix and angiogenesis stimulators. Although numerous studies are available that support delayed wound healing in diabetes but detailed mechanistic insight including factors involved and their role still needs to be revealed. This review mainly focuses on the molecular cascades of cytokines (with growth factors) and erstwhile factors responsible for delayed wound healing, molecular targets and recent advancements in complete healing and its cure. Present article briefed recent pioneering information on possible molecular targets and treatment strategies including clinical trials to clinicians and researchers working in similar area.
Assuntos
Diabetes Mellitus/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Transplante de Células-Tronco/métodos , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Humanos , Transplante de Células-Tronco/tendências , Resultado do Tratamento , Cicatrização/fisiologiaRESUMO
Physicochemical characteristics and in vitro anti-skin aging activity of gallic acid loaded in niosomes were investigated. Gallic acid was loaded in neutral (Brij 52/cholesterol at 7:3) and cationic CTAB niosomes (Brij 52/cholesterol/cetyltrimethylammonium bromide at 7:3:0.65). The maximum loading capacity and entrapment efficiency of gallic acid were 3.5, 4.48⯱â¯2.10 in neutral and 50%, w/w, 10.94⯱â¯0.78% in cationic CTAB niosomes, respectively. All gallic acid loaded in niosomes showed the unilamellar structure under transmission electron microscope with size range of 131.23-508.03â¯nm at initial and after storage for 3â¯months. The highest remaining percentage of gallic acid at all storage temperatures after 3â¯months was about 77% when loaded in the cationic CTAB niosome, whereas gallic acid in solution was about 64%. The release profiles of gallic acid loaded in neutral and cationic CTAB niosomes revealed the gradual release in 24â¯h. The cytotoxicity of gallic acid loaded in neutral and cationic CTAB niosomes appeared the non-cytotoxic effect in B16F10 melanoma cells and human skin fibroblasts. The cationic CTAB niosome loaded with gallic acid demonstrated the highest anti-skin aging activity, including melanin suppression effect (55.92⯱â¯4.92% of control) by inhibition of tyrosinase (53.18⯱â¯3.67% of control) and tyrosinase-related protein-2 (24.61⯱â¯7.92% of control), antioxidant (87.03⯱â¯0.99% cell viability) and inhibition of matrix metalloproteinase-2 (38.46⯱â¯1.53% of control). This study has demonstrated the superior stability and anti-skin aging activity of gallic acid loaded in cationic CTAB niosome for potential utilization in pharmaceutical and cosmetic products.