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1.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 605-611, 2020 Apr 25.
Artículo en Chino | MEDLINE | ID: mdl-32347055

RESUMEN

Cyclophilin A (CypA) is a widely distributed and highly conserved protein in organisms. It has peptidyl-prolyl cis/trans isomerase activity and is a receptor for cyclosporin A (CsA). Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses. Seven types of coronaviruses are currently known to infect humans, among which SARS-CoV, MERS-CoV, and SARS-CoV-2 are fatal for humans. It is well established that CypA is essential for the replication of various coronaviruses such as SARS-CoV, CoV-229E, CoV-NL63, and FCoV. Additionally, CsA and its derivatives (ALV, NIM811, etc.) have obvious inhibitory effects on a variety of coronaviruses. These results suggest that CypA is a potential antiviral target and the existing drug CsA might be used as an anti-coronavirus drug. At the end of 2019, SARS-CoV-2 raged in China, which seriously theatern human health and causes huge economic lases. In view of this, we describe the effects of CypA on the replication of coronaviruses and the antiviral activities of its inhibitors, which will provide the scientific basis and ideas for the development of antiviral drugs for SARS-CoV-2.


Asunto(s)
Antivirales/farmacología , Infecciones por Coronavirus , Coronavirus/efectos de los fármacos , Coronavirus/crecimiento & desarrollo , Ciclofilina A/antagonistas & inhibidores , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Pandemias , Neumonía Viral , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/crecimiento & desarrollo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Ciclosporina/química , Humanos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Neumonía Viral/virología , Virus del SRAS/efectos de los fármacos , Virus del SRAS/crecimiento & desarrollo , Replicación Viral/efectos de los fármacos
2.
Braz Oral Res ; 34: e007, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32049108

RESUMEN

The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and ß-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFß1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Sustitutos de Huesos/farmacología , Inhibidores de la Calcineurina/farmacología , Ciclosporina/farmacología , Osteogénesis/efectos de los fármacos , Animales , Proteína Morfogenética Ósea 2/análisis , Inmunohistoquímica , Masculino , Osteocalcina/análisis , Distribución Aleatoria , Ratas , Reproducibilidad de los Resultados , Cráneo/efectos de los fármacos , Cráneo/patología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/análisis , Microtomografía por Rayos X
3.
Clin Sci (Lond) ; 134(2): 239-259, 2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-31943002

RESUMEN

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.


Asunto(s)
Ciclofilina D/metabolismo , Diabetes Mellitus Experimental/metabolismo , Enfermedades Renales/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Albuminuria/genética , Albuminuria/metabolismo , Animales , Ciclofilina D/antagonistas & inhibidores , Ciclofilina D/genética , Ciclosporina/farmacología , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Peróxido de Hidrógeno/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , ATPasas de Translocación de Protón/metabolismo
4.
J Stroke Cerebrovasc Dis ; 29(2): 104562, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31836361

RESUMEN

INTRODUCTION: Recent studies have indicated that the damaging effects of stroke are not only limited to the brain. We sought to examine the changes of liver and renal enzymes in the acute phase of ischemic stroke and to investigate possible explanations and therapeutic options, concerning in particular the functional alterations of peripheral organs after administration of an anti-inflammatory agent. MATERIAL/METHODS: Twelve-week-old Wistar male rats were randomly divided into control and Cyclosporine groups (n = 10 each). Cyclosporine was given orally by gavage for 5 days prior to cerebral ischemia at a total volume of 15 mg/kg/day. All animals were subjected to 60 minutes focal ischemia by filament occlusion of the middle cerebral artery. Serum concentrations of Creatinine, Urea, SGOT, SGPT, and γGT were determined at the time before surgery and after 60 minutes brain ischemia. RESULTS: Comparing data of 2 time-points, in both groups the serum liver enzyme levels increased progressively during the ischemic period. The liver enzymes and Urea were significantly lower in the Cyclosporine group than in the control group and the levels of Creatinine were slightly higher in the Cyclosporine group, in both time-points. CONCLUSIONS: The detection of high liver enzyme serum levels in the acute phase of ischemic stroke implies the secondary effect of cerebral infraction on the peripheral organs and particularly on the liver function. Cyclosporine seems to exhibit a protective activity and to affect both liver and renal function after ischemic stroke.


Asunto(s)
Antiinflamatorios/farmacología , Isquemia Encefálica/tratamiento farmacológico , Ciclosporina/farmacología , Enfermedades Renales/prevención & control , Riñón/efectos de los fármacos , Hepatopatías/prevención & control , Hígado/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Biomarcadores/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Modelos Animales de Enfermedad , Riñón/enzimología , Riñón/fisiopatología , Enfermedades Renales/sangre , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Hígado/enzimología , Hígado/fisiopatología , Hepatopatías/sangre , Hepatopatías/etiología , Hepatopatías/fisiopatología , Masculino , Ratas Wistar , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Factores de Tiempo
5.
Can J Vet Res ; 83(4): 279-284, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31571728

RESUMEN

A lack of understanding of specific immune defects underlying canine immune-mediated diseases hampers optimal therapy. Failure to tailor treatment to an individual's immune abnormality can result in lack of efficacy, secondary complications, added expense, and drug-potentiated adverse effects. We adopted a small-volume whole-blood flow cytometric assay to determine the effect of immunosuppressant drugs on T-lymphocyte proliferation. Using healthy dogs in this proof-of-principle study, we hypothesized that there would be dose-dependent suppression of T-lymphocyte proliferation in response to dexamethasone, cyclosporine, mycophenolic acid, and the active metabolite of leflunomide (A77 1726). Whole blood was collected from 6 healthy pet dogs and incubated for 4 d with or without the mitogens concanavalin A and lipopolysaccharide and with increasing concentrations of immunosuppressant. Samples were subsequently stained with viability dye and with antibodies against the pan-T-lymphocyte marker CD5 and the cell proliferation marker Ki67. Percentages of proliferating T-lymphocytes were determined by flow cytometry, and the 50% inhibitory concentration (IC50) was calculated. Inhibition of T-lymphocyte proliferation by the panel of immunosuppressants was shown to be dose-dependent, with marked variability among the dogs. The mean IC50 was 394.8 ± 871 (standard deviation) µM for dexamethasone, 18.89 ± 36.2 ng/mL for cyclosporine, 106.3 ± 157.7 nM for mycophenolic acid, and 3.746 ± 6.8 µM for A77 1726. These results support the use of this assay for detecting the efficacy of individual immunosuppressants used to diminish T-lymphocyte proliferation. In future, the assay may be applied to pet dogs with spontaneous immune-mediated disease to help tailor individual treatment.


Asunto(s)
Ciclosporina/farmacología , Dexametasona/farmacología , Perros , Leflunamida/metabolismo , Ácido Micofenólico/farmacología , Linfocitos T/efectos de los fármacos , Animales , Antiinflamatorios , Antibióticos Antineoplásicos/farmacología , Antígenos CD5/genética , Antígenos CD5/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inmunosupresores/farmacología , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Leflunamida/química , Leflunamida/farmacología , Linfocitos T/fisiología
6.
Acta Cir Bras ; 34(8): e201900806, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31618406

RESUMEN

PURPOSE: To assess Cyclosporine A (CsA) therapy at an intraperitoneal dose of 15 mg.kg -1 in a rodent model of non-septic renal ischemia. METHODS: Twenty male Wistar rats were randomized to receive CsA therapy or none therapy before undergoing 30 minutes of renal ischemia followed by reperfusion. Additionally, 10 rats were randomized to undergo the same surgical procedure of the aforementioned animals with neither ischemia nor CsA therapy. Twelve hours after kidney ischemia, the left kidneys were evaluated for histological injury according to Park's criteria. Serum creatinine (Cr), urea nitrogen (Ur) and sodium levels were obtained at different times of the experimental protocol. RESULTS: Rodents in the CsA group showed negative results (p<0.05) in serum variables (Cr: 0.41±0.05mg/dL vs . 4.17±1.25mg/dL; Ur: 40.90±3.98mg/dL vs . 187.70±22.93mg/dL) even the non CsA or control group (Cr: 0.35±0.07mg/dL vs . 3.80±1.20mg/dL; Ur: 40.10±4.70mg/dL vs . 184.50±49.80mg/dL). The negative results were also verified in histological evaluation, CsA group had 50% in the very severe grade of lesion, 10% in the severe and 40% in the moderate to severe whereas the control group had 90% in the very severe grade. CONCLUSION: CsA was incapable of preventing the deleterious effects of ischemia-reperfusion injury in rat kidneys.


Asunto(s)
Ciclosporina/farmacología , Inmunosupresores/farmacocinética , Riñón/irrigación sanguínea , Daño por Reperfusión/tratamiento farmacológico , Animales , Creatinina/sangre , Modelos Animales de Enfermedad , Isquemia/prevención & control , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Daño por Reperfusión/patología , Sodio/sangre , Urea/sangre
7.
Sheng Li Xue Bao ; 71(5): 681-688, 2019 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-31646321

RESUMEN

Polyamines (putrescine, spermidine, and spermine) are essential polycations that play important roles in various physiological and pathophysiological processes in mammalian cells. The study was to investigate their role in cardioprotection against ischemia/reperfusion (I/R) injury and the underlying mechanism. Isolated hearts from male Sprague-Dawley rats were Langendorff-perfused and cardiac I/R was achieved by 30 min of global ischemia followed by 120 min of reperfusion. Different concentrations of polyamines (0.1, 1, 10, and 15 µmol/L of putrescine, spermidine, and spermine), cyclosporin A (0.2 µmol/L), or atractyloside (20 µmol/L) were given 10 min before the onset of reperfusion. The hemodynamics were monitored; the lactate dehydrogenase (LDH) levels in the coronary effluent were measured spectrophotometrically; infarct size was determined by the 2,3,5-triphenyltetrazolium chloride staining method; and mitochondrial permeability transition pore (MPTP) opening was determined spectrophotometrically by the Ca2+-induced swelling of isolated cardiac mitochondria. The results showed that compared to I/R alone, 0.1 and 1 µmol/L polyamines treatment improved heart function, reduced LDH release, decreased infarct size, and these effects were inhibited by atractyloside (MPTP activator). In isolated mitochondria from normal rats, 0.1 and 1 µmol/L polyamines treatment inhibited MPTP opening. However, 10 and 15 µmol/L polyamines treatment had the opposite effects, and these effects were inhibited by cyclosporin A (MPTP inhibitor). Our findings showed that polyamines may have either protective or damaging effects on hearts suffering from I/R by inhibiting or activating MPTP opening.


Asunto(s)
Proteínas de Transporte de Membrana Mitocondrial/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Poliaminas/metabolismo , Animales , Ciclosporina/farmacología , Masculino , Mitocondrias Cardíacas/fisiología , Ratas , Ratas Sprague-Dawley
8.
Life Sci ; 235: 116841, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31494173

RESUMEN

Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury. Mitochondria are the key arbitrators of cell life and death pathways. Both oxidative stress and calcium overload in the mitochondria, elicit pathways resulting in the opening of mitochondrial permeability transition pore (mPTP) leading to cell death. Therefore, in this study we explored the role of IAA-94 in MI and in maintaining calcium retention capacity (CRC) of cardiac mitochondria after IR. IAA-94 inhibited the CRC of the isolated cardiac mitochondria in a concentration-dependent manner as measured spectrofluorimetrically using calcium green-5 N. Interestingly, IAA-94 did not change the mitochondrial membrane potential. Further, CsA a blocker of mPTP opening could not override the effect of IAA-94. We also showed for the first time that IAA-94 perfusion after ischemic event augments MI by reducing the CRC of mitochondria. To conclude, our results demonstrate that the mechanism of IAA-94 mediated cardio-deleterious effects is via modulating the mitochondria CRC, thereby playing a role in mPTP opening. These findings highlight new pharmacological targets, which can mediate cardioprotection from IR injury.


Asunto(s)
Calcio/metabolismo , Glicolatos/efectos adversos , Infarto del Miocardio/metabolismo , Animales , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Glicolatos/antagonistas & inhibidores , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Infarto del Miocardio/inducido químicamente , Ratas
9.
J Photochem Photobiol B ; 198: 111578, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31408842

RESUMEN

In recent years, biological nanomedicine-based biomaterials have an extreme attention for biomedical uses, herein we examined a novel kind advance of photoluminescent Graphene quandum dots encapsulated mesoporous nanoparticles (GND@MSNs) encapsulated by well-known anticancer drugs Doxorubicin (DOX) and Cyclosporin (CsA) for lung carcinoma. Electron microscopic technique exhibit the nanostructure and spherical morphology of GND@MSNs+DOX+CsA with mean size ≈110 nm. Moreover, Dynamic Light Scattering (DLS) exposed that blended GND@MSNs+DOX+CsA nanoparticles were highly stable with extremely negatively charged nanoparticles. Raman investigation was done on the all naturally dynamic nanoparticles containing shed graphene to survey the blend condition of the graphene inside the silica mesoporous nanoparticles. GND@MSNs+DOX+CsA provided an outstanding anti-cancer efficiency against the lung cancer cell lines (i.e., A549 and HEL-299). MTT assay monitored that GND@MSNs, GND@MSNs+DOX and GND@MSNs+DOX+CsA have a robust toxicity behaviour on the A549 and HEL-299 model lung cancer cell lines. Additionally, investigation of the cell death was found on AO-EB, Hoechst 33452 staining and flowcytometry techniques. Furthermore, the DNA damage were confirmed by cell cycle arrest and comet assay. Hence, we suggesting that these GND@MSNs+DOX+CsA could be applied as auspicious drug vesicles for novel lung cancer therapeutic potential and new openings to solve the complexity of lung cancer in the care of cancer patients.


Asunto(s)
Apoptosis/efectos de los fármacos , Ciclosporina/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/química , Grafito/química , Nanopartículas/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclosporina/química , Ciclosporina/uso terapéutico , Daño del ADN/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Porosidad
10.
Vet Immunol Immunopathol ; 216: 109892, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31446206

RESUMEN

Cyclosporine and glucocorticoids are powerful immunosuppressive agents used to treat many inflammatory diseases in dogs. Cyclosporine inhibits calcineurin-dependent pathways of T cell activation and resultant T cell cytokine production, and glucocorticoids directly inhibit genes coding for cytokines. Little work has been done comparing the effects of these agents on T cell cytokine production in dogs. Our study measured T cell interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production using flow cytometry and T cell IL-2 and IFN-γ gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in activated canine T cells incubated with cyclosporine and dexamethasone in vitro. For flow cytometric assays, diluted whole blood was cultured for 7 h in the presence of cyclosporine (10, 100, 500, and 1000 ng/mL) or dexamethasone (10 ng/mL, 100 ng/mL, 1 µg/mL, and 10 µg/mL). For qRT-PCR, whole blood was cultured for 5 h with the same drugs at the same concentrations, and RNA was then extracted from leukocytes. Flow cytometry and qRT-PCR both demonstrated inhibition of IL-2 and IFN-γ that was concentration-dependent in response to cyclosporine, and was more variable for dexamethasone. Quantitative RT-PCR but not flow cytometry documented significant reduction of IL-2 expression after dexamethasone treatment, while both methods showed concentration-dependent suppression of IFN-γ. Quantitative RT-PCR also revealed additional cytokine suppression at higher cyclosporine concentrations, an effect not found using flow cytometry, and may therefore be the preferred method for cytokine determination in dogs. Suppression of IL-2 and IFN-γ in activated T cells may have potential as an indicator of the efficacy of cyclosporine and glucocorticoids in suppressing canine T cell function in vivo, and may therefore be of value for characterizing the immunosuppression induced by these drugs in clinical patients.


Asunto(s)
Ciclosporina/farmacología , Dexametasona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Linfocitos T/efectos de los fármacos , Animales , Ciclosporina/administración & dosificación , Dexametasona/administración & dosificación , Perros , Relación Dosis-Respuesta a Droga , Glucocorticoides/farmacología , Inmunidad Celular/efectos de los fármacos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Interferón gamma/genética , Interleucina-2/genética
11.
Hum Exp Toxicol ; 38(11): 1266-1274, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31446784

RESUMEN

Cyclophosphamide (CYP) and methotrexate (MTX) have been evaluated for their ability to induce toxicity in human peripheral blood lymphocytes (PBLs) and the protective role of mitochondrial and lysosomal stabilizing agents. The potential toxicity effects of CYP and MTX were measured in vitro by cellular parameters assays such as cellular viability, reactive oxygen species (ROS) formation, mitochondrial membrane permeability transition (mitochondrial membrane potential (MMP)) collapse, lysosomal membrane damage, intracellular reduced glutathione (GSH), extracellular oxidized glutathione (GSSG), and lipid peroxidation. Separately, human lymphocytes were treated with concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 ng/mL for CYP and 1, 2, 5, and 10 µg/mL for MTX for 6 h. Statistical evaluations showed that CYP and MTX significantly decreased the cell viability at the three highest concentrations when compared with both the negative and solvent controls. In addition, CYP and MTX were significantly induced ROS formation, MMP collapse, lysosomal membrane damage, lipid peroxidation, and GSH depletion compared with the controls. Mitochondrial and lysosomal protective agents like cyclosporine A and chloroquine, respectively, decreased cytotoxicity and oxidative stress induced by CYP and MTX. The present results indicate that CYP and MTX are toxic to human PBLs and their toxicity could be ameliorated by mitochondrial and lysosomal protective agents.


Asunto(s)
Antineoplásicos/toxicidad , Ciclofosfamida/toxicidad , Inmunosupresores/toxicidad , Linfocitos/efectos de los fármacos , Metotrexato/toxicidad , Sustancias Protectoras/farmacología , Adolescente , Adulto , Hidroxitolueno Butilado/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cloroquina/farmacología , Ciclosporina/farmacología , Glutatión/metabolismo , Humanos , Linfocitos/metabolismo , Lisosomas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Adulto Joven
12.
Biomed Res Int ; 2019: 6539050, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31309111

RESUMEN

Objective: To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC). Methods: Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs. Results: Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms. Conclusions: Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.


Asunto(s)
Cardiomiopatías/tratamiento farmacológico , Ciclosporina/farmacología , Paro Cardíaco/tratamiento farmacológico , Metilprednisolona/farmacología , Animales , Gasto Cardíaco/efectos de los fármacos , Reanimación Cardiopulmonar/métodos , Ecocardiografía/métodos , Cardioversión Eléctrica/métodos , Epinefrina/farmacología , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Porcinos , Vasoconstrictores/farmacología , Fibrilación Ventricular/tratamiento farmacológico
13.
Drug Des Devel Ther ; 13: 2001-2008, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31354245

RESUMEN

Background: Effective and tolerable therapeutic strategies for patients with refractory persistent epithelial defects (PEDs) are limited and generally provide poor outcomes. This retrospective case review describes four refractory cases of PEDs associated with recurrent corneal erosions (RCEs) and dry eye disease (DED), which were successfully treated with cyclosporine eye drops. Methods: Patients were treated with cyclosporine A 0.05% eye drops twice a day for at least 12 months. At enrolling time, each patient was asked to suspend topical steroids or other eye drops used for ocular surface abnormalities with the exception of lubricants and eye washing. A complete evaluation of ocular surface symptoms was performed including the McMonnies Dry Eye Questionnaire, Ocular Surface Disease Index, slit-lamp biomicroscopy, fluorescein break-up time, the fluorescein staining of the cornea and conjunctiva (according to the Oxford grading system), the Schirmer I test, and the meibomian secretion after digital pressure application on the lids. This set of exams was carried out at baseline and repeated at all follow-up assessments. Results: All participants that did not benefit from previous therapies, including corticosteroids tapering schedule, showed an important improvement in the clinical picture after two months with topical cyclosporine medication. Moreover, after 12 months of continuous therapy, all patients showed a clinical improvement in DED signs and symptoms, related to the absence of new RCE episodes. The treatment was well tolerated, and no adverse effects were reported. Conclusion: Although a small number of cases were available of our analysis, the treatment with cyclosporine eye drops represents a promising approach in the management of refractory PEDs with associated ocular comorbidities, since it may reduce the RCE episodes and improve the tear film stability, in absence of systemic or local side effects.


Asunto(s)
Enfermedades de la Córnea/tratamiento farmacológico , Ciclosporina/farmacología , Síndromes de Ojo Seco/tratamiento farmacológico , Epitelio Anterior/efectos de los fármacos , Soluciones Oftálmicas/farmacología , Administración Tópica , Adulto , Enfermedades de la Córnea/patología , Ciclosporina/administración & dosificación , Síndromes de Ojo Seco/patología , Epitelio Anterior/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas/administración & dosificación , Tamaño de la Partícula , Estudios Retrospectivos , Propiedades de Superficie
14.
Exp Mol Pathol ; 110: 104271, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31251898

RESUMEN

Testicular torsion/detorsion (T/D) is an inflammatory problem in men genital system with infertility effects. Cyclosporine A (CsA) as an immunosuppressant medication, exerts anti-inflammatory properties in tissue injuries. We sought to compare the efficacy of 3 doses of CsA on oxidative stress, apoptosis and epididymal sperm quality after ipsilateral testicular T/D. METHODS: 96 mature male rats were divided into six groups 16 each in: Control group (Group1), Sham operated (Group2), In rest groups, the right testis was twisted 720° in a clockwise direction for 1 h; T/D + 0.1% dimethylsulfoxide) DMSO((Group3), and in groups 4-6; CsA were administered 1, 5, and 10 mg/kg, intravenously (iv) 30 and 90 min after torsion, respectively. RESULTS: Tissue malondialdehyde (MDA) level and caspase-3 activity increased and catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities decreased in compared with control group 4 h after detorsion (p < .001). In six rats of each group 24 h after detorsion, histopathological changes and germ cell apoptosis were significantly deteriorated by determining mean of seminiferous tubules diameters (MSTD) and TUNEL assay. Moreover, 30 days after T/D, sperm concentration and motility were examined in rest of animals. CONCLUSIONS: Pre- and post-reperfusion CsA diminished MDA and caspase-3levels and normalized antioxidant enzymes activities. Germ cell apoptosis was significantly reduced, as well as, MSTD and long-term sperm insults were improved. Inhibition of mitochondrial permeability transition pore opening is suggested mechanism for cell protection against testicular T/D insults.


Asunto(s)
Apoptosis/efectos de los fármacos , Ciclosporina/farmacología , Epidídimo/efectos de los fármacos , Daño por Reperfusión/fisiopatología , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Caspasa 3/metabolismo , Catalasa/metabolismo , Epidídimo/metabolismo , Epidídimo/patología , Células Germinativas , Glutatión Peroxidasa/metabolismo , Inmunosupresores/farmacología , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Torsión del Cordón Espermático/fisiopatología , Espermatozoides/patología , Superóxido Dismutasa/metabolismo , Testículo/irrigación sanguínea , Testículo/metabolismo
16.
Inflamm Res ; 68(9): 787-799, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31227843

RESUMEN

OBJECTIVE: Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS: Differentiated M0, M1 and M2 subsets of THP-1 human macrophages were subjected to various concentrations of either MPA or CsA. Expression of proteins involved in reverse cholesterol transport (ABCA1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), were evaluated by real-time PCR and confirmed with Western blot. DiI-oxidized LDL internalization assay was used to assess foam cell formation. The influence of MPA was also evaluated in BMDM obtained from atherosclerosis-prone transgenic mice, ApoE-/- and ApoE-/-Fas-/-. RESULTS: In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS: Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.


Asunto(s)
Ciclosporina/farmacología , Inmunosupresores/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ácido Micofenólico/farmacología , Animales , Aterosclerosis/metabolismo , Células de la Médula Ósea/citología , Diferenciación Celular , Colesterol/metabolismo , Células Espumosas , Humanos , Inmunosupresión , Macrófagos/metabolismo , Ratones , Monocitos/citología , Células THP-1
17.
Int J Pharm ; 565: 306-315, 2019 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-31085259

RESUMEN

The aim of the present study was to investigate the ability of non-ionic surfactants to inhibit MRP2-mediated transport in vitro in MDCKII MRP2 cells. Transport studies across MDCKII MRP2 cell monolayers were performed using 3H-etoposide and 3H-digoxin. 19 different non-ionic surfactants, including several polysorbates (PS), cremophor EL, vitamin E-TPGS, and n-nonyl ß-D-glucopyranoside (NG), were investigated. Barrier function of the cells was investigated measuring TEER and transport of 14C-glycine. The amount of isotope was quantified using liquid scintillation counting. In MDCKII MRP2 cells a polarized transport of etoposide and digoxin in the secretory (basolateral to apical) direction with efflux ratios of 5.5 ±â€¯0.7 and 18.5 ±â€¯4.2, respectively, was measured. P-gp inhibitors such as valspodar and zosuquidar did not affect etoposide transport, and furthermore PS20 decreased secretory transport of digoxin, but not of etoposide. Transport of etoposide was therefore mainly MRP2-mediated and used as a probe to investigate pharmaceutical excipients. Non-ionic surfactants did not modulate etoposide transport across intact cell monolayers of MRP2 overexpressing MDCKII cells, although preliminary studies suggest that most were able to alter MRP2-mediated efflux of the fluorescent 5-chloromethylfluorescein (CMF). In conclusion, etoposide transport across MDCKII MRP2 cells was modulated by cyclosporin A, an inhibitor of MRP2 and P-gp, but not by specific P-gp inhibitors (valspodar and zosuquidar), which suggests that etoposide transport is primarily influenced by MRP2. In addition, commonly used non-ionic surfactants did not decrease MRP2-mediated etoposide transport in MDCKII MRP2 cells. These results suggest that etoposide transport in MDCKII MRP2 cells is a model system to investigate MRP2 interactions, and that surfactants may not have a large potential for increasing oral bioavailability of drugs through inhibition of MRP2 transport activity.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Etopósido/administración & dosificación , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Animales , Transporte Biológico , Ciclosporina/farmacología , Perros , Células de Riñón Canino Madin Darby , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Tensoactivos/farmacología
18.
Oxid Med Cell Longev ; 2019: 1729013, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31089403

RESUMEN

Pathological stimuli, such as bacterial activity, dental bleaching, and nonpolymerized resin monomers, can cause death of dental pulp cells (DPCs) through oxidative stress- (OS-) induced mitochondrial dysfunction. However, the crucial molecular mechanisms that mediate such a phenomenon remain largely unknown. OS is characterized by the overproduction of reactive oxygen species (ROS), e.g., H2O2, O2 -, and ·OH. Mitochondria are a major source of ROS and the principal attack target of ROS. Cyclophilin D (CypD), as the only crucial protein for mitochondrial permeability transition pore (mPTP) induction, facilitates the opening of mPTP and causes mitochondrial dysfunction, leading to cell death. In the present study, we hypothesized that CypD-mediated mitochondrial molecular pathways were closely involved in the process of OS-induced death of human DPCs (HDPCs). We tested the phenotypic and molecular changes of HDPCs in a well-established OS model-H2O2 treatment. We showed that H2O2 dramatically reduced the viability and increased the death of HDPCs in a time- and dose-dependent manner by performing MTT, flow cytometry, and TUNEL assays and quantifying the expression changes of Bax and Bcl-2 proteins. H2O2 also induced mitochondrial dysfunction, as reflected by the increased mitochondrial ROS, reduced ATP production, and activation of mPTP (decreased mitochondrial membrane potential and enhanced intracellular Ca2+ level). An antioxidant (N-acetyl-L-cysteine) effectively preserved mitochondrial function and significantly attenuated H2O2-induced cytotoxicity and death. Moreover, H2O2 treatment markedly upregulated the CypD protein level in HDPCs. Notably, genetic or pharmacological blockade of CypD significantly attenuated H2O2-induced mitochondrial dysfunction and cell death. These findings provided novel insights into the role of a CypD-dependent mitochondrial pathway in the H2O2-induced death in HDPCs, indicating that CypD may be a potential therapeutic target to prevent OS-mediated injury in dental pulp.


Asunto(s)
Apoptosis , Pulpa Dental/patología , Estrés Oxidativo , Acetilcisteína/farmacología , Apoptosis/efectos de los fármacos , Ciclosporina/farmacología , Humanos , Peróxido de Hidrógeno/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , ARN Interferente Pequeño/metabolismo
19.
Drug Deliv ; 26(1): 542-550, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31090467

RESUMEN

Self-nanoemulsifying drug delivery system (SNEDDS) have been considered as a promising platform for oral delivery of many BCS (biopharmaceutics classification system) class IV drugs, such as docetaxel (DTX). However, oral chemotherapy with DTX is also restricted by its active P-glycoprotein (P-gp) efflux and hepatic first-pass metabolism. To address these challenges, we developed a novel SNEDDS co-loaded with DTX and cyclosporine A (CsA) to achieve effective inhibition of P-gp efflux and P450 enzyme metabolization, improving oral bioavailability of DTX. The SNEDDS showed uniform droplet size of about 30 nm. Additionally, the prepared SNEDDS exhibited a sequential drug release trend of CsA prior to DTX. The intestinal experiments confirmed that the membrane permeability of DTX was significantly increased in the whole intestinal tract, especially in the jejunum segment. Furthermore, the oral bioavailability of co-loaded SNEDDS was 9.2-fold and 3.4-fold higher than DTX solution and DTX SNEDDS, respectively. More importantly, it exhibited a remarkable antitumor efficacy with a reduced toxicity compared with intravenously administered DTX solution. In summary, DTX-CsA co-loaded SNEDDS is a promising platform to facilitate oral docetaxel-based chemotherapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Ciclosporina/administración & dosificación , Docetaxel/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ciclosporina/farmacocinética , Ciclosporina/farmacología , Docetaxel/farmacocinética , Docetaxel/uso terapéutico , Liberación de Fármacos , Emulsiones , Femenino , Absorción Intestinal , Ratones Endogámicos BALB C , Nanopartículas/química , Ratas Sprague-Dawley , Solubilidad , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Arq Bras Oftalmol ; 82(4): 310-316, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31038554

RESUMEN

PURPOSE: Chronic instillation of benzalkonium chloride, a preservative, has inflammatory effects on the ocular surface. However, addition of the anti-inflammatory agent cyclosporine to a therapeutic protocol may mitigate these effects. This study compared the toxic effects of a 0.1% benzalkonium chloride solution and the possible protective effect of 0.05% cyclosporine when applied topically to the rabbit conjunctiva. METHODS: Fifteen age- and weight-matched, female New Zealand white rabbits were categorized into three groups and treated for 30 consecutive days. Group 1, 2, and 3 - benzalkonium chloride received 0.1% every 24 h, 0.05% cyclosporine every 6 h, and both treatments, respectively. In each rabbit, the left eye was subjected to treatment and the right eye was a control. The rabbits were euthanized at after the experiment. Goblet cells and blood vessels were then enumerated in conjunctival tissues stained with periodic acid-Schiff and hematoxylin-eosin, respectively. Differences between treated and untreated eyes and between groups were compared using the t-test and analysis of variance. RESULTS: Benzalkonium chloride treatment, with and without cyclosporine, significantly reduced (p≤0.05) in the number of goblet cells in treatment eyes compared with that in respective control eyes. Alternatively, adding cyclosporine to benzalkonium chloride did not prevent the loss of conjunctival goblet cells, and a significant reduction in the number of goblet cells was noted. Benzalkonium chloride-induced significant increase in the number of new blood vessels was mitigated significantly by the addition of cyclosporine. CONCLUSION: This study demonstrated the magnitude of conjunctival injury caused by chronic instillation of benzalkonium chloride. Although cyclosporine did not mitigate the effects on goblet cells, its addition minimized inflammatory angiogenesis induced by benzalkonium chloride.


Asunto(s)
Antiinflamatorios/farmacología , Compuestos de Benzalconio/efectos adversos , Conjuntiva/efectos de los fármacos , Ciclosporina/farmacología , Conservadores Farmacéuticos/efectos adversos , Sustancias Protectoras/farmacología , Inductores de la Angiogénesis/farmacología , Animales , Conjuntiva/patología , Femenino , Células Caliciformes/efectos de los fármacos , Conejos , Distribución Aleatoria , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del Tratamiento
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