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1.
Front Pharmacol ; 10: 1335, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31798448

RESUMEN

Diabetes mellitus is a growing problem worldwide; however, only 23% of low-income countries have access to insulin, and ironically it costs higher in such countries than high-income ones. Therefore, new strategies for insulin and insulin analogs production are urgently required to improve low-cost access to therapeutic products, so as to contain the diabetes epidemic. SCI-57 is an insulin analog with a greater affinity for the insulin receptor and lower thermal degradation than native insulin. It also shows native mitogenicity and insulin-like biological activity. In this work, SCI-57 was transiently expressed in the Nicotiana benthamiana (Nb) plant, and we also evaluated some of its relevant biological effects. An expression plasmid was engineered to translate an N-terminal ubiquitin and C-terminal endoplasmic reticulum-targeting signal KDEL, in order to increase protein expression and stability. Likewise, the effect of co-expression of influenza M2 ion channel (M2) on the expression of insulin analog SCI-57 (SCI-57/M2) was evaluated. Although using M2 increases yield, it tends to alter the SCI-57 amino acid sequence, possibly promoting the formation of oligomers. Purification of SCI-57 was achieved by FPLC cation exchange and ultrafiltration of N. benthamiana leaf extract (NLE). SCI-57 exerts its anti-diabetic properties by stimulating glucose uptake in adipocytes, without affecting the lipid accumulation process. Expression of the insulin analog in agroinfiltrated plants was confirmed by SDS-PAGE, RP-HPLC, and MS. Proteome changes related to the expression of heterologous proteins on N. benthamiana were not observed; up-regulated proteins were related to the agroinfiltration process. Our results demonstrate the potential for producing a biologically active insulin analog, SCI-57, by transient expression in Nb.

2.
Exp Ther Med ; 18(4): 3125-3138, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31572553

RESUMEN

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty-five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high-fat, high-carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low-dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α-smooth muscle actin (αSMA) and oxidative-associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra- and extracellular collagen type I expression and Pdgfb, Tgfß1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG-treated myofibroblasts. Thus, AG reduces oxidative stress-associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.

3.
BMC Pharmacol Toxicol ; 18(1): 79, 2017 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-29216902

RESUMEN

BACKGROUND: The aim of this study was to detect and analyze Adverse Drug Reactions (ADRs) through Intensive Pharmacovigilance (IPV) in hospitalized pediatric patients to improve drug safety. METHODS: A prospective 6-month cross-sectional study was performed in the pediatric service of a regional hospital in Mexico in order to assess hospitalized children from 1 day to 18 years old. The inclusion criteria were: both genders, all hospitalization causes, and at least one prescribed medication (indistinct drug group). Notifications were performed through medical visits, phone calls, or spontaneous reports. ADR suspicions were assessed with severity scales: Naranjo algorithm, Schumock & Thornton and Hartwig and Siegel. RESULTS: From a total of 1083 hospital admissions, 19 ADRs were recorded. The average age of patients in years was 7.2 (±5.9). The causality assessment in this study showed that most of the ADRs were probable (68.4%) and 4 certain (8.2%); causality was mainly attributed to antibiotics (AB) and an antiepileptic drug. We found a relationship of AB with ADRs (p < 0.05) with an increased risk at the third day of prescription (p < 0.05). The average severity was level 2 and 21% were classified as "preventable". Lastly, an increase in hospital stay associated with ADRs (p < 0.05) and with concomitant medications (p < 0.05), was also found. The most severe ADRs were hemolysis and toxic epidermal necrolysis. CONCLUSIONS: IPV was an effective tool for ADR prevention, detection, and treatment in hospitalized patients. The intensive monitoring approach in pharmacovigilance amplifies ADR detection and this translates into the improvement of drug safety in children.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Hospitalización , Farmacovigilancia , Adolescente , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , México/epidemiología
4.
Immunopharmacol Immunotoxicol ; 37(2): 207-13, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25721154

RESUMEN

Macrophage migration inhibitory factor (MIF) and tumor necrosis factor alpha (TNFα) play a pivotal role in rheumatoid arthritis (RA). MIF is considered a relevant cytokine because it appears before TNFα in the inflammatory cascade thus stimulating TNFα production and MIF's relationship with traditional synthetic disease modifying antirheumatic drugs (sDMARDs) is unknown. In this cross-sectional study, we investigated the association of MIF and TNFα serum levels with methotrexate (MTX) and in combination with chloroquine (CLQ) and sulfasalazine (SSZ) in RA patients classified according to the ACR/EULAR 2010 criteria. Patients were divided into three groups: MTX-monotherapy group (n = 40), MTX combination therapy groups: MTX + CLQ (n = 41), and MTX + CLQ + SSZ (n = 42). MIF and TNFα serum levels were determined by ELISA. We found high levels of ESR, CRP, RF, and anti-CCP in all therapy groups. Furthermore, we subclassified 97 patients with established RA (≥2 years of disease duration) and found that TNFα serum levels were lower in the combination therapy group (MTX + CLQ + SSZ) in comparison with the monotherapy MTX group (16.7 pg/mL versus 13.6 pg/mL, p = 0.02). However, we did not find differences between sDMARD therapies in MIF serum levels. We did find a significant reduction in MIF serum levels in patients treated with oral steroids compared with patients without oral steroids (1.7 ng/mL versus 4.3 ng/mL, p < 0.001). In conclusion, this study supports the role of sDMARDs in modifying TNFα serum levels and oral steroids MIF serum levels. Nevertheless, we found that MIF serum levels are not modified by sDMARD treatment.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Oxidorreductasas Intramoleculares/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto , Anciano , Artritis Reumatoide/diagnóstico , Biomarcadores/sangre , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
5.
Case Rep Dermatol ; 4(1): 104-13, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22787447

RESUMEN

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders whose primary clinical features include soft and extensible skin, articular hypermobility and tissue fragility. EDS type VIIC or 'human dermatosparaxis' is an autosomal recessive disease characterized by severe skin fragility and sagging redundant skin (major criteria) with a soft, doughy texture, easy bruising, premature rupture of fetal membranes and large hernias (minor criteria). Dermatosparaxis (meaning 'tearing of skin'), which has been described in several non-human species, is a disorder of the connective tissue resulting from a deficiency of the enzyme that cleaves the registration peptide off the N-terminal end of collagen after it has been secreted from fibroblasts. We describe a Mexican case from consanguineous parents with all the phenotypical characteristics previously described, plus skeletal abnormalities.

6.
Am J Physiol Gastrointest Liver Physiol ; 302(11): G1264-73, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22442156

RESUMEN

We evaluated the participation of oxidative stress in the negative regulation of hepatitis C virus (HCV)-RNA induced by acetylsalicylic acid (ASA). We used the HCV subgenomic replicon cell system that stably expresses HCV-nonstructural proteins (Huh7 HCV replicon cells) and the parental cell line. Cells were exposed to 4 mM ASA at different times (12-72 h), and pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control. Reactive oxygen species (ROS) production, oxidized protein levels, cytosolic superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GPx) activity were measured to evaluate oxidative stress. In addition, viral RNA and prostaglandin (PGE(2)) levels were determined. We observed that ASA treatment decreased ROS production and oxidized protein levels in a time-dependent fashion in both parental and HCV replicon cells with a greater extent in the latter. Similar results were found with PDTC exposure. Average GPx activity was decreased, whereas a striking increase was observed in average cytosolic SOD activity at 48 and 72 h in both cells exposed to ASA, compared with untreated cells. HCV replicon cells showed higher levels of Cu/Zn-SOD expression (mRNA and protein) with ASA treatment (48 and 72 h), whereas NS5A protein levels showed decreased expression. In addition, we found that inhibition of SOD1 expression reversed the effect of ASA. Interestingly, PDTC downregulated HCV-RNA expression (55%) and PGE(2) (60%) levels, imitating ASA exposure. These results suggest that ASA treatment could reduce cellular oxidative stress markers and modify Cu/Zn-SOD expression, a phenomenon that may contribute to the mechanisms involved in HCV downregulation.


Asunto(s)
Antioxidantes/farmacología , Antivirales/farmacología , Aspirina/farmacología , Hepacivirus/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Línea Celular , Células Cultivadas , Hepacivirus/metabolismo , Hepatocitos/metabolismo , Hepatocitos/virología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1 , Replicación Viral/efectos de los fármacos
7.
J Investig Med ; 56(7): 944-53, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18797412

RESUMEN

BACKGROUND/AIM: The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms. METHODS: We analyzed TGF-beta polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-beta by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment. RESULTS: Established liver fibrosis patients had the homozygote G/G TGF-beta genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-beta genotype (100% vs 37% control) (P = 0.0006). The odds of having TGF-beta G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects (P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes. CONCLUSION: Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively.


Asunto(s)
Angiotensinógeno/genética , Cirrosis Hepática/genética , Inhibidor 1 de Activador Plasminogénico/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Hepatitis C/tratamiento farmacológico , Hepatitis C/genética , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática Alcohólica/tratamiento farmacológico , Cirrosis Hepática Alcohólica/genética , Masculino , México , Persona de Mediana Edad , Polimorfismo Genético , Piridonas/uso terapéutico
8.
Exp Toxicol Pathol ; 58(2-3): 185-95, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16829063

RESUMEN

UNLABELLED: Renal failure is a common complication in patients with alcohol-induced cirrhosis who undergo a superimposed severe alcoholic hepatitis. AIM: Our aim was to evaluate renal dysfunction established as a consequence of acute liver damage (ALD) induced by bile duct ligation (BDL) in cirrhotic rats. Hepatic and renal functional assays were performed. RESULTS: Hyperbilirubinemia and increased alanine aminotransferase and aspartate aminotransferase (p<0.05) in rats with BDL were observed since the first day of bile obstruction in cirrhotic rats. Urinary volume and urinary sodium concentration showed a significant reduction (p<0.05) on days 3 and 5 after BDL. Plasma renin activity, plasma renin concentration, serum creatinine, and BUN values increased (p<0.05) from day 1 to day 7 after BDL. Glomerular filtration rate was substantially decreased from day 1 to day 7. Histological changes became apparent since day 3 after BDL in which glomeruli with mesangial hypercellularity took place in the absence of tubular necrosis; with portal inflammation and proliferation of biliar conduits. Results of the present work demonstrate that ALD induced by BDL in cirrhotic rats produces changes in renal function. In conclusion, this experimental model demonstrates that an ALD of variable etiology, either surgical or induced by CCl(4), can cause important damage that eventually results in renal function deterioration. This experimental model may be suitable, to study the physiopathology of this syndrome, as well as for the evaluation of different pharmacological therapies.


Asunto(s)
Síndrome Hepatorrenal/etiología , Cirrosis Hepática Experimental/complicaciones , Animales , Conductos Biliares , Presión Sanguínea , Tetracloruro de Carbono/toxicidad , Síndrome Hepatorrenal/patología , Riñón/patología , Riñón/fisiopatología , Ligadura , Hígado/patología , Hígado/fisiopatología , Masculino , Óxido Nítrico Sintasa de Tipo II/análisis , Ratas , Ratas Wistar
9.
Exp Toxicol Pathol ; 56(4-5): 291-303, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15816358

RESUMEN

In this study, we evaluated the effect of prostaglandin E2 (PGE2) on renal and hepatic function using an experimental cirrhosis model plus acute liver damage (ALD). Male Wistar rats treated with carbon tetrachloride (CCl4) for 8 weeks were used for the cirrhosis model. Cirrhotic rats were further exposed to an additional acute dose of CCl4 to induce ALD and then treated with PGE2 intramuscularly twice a day for 7 days (200 microg/Kg/day). PGE2 administration started 3 h after the additional dosing of CCl4 and PGE2 effect on hepatorenal function was examined on days 1, 2, 3, and 7. PGE2-treatment ameliorated the decrease in urinary sodium excretion, and normalized serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and plasma renin observed in cirrhotic rats with ALD. In addition, PGE2-treatment decreased mean arterial pressure, glomerular hypercellularity and thickening of the kidney capillary wall, and liver steatosis and cellular necrosis. Also, PGE2 increased the number of regenerative nodules. Finally, PGE2-treatment inhibited the increase in Alpha 1-acid glycoprotein (pAGP), fibrinogen, and Apo A-1 mRNA expression by 83%, 59%, and 77%, respectively. These results suggest that PGE2 administration may decrease the expression of acute phase proteins. In conclusion, PGE2-treatment improved hepatic and renal function and may be useful to down-regulate the acute phase response in cirrhotic rats presenting ALD induced by CCl4.


Asunto(s)
Proteínas de Fase Aguda/efectos de los fármacos , Dinoprostona/farmacología , Cirrosis Hepática Experimental/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Renina/efectos de los fármacos , Proteínas de Fase Aguda/biosíntesis , Animales , Northern Blotting , Tetracloruro de Carbono/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Expresión Génica/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/patología , Hepatopatías/patología , Masculino , Ratas , Ratas Wistar , Renina/sangre
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