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1.
J Drugs Dermatol ; 18(9): 943-945, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31524993

RESUMO

Raynaud's phenomenon is an exaggerated physiological response of blood vessels in the distal extremities to emotional stress and cold. It can be idiopathic or secondary to a connective tissue disorder, such as scleroderma or systemic lupus erythematosus. Treatment for Raynaud's phenomenon consists primarily of lifestyle modifications; if unsuccessful, pharmacotherapy with dihydropyridine calcium channel blockers can be added. Botulinum toxin (BTX-A) is a neurotoxic protein produced by Clostridium botulinum spores. While most widely known for its cosmetic use, BTX-A has many therapeutic utilities due to its ability to inhibit multiple neurotransmitters. In this report, we present a patient with Raynaud's phenomenon refractory to standard therapies whose symptoms resolved after treatment with BTX-A. Follow-up with the patient after one and five years showed no relapse or recurrence of symptoms. J Drugs Dermatol. 2019;18(9):943-945.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Neurotoxinas/administração & dosagem , Doença de Raynaud/tratamento farmacológico , Pele/patologia , Resistência a Medicamentos , Feminino , Dedos , Humanos , Injeções Subcutâneas , Necrose/tratamento farmacológico , Necrose/etiologia , Doença de Raynaud/complicações , Pele/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Khirurgiia (Mosk) ; (7): 63-70, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31355817

RESUMO

AIM: Structural and functional analysis of cells from purulent-necrotic wounds in patients with diabetic foot syndrome undergoing ultrasonic treatment with 0.2% Lavasept solution. MATERIAL AND METHODS: It is presented morphological/ultrastructural analysis of wound specimens in 90 (DFS) patients aged 27-80 years with diabetic foot syndrome and purulent-necrotic complications who were hospitalized in the department of wounds and wound infections of the Vishnevsky Institute of Surgery in 2013-2016. Main group consisted of 75 patients, control group - 15 patients. Mean age was 58.4±8.2 years. All patients had diabetes mellitus type II for previous 13±4.5 years. Severity of foot tissue damage was assessed according to Wagner classification (F. Wagner, 1981). 46 (51.1%) patients had Wagner III-IV, 44 (48.9%) patients - Wagner II. Complex treatment included radical surgical management of purulent lesion, surgical revascularization for critical limb ischemia and foot reconstruction at the final stage. Additional measures were complete unloading of the foot, correction of carbohydrate metabolism and concomitant diseases. Topical treatment between surgical stages included dressing with 1.0% betadine solution (once a day). Ultrasonic cavitation was additionally applied in the main group. Electron microscopic examination of specimens was used before treatment, after 3-5 and 7-10 days in order to assess effectiveness of ultrasound cavitation for purulent-necrotic complications of DFS. RESULTS: Ultrasound cavitation with 0.2% Lavasept solution effectively cleans wounds from microbial and cellular detritus, destroys cellular membranes of biofilm-forming microorganisms, prevents their redo development and reinfection of the wound. Effective management of the wounds accelerates reparative processes that allows to perform foot reconstruction early.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Biguanidas/administração & dosagem , Pé Diabético/cirurgia , Necrose/cirurgia , Procedimentos Cirúrgicos Ultrassônicos , Administração Tópica , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Pé Diabético/tratamento farmacológico , Pé Diabético/patologia , Humanos , Pessoa de Meia-Idade , Necrose/tratamento farmacológico , Necrose/patologia , Soluções/administração & dosagem
4.
Neurochem Res ; 44(7): 1678-1689, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982205

RESUMO

Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality and disability rate. Mitochondria plays a crucial role in neuronal survival after ICH. This study first showed that activation of adiponectin receptor 1 (AdipoR1) by AdipoRon could attenuate mitochondrial dysfunction after ICH. In vivo, experimental ICH model was established by autologous blood injection in mice. AdipoRon was injected intraperitoneally (50 mg/kg). Immunofluorescence staining were performed to explicit the location of AdipoR1, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1a (PGC1α). The PI staining was used to quantify neuronal survival. The expression of AdipoR1 and its downstream signaling molecules were detected by Western blotting. In vitro, 10 µM oxyhemoglobin (OxyHb) was used to induce the neuronal injury in SH-SY5Y cells. Annexin V-FITC/PI staining was used to detect the neuronal apoptosis and necrosis. Mitochondrial membrane potential (Δψm) was measured by a JC-1 kit and mitochondrial mass was quantified by mitochondrial fluorescent probe. In vivo, PI staining showed that the administration of AdipoRon could reduce neuronal death at 72 h after ICH in mice. AdipoRon treatment enhanced ATP levels and reduced ROS levels in perihematoma tissues, and increased the protein expression of AdipoR1, P-AMPK, PGC1α, NRF1 and TFAM. In vitro, the JC-1 staining and Mito-tracker™ Green showed that AdipoRon significantly alleviated OxyHb-induced collapse of Δψm and enhanced mitochondrial mass. Moreover, flow cytometry analysis indicated that the neurons treated with AdipoRon showed low necrotic and apoptotic rate. AdipoRon alleviates mitochondrial dysfunction after intracerebral hemorrhage via the AdipoR1-AMPK-PGC1α pathway.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/prevenção & controle , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Necrose/tratamento farmacológico , Neurônios/patologia , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Adiponectina/metabolismo
5.
BMJ Case Rep ; 12(4)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30996070

RESUMO

A 61-year-old Hispanic man presented to a county hospital for subacute progressive weakness, heliotrope rash and dysphagia. There was initial suspicion for dermatomyositis (DM) given the history; however, the physical exam was not consistent. An MRI followed by a muscle biopsy revealed necrotising autoimmune myositis and anti-3-hydroxy-3-methylglutary-coenzyme A-reductase antibody titers returned positive; the patient was diagnosed with necrotising autoimmune myositis. He was treated with corticosteroids and intravenous immunoglobulin, which resulted in improvement in his weakness and functional status. This case represents a unique instance in which a cardinal feature of DM, the heliotrope rash, prompted an erroneous initial diagnosis. It highlights the necessity of developing abroad differential diagnosis and subsequent thorough investigation into patients presenting with suspected idiopathic immune-mediated myopathies.


Assuntos
Corticosteroides/uso terapêutico , Hispano-Americanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Músculo Esquelético/patologia , Miosite/diagnóstico , Necrose/patologia , Autoanticorpos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Miosite/fisiopatologia , Necrose/tratamento farmacológico , Resultado do Tratamento
6.
J Med Case Rep ; 13(1): 55, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30850017

RESUMO

BACKGROUND: Polyarteritis nodosa is a disease that presents with necrotizing vasculitis in small and medium-sized arteries. It may occur in various organs, but approximately half of cases have gastrointestinal involvement. Prognosis is not favorable once organ dysfunction begins as evidenced by gastrointestinal symptoms; thus, treatment with steroids should be promptly initiated. We report the case of a patient who presented with necrosis of the small intestine, which was pathologically diagnosed as polyarteritis nodosa and treated successfully with steroids. CASE PRESENTATION: An 18-year-old Japanese woman reported a sudden onset of abdominal pain and vomiting that led her to visit our emergency department, where she was evaluated by a physician. On physical examination, tenderness to palpation in the upper umbilical region was noted, and diagnostic imaging with computed tomography showed emphysema of the wall of her small intestine. She was diagnosed as having necrosis of the small intestine requiring urgent surgery. No strangulations were noted intraoperatively but approximately 20 cm of her small intestine was necrotized. The surrounding arteries were examined and no palpable pulse was observed; therefore, segmentectomy of the necrotized regions was performed. Pathological findings revealed active vasculitis with fibrinoid necrosis, as well as destruction, fibrogenesis, and luminal stenosis of the elastic lamina found in the muscular arteries. A diagnosis of polyarteritis nodosa was confirmed as the cause of the necrosis of her small intestine. No recurrence of polyarteritis nodosa symptoms was observed when she was administered 40 mg of prednisolone daily. CONCLUSION: In cases of idiopathic intestinal necrosis or perforation, systemic diseases such as polyarteritis nodosa should be considered in the differential diagnosis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Intestino Delgado/patologia , Necrose/etiologia , Poliarterite Nodosa/complicações , Prednisolona/uso terapêutico , Dor Abdominal , Adolescente , Feminino , Humanos , Intestino Delgado/diagnóstico por imagem , Necrose/diagnóstico por imagem , Necrose/tratamento farmacológico , Poliarterite Nodosa/diagnóstico por imagem , Poliarterite Nodosa/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vômito
7.
Mar Drugs ; 17(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717235

RESUMO

The marine α-pyrone macrolide neurymenolide A was previously isolated from the Fijian red macroalga, Neurymenia fraxinifolia, and characterized as an antibacterial agent against antibiotic-resistant strains that also exhibited moderate cytotoxicity in vitro against cancer cell lines. This compound was also shown to exhibit allelopathic effects on Scleractinian corals. However, to date no mechanism of action has been described in the literature. The present study showed, for the first time, the isolation of neurymenolide A from the New Caledonian Rhodophyta, Phacelocarpus neurymenioides. We confirmed the compound's moderate cytotoxicity in vitro against several human cell lines, including solid and hematological malignancies. Furthermore, we combined fluorescence microscopy and flow cytometry to demonstrate that treatment of U-2 OS osteosarcoma human cells with neurymenolide A could block cell division in prometaphase by inhibiting the correct formation of the mitotic spindle, which induced a mitotic catastrophe that led to necrosis and apoptosis. Absolute configuration of the stereogenic center C-17 of neurymenolide A was deduced by comparison of the experimental and theoretical circular dichroism spectra. Since the total synthesis of this compound has already been described, our findings open new avenues in cancer treatment for this class of marine molecules, including a new source for the natural product.


Assuntos
Macrolídeos/química , Macrolídeos/farmacologia , Pironas/química , Pironas/farmacologia , Rodófitas/química , Fuso Acromático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Microtúbulos/patologia , Mitose/efeitos dos fármacos , Necrose/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia
8.
Mol Cancer ; 18(1): 21, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732625

RESUMO

Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism forradiation brain necrosis development. Bevacizumab alleviates brain edema symptoms caused by radiation brain necrosis through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' Karnofsky performance status (KPS) scores and brain necrosis imaging. However, necrosis is irreversible, and hypoxia and ischemia localized in the brain necrosis area may easily lead to radiation brain necrosis recurrence after bevacizumab is discontinued. Further studies are necessary to investigate brain necrosis diagnoses, bevacizumab indications, and the optimal mode of administration, bevacizumab resistance and necrosis with a residual or recurrent tumor.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Necrose/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Lesões por Radiação/tratamento farmacológico , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos da radiação , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Resistência a Medicamentos/genética , Raios gama/efeitos adversos , Expressão Gênica , Humanos , Necrose/genética , Necrose/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Lesões por Radiação/genética , Lesões por Radiação/patologia , Recidiva , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Biomed Pharmacother ; 111: 638-648, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611988

RESUMO

Bromocriptine, the most commonly used dopamine (DA) receptor agonists for prolactinoma, can effectively reduce tumor size of prolactinoma, but the mechanism was not fully understood. Apoptosis had been well-recognized to contribute to the tumor mass regression caused by bromocriptine. However, whether other types of non-apoptotic cell death involved in the bromocriptine-induced prolactinoma shrinkage had not been fully clarified. The newly discovered molecular mechanism of necroptosis provides the possibility to examine this programmed necrosis in the pharmacological function of bromocriptine. The aim of present study was to evaluate and investigate the underlying mechanism of necroptosis in involution of prolactinoma induced by bromocriptine. By immunohistochemistry, we found that the numbers of receptor-interacting serine-threonine kinase 3(RIP3) and phosphorylated mixed lineage kinase domain-like protein (pMLKL)-positive cells and their expression intensities were increased in patients with prolactinoma after bromocriptine therapy. For further exploring the mechanism of bromocriptine, prolactinoma cell line (MMQ cells) was adopted to study the mechanism of necroptosis in vitro. Cell viability and ATP level of MMQ cells were decreased, while reactive oxygen species (ROS) level was increased after bromocriptine treatment. The above effects could be partially reversed by Necrostatin-1, an inhibitor of necroptosis. Ultrastructural study further confirmed the necroptosis of MMQ cells, which was characterized by ruptured membrane, dissolved cytoplasm and especially the dramatically swollen mitochondria. Furthermore, we demonstrated that bromocriptine induced RIP3/MLKL-dependent necroptosis of prolactinoma cells and phosphoglycerate mutase family 5(PGAM5)/ Cyclophilin D (CypD) pathway was involved. The results suggested that necroptosis might be a promising target for clinical therapy for prolactinoma.


Assuntos
Bromocriptina/farmacologia , Ciclofilinas/metabolismo , Proteínas Mitocondriais/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Prolactinoma/metabolismo , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Bromocriptina/uso terapêutico , Sobrevivência Celular , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose/tratamento farmacológico , Necrose/metabolismo , Necrose/patologia , Prolactinoma/tratamento farmacológico , Prolactinoma/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto Jovem
10.
Int J Biol Macromol ; 121: 936-946, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30342937

RESUMO

Necrotic tissues are the dead tissues present in the wounded areas, which need to be removed for rapid wound healing. Various biopolymer-based dressings have been exploited to heal infected wounds, but with limited success. In a quest to develop an effective and economic wound dressing, a biodegradable dressing containing chitosan nanoparticles has been successfully developed. Chitosan nanoparticles were prepared by ionic gelation method and then assembled into the porous chitosan dressing, by lyophilization. The resulting dressing was analyzed for morphology, porosity, pore volume, surface area and biodegradability. Higher surface area and porosity of the dressing facilitated its partial biodegradation by enzymatic action. In vitro cellular investigations with Human Dermal Fibroblasts (HDF) confirmed the safety of the dressing for wound healing applications. Human Thrombin-Antithrombin (TAT) based in vitro ELISA assay, for evaluating the hemostasis activity, illustrated an accelerated hemostasis activity, through higher thrombin generation and stable blood clot formation. The blood in contact with the dressing contained two-fold higher levels of TAT, as compared to that in contact with the TAT standard. Our results suggest the potential of the developed dressing for removing the necrotic tissues and accelerating the hemostasis activity, for efficient and rapid wound healing.


Assuntos
Bandagens , Quitosana/química , Quitosana/farmacologia , Hemostasia/efeitos dos fármacos , Nanopartículas , Cicatrização/efeitos dos fármacos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Materiais Biocompatíveis/toxicidade , Quitosana/uso terapêutico , Quitosana/toxicidade , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Necrose/tratamento farmacológico , Porosidade , Propriedades de Superfície
11.
Biomed Pharmacother ; 109: 1532-1540, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551405

RESUMO

Nifedipine is a calcium channel blocker dihydropyridine that has been used in the treatment of hypertension. The production of reactive species and calcium overload are the main contributors to myocardial ischemia-reperfusion (I / R) injury. We investigated the ability of novel dihydropyridines (DHPs) to improve the effect of protecting against the injury induced by ischemia and reperfusion in cardioblasts when compared to nifedipine. Forty three DHPs were created varying the fatty chains derived from palmitic acid, stearic acid and oleic acids and aromatic moiety in addition to the addition of chemical elements such as chlorine, nitrogen dioxide, furfural, hydroxyl and methoxy. Cytotoxicity and inhibition of linoleic oxidation were evaluated for all new DHPs and also for nifedipine. The alpha-tocopherol and butylated hydroxytoluene (BHT) were used as antioxidants controls. The compounds with the best antioxidant potential were used in the ischemia and reperfusion (I / R) induction test in cardioblasts (H9c2). Cardioblasts were treated 24 h after assembly of plates and submitted to the ischemia simulation (30 min), after which, normoxia and cellular nutrition conditions were reestablished, simulating reperfusion (additional 30 min). Right after, cell viability, apoptosis, necrosis, and the generation of reactive oxygen species (ROS) were evaluated. Cell viability during I / R was not altered in cells treated with nifedipine, BHT and the new DHP composed of palmitic acid with hydroxyl group in the aromatic substituent. The other new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the I / R group, demonstrating the antioxidant capacity of the new DHPs. Therefore, DHPS with palmitic and oleic acids in the C3 and C5 position with NO2 or Cl in aromatic moiety, presented the highest antioxidant potential (linoleic oxidant test). The new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the ischemia and reperfusion group, demonstrating the antioxidant capacity of the new DHPs. Taken together, these results indicate that those new DHPs have a greater cardioprotective antioxidant capacity to face the damages of ischemia and reperfusion.


Assuntos
Cardiotônicos/farmacologia , Di-Hidropiridinas/farmacologia , Mioblastos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Mioblastos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Necrose/tratamento farmacológico , Necrose/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo
12.
Molecules ; 23(8)2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30065214

RESUMO

Snake venom is a complex cocktail of toxins which induces a series of clinical and pathophysiological manifestations in victims, including severe local tissue damage and systemic alterations. Deinagkistrodon acutus (D. acutus) ranks among the "big four" life-threatening venomous species in China, whose venom possesses strong myotoxicity and hematotoxicity that often lead to permanent disability or muscle atrophy. Varespladib, an inhibitor of mammalian phospholipase A2 (PLA2), has been recently reproposed as an effective antidote against snakebite envenomation. The present study aimed at evaluating the protective role of varespladib on muscle regeneration in envenomed mice. Mice were grouped and subjected to inoculation with D. acutus venom or a mixture of venom and varespladib or control vehicle in the gastrocnemius muscle. Local injuries including hemorrhage, myonecrosis, ulceration, and systemic damages including general dysfunction, visceral failure, and inflammatory responses were observed at 1, 3, 7, 14, and 21 days. The results indicated that most of the muscle myonecrosis and hemorrhage were alleviated by varespladib. Besides, the pretreated mice recovered rapidly with lesser atrophy and muscle fibrosis. In conclusion, the findings of the present study suggested that varespladib is an effective antidote that could neutralize D. acutus venom and allow for earlier and improved rehabilitation outcome.


Assuntos
Acetatos/farmacologia , Antídotos/farmacologia , Venenos de Crotalídeos/antagonistas & inibidores , Indóis/farmacologia , Necrose/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Úlcera/tratamento farmacológico , Angiopoietinas/genética , Angiopoietinas/metabolismo , Animais , Venenos de Crotalídeos/isolamento & purificação , Venenos de Crotalídeos/toxicidade , Crotalinae/fisiologia , Regulação da Expressão Gênica , Hemorragia/fisiopatologia , Hemorragia/prevenção & controle , Masculino , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Músculo Esquelético/inervação , Proteína MyoD/genética , Proteína MyoD/metabolismo , Miogenina/genética , Miogenina/metabolismo , Necrose/patologia , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Fosfolipases A2 Citosólicas/antagonistas & inibidores , Fosfolipases A2 Citosólicas/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Mordeduras de Serpentes/patologia , Úlcera/patologia
13.
Acta Cir Bras ; 33(4): 296-305, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29768532

RESUMO

PURPOSE: To evaluate the effect of the cilostazol on the evolution of partially avulsed flaps, using experimental model of cutaneous degloving in rat limbs. METHODS: A controlled and randomized experimental study was carried out in which the blood flow and the percentage of flap necrosis were evaluated. We compared the study group, which received cilostazol, and the control group, which received enteral saline solution in the postoperative period. The blood flow in the flap was evaluated through Laser Doppler flowmetry, and a planimetry using the IMAGE J® software was employed for the calculation of the area of necrosis. RESULTS: Enteral administration of cilostazol was associated with a higher mean blood flow in all regions of the flap, with a statistically significant difference in the proximal and middle regions (p<0.001) and a lower percentage of necrotic area in the flap (p<0.001). CONCLUSION: Postoperative enteral administration of cilostazol increased blood flow and decreased the total area of necrosis of avulsed cutaneous flaps of rat limbs.


Assuntos
Desenluvamentos Cutâneos/tratamento farmacológico , Modelos Animais de Doenças , Inibidores da Fosfodiesterase 3/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Cilostazol , Desenluvamentos Cutâneos/patologia , Desenluvamentos Cutâneos/cirurgia , Humanos , Fluxometria por Laser-Doppler , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/lesões , Extremidade Inferior/patologia , Masculino , Necrose/tratamento farmacológico , Inibidores da Fosfodiesterase 3/farmacologia , Distribuição Aleatória , Ratos Wistar , Valores de Referência , Fluxo Sanguíneo Regional/efeitos dos fármacos , Reprodutibilidade dos Testes , Retalhos Cirúrgicos , Tetrazóis/farmacologia , Fatores de Tempo , Resultado do Tratamento
14.
Curr Neuropharmacol ; 16(9): 1327-1339, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29663889

RESUMO

It has been confirmed that apoptosis, autophagy and necrosis are the three major modes of cell death. For a long time, necrosis is regarded as a deranged or accidental cell demise. In recent years, there is evidence showing that necrotic cell death can be a well regulated and orchestrated event, which is also known as programmed cell death or "necroptosis". Necroptosis can be triggered by a variety of external stimuli and regulated by a caspase-independent pathway. It plays a key role in the pathogenesis of some diseases including neurological diseases. In the past two decades, a variety of studies have revealed that the necroptosis related pathway is activated in stroke, and plays a crucial role in the pathogenesis of stroke. Moreover, necroptosis may serve as a potential target in the therapy of stroke because genetic or pharmacological inhibition of necroptosis has been shown to be neuroprotective in stroke in vitro and in vivo. In this review, we briefly summarize recent advances in necroptosis, introduce the mechanism and strategies targeting necroptosis in stroke, and finally propose some issues in the treatment of stroke by targeting necroptosis.


Assuntos
Necrose/tratamento farmacológico , Necrose/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Animais , Humanos , Transdução de Sinais
16.
Microb Pathog ; 119: 193-199, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29655615

RESUMO

BACKGROUND: Protozoan parasites of the genus Leishmania are etiologic agents which are intracellular pathogens of vertebrates and replicate inside infected macrophages. Leishmania have developed complex strategies to reverse host immune responses in favor of it. One of the major species causing cutaneous involvements is Leishmania major. MicroRNAs (miRNA) are non-coding small RNAs encoding 22-nucleotide (nt) long RNAs. miRNAs affect diverse biological processes, including cell cycle, proliferation, differentiation, growth and development, metabolism, aging, apoptosis, gene expression and immune regulation. This study aimed at evaluating apoptosis and necrosis after transfection locked nucleic acid (LNA) inhibitor of let-7a in the human macrophages miRNAs upon infectionwith L. major. MATERIALS AND METHODS: Inhibition of let-7a in macrophages was derived originally from the human monocytes (MDM), using locked nucleic acid (LNA) antagomir. The total cellular RNA was extracted 24 and 48 h post transfection. The levels o Let-7a expression was measured by qPCR Real Time using specific primer. Annexin-V/Propidium Iodide staining method was performed to detect apoptosis and necrosis in the MDM cells. Data were analyzed using the Kruskal-Wallis and Mann-Whitney tests. RESULTS: Let-7a inhibition increased the MDM cells apoptosis and necrosis using flow cytometry method. CONCLUSIONS: The results suggested that inhibition of let-7a could be a new approach in treatment of leishmaniasis.


Assuntos
Apoptose/efeitos dos fármacos , Leishmania major/patogenicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/parasitologia , MicroRNAs/efeitos dos fármacos , Necrose/tratamento farmacológico , Oligonucleotídeos/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Leishmaniose/imunologia , Leishmaniose/parasitologia , MicroRNAs/genética , MicroRNAs/metabolismo , Pequeno RNA não Traduzido , Transfecção
17.
World Neurosurg ; 114: e1186-e1191, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29614353

RESUMO

OBJECTIVE: Spinal cord injury (SCI) is a serious trauma without efficient treatment currently. Necroptosis can be blocked post injury by special inhibitors. This study is to investigate the effects, mechanism, and potential benefit of necrosulfonamide (NSA) for SCI therapy. METHODS: Pathologic condition was detected using hematoxylin-eosin staining on injured spinal cord and other major organs. Necroptosis-related factors-RIP1, RIP3, and MLKL-were detected using Western blot. Detections on mitochondrial functions such as adenosine triphosphate generation and activities of superoxide dismutase and caspase-3 were also performed. Finally, ethologic performance was detected using a 21-point open-field locomotion test. RESULTS: Reduced lesions and protected neurons were found in the injured spinal cord after treatment with NSA using hematoxylin-eosin staining for pathologic detection. No obvious toxicity on rat liver, kidney, heart, and spleen was detected. Rather than RIP1 and RIP3, MLKL was significantly inhibited by the NSA using Western blot detection. Adenosine triphosphate generation was obviously decreased post injury but slightly increased after the NSA treatment, especially 24 hours post injury. No significant changes were found on activities of superoxide dismutase and caspase-3 after the treatment of NSA. Ethologic performance was significantly improved using a 21-point, open-field locomotion test. CONCLUSIONS: Our research indicates NSA attenuates the spinal cord injury via necroptosis inhibition. It might be a potential and safe chemical benefit for SCI therapy. To our knowledge, this is the first study on the effects of NSA as treatment of traumatic SCI.


Assuntos
Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Apoptose/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Animais , Apoptose/fisiologia , Masculino , Necrose/tratamento farmacológico , Necrose/patologia , Ratos , Ratos Sprague-Dawley
18.
Cell Physiol Biochem ; 45(6): 2268-2282, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29550818

RESUMO

BACKGROUND/AIMS: Klotho is a multifunctional protein expressed predominantly in kidney tubular epithelium. Here, we investigated the protective effects of Klotho on necroptosis in renal ischemic-reperfusion injury (IRI) and the role of oxidative stress in this process. METHODS: Mice were subjected to bilateral renal pedicle clamping. Mouse renal tubular epithelial (TCMK-1) cells were exposed to hypoxia/reoxygenation (H/R) or H2O2. Kidney samples from acute kidney injury (AKI) patients and controls were examined by immunofluorescence. Klotho protein and N-acetyl-L-cysteine (NAC) were used to define their roles in mediating necroptosis. Necroptosis was assessed by TUNEL staining, immunoblotting, and real-time PCR. Oxidative stress was studied via ELISA, immunoblotting, colorimetric, and thiobarbituric acid reactive substances assays. RESULTS: Renal IRI induced Klotho deficiency in the serum and kidney, but an increase in the urine. The levels of the necroptotic markers receptor-interacting protein kinase (RIP) 1, RIP3, IL-1ß, and TUNEL-positive cells increased after IRI; all increases were ameliorated by Klotho. In TCMK-1 cells, Klotho and NAC attenuated the elevation in RIP1, RIP3, and LDH release induced by H/R or H2O2. Moreover, Klotho decreased the levels of oxidative stress biomarkers and elevated superoxide dismutase 2 expression in both in vivo and in vitro experiments. Studies in human samples further confirmed the Klotho deficiency and increased formation of RIP3 puncta in AKI kidneys. CONCLUSION: Klotho protects tubular epithelial cells from IRI and its anti-necroptotic role may be associated with oxidative stress inhibition.


Assuntos
Lesão Renal Aguda/patologia , Glucuronidase/metabolismo , Rim/patologia , Necrose/patologia , Estresse Oxidativo , Traumatismo por Reperfusão/patologia , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Animais , Linhagem Celular , Feminino , Glucuronidase/análise , Glucuronidase/uso terapêutico , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Necrose/tratamento farmacológico , Necrose/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
19.
Biochem Biophys Res Commun ; 497(1): 80-86, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29407174

RESUMO

Multiple sclerosis (MS) is a long-lasting autoimmune disease of the central nervous system. Currently, the etiology of MS is not known. Experimental autoimmune encephalomyelitis (EAE), has been recognized as the most widely used animal models to study the molecular mechanisms underlying MS and the efficacy of potential drugs for treatment of MS. In the present study, we found that Dl-3-n-butylphthalide (NBP), a neuroprotective drug in ischemic brain injury, prevented development of disease in experimental autoimmune encephalomyelitis (EAE) and significantly reduced inflammatory factors and necroptosis-associated genes, including PGAM5 in the spinal cord tissues. Similarly, silence of PGAM5 in spinal cord also ameliorated the disease severity in the mice with EAE. Moreover, re-expression of PGAM5 counteracted the protective effect of NBP on the pathogenesis of EAE. Importantly, we found that both NBP and silence of PGAM5 inhibited cellular necroptosis and inflammation in microglia induced by TNFα plus zVAD-fmk. Meanwhile, overexpression of PGAM5 reactivated cellular necroptosis and inflammation suppressed by NBP in vitro. Taken together, our findings provide evidence that NBP can attenuate the progression of EAE by suppressing PGAM5-induced necroptosis and inflammation in microglia and represents a new therapeutic strategy for treating autoimmune diseases.


Assuntos
Benzofuranos/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Microglia/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Fosfoproteínas Fosfatases/imunologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Esclerose Múltipla/patologia , Necrose/tratamento farmacológico , Necrose/imunologia , Necrose/patologia , Fármacos Neuroprotetores/administração & dosagem , Fosfoproteínas Fosfatases/antagonistas & inibidores , Resultado do Tratamento
20.
World J Gastroenterol ; 24(6): 706-715, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29456409

RESUMO

AIM: To investigate the modulatory effect of recombinant-expressed vasoactive intestinal peptide (VIP) analogue (rVIPa) on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. METHODS: Forty-eight rats were randomized into six groups: normal control group (Control), model control group (TNBS), ethanol treatment group (ETOH), and VIP treatment groups with different dosage (rVIPa1nmol, rVIPa2nmol, rVIPa4nmol). Diarrhea and bloody stool were observed. Colonic damage was evaluated histologically. The levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), myeloperoxidase (MPO) and endotoxin in colonic tissue and serum were determined by enzyme-linked immunosorbent assay (ELISA). The expression of occludin, ZO-1, Toll-like receptor 4 (TLR4), and nuclear factor-kappa B p65 (NF-κB p65), IκBα, and p-IκBα were detected by Western blot. RESULTS: Administration with 2 nmol rVIPa prevented TNBS-induced necrosis, hyperemia, swelling, inflammation, etc., pathologic changes observed in the inner surface of colon in experimental rats. Moreover, rVIPa significantly decreased colonic TNF-α level (P < 0.001), MPO activity (P < 0.001) and serum endotoxin level (P < 0.01), and remarkably increased colonic IL-10 content (P < 0.001) in rats with TNBS-induced colitis. Furthermore, compared to the TNBS-induced colitis group, 2 nmol rVIPa treatment up-regulated the levels of occludin (P < 0.05) and ZO-1 (P < 0.05), NF-κB p65 (P < 0.01) and IκBα (P < 0.001), and down-regulated the levels of TLR4. CONCLUSION: rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TLR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.


Assuntos
Colo/efeitos dos fármacos , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/análogos & derivados , Animais , Colo/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/patologia , Modelos Animais de Doenças , Fármacos Gastrointestinais/farmacologia , Humanos , Mucosa Intestinal/patologia , Masculino , NF-kappa B/metabolismo , Necrose/tratamento farmacológico , Necrose/patologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento , Ácido Trinitrobenzenossulfônico/toxicidade
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