RESUMEN

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Asunto(s)

ADP-Ribosil Ciclasa 1 , Linfocitos T CD4-Positivos , Infecciones por VIH , Humanos , ADP-Ribosil Ciclasa 1/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Jurkat , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Glicoproteínas de Membrana/metabolismo , Glucólisis , Mitocondrias/metabolismo

RESUMEN

Acetylcholinesterase is a well-known protein because of the relevance of its enzymatic activity in the hydrolysis of acetylcholine in nerve transmission. In addition to the catalytic action, it exerts non-catalytic functions; one is associated with apoptosis, in which acetylcholinesterase could significantly impact the survival and aggressiveness observed in cancer. The participation of AChE as part of the apoptosome could explain the role in tumors, since a lower AChE content would increase cell survival due to poor apoptosome assembly. Likewise, the high Ach content caused by the reduction in enzymatic activity could induce cell survival mediated by the overactivation of acetylcholine receptors (AChR) that activate anti-apoptotic pathways. On the other hand, in tumors in which high enzymatic activity has been observed, AChE could be playing a different role in the aggressiveness of cancer; in this review, we propose that AChE could have a pro-inflammatory role, since the high enzyme content would cause a decrease in ACh, which has also been shown to have anti-inflammatory properties, as discussed in this review. In this review, we analyze the changes that the enzyme could display in different tumors and consider the different levels of regulation that the acetylcholinesterase undergoes in the control of epigenetic changes in the mRNA expression and changes in the enzymatic activity and its molecular forms. We focused on explaining the relationship between acetylcholinesterase expression and its activity in the biology of various tumors. We present up-to-date knowledge regarding this fascinating enzyme that is positioned as a remarkable target for cancer treatment.

RESUMEN

CTCF is an architectonic protein that organizes the genome inside the nucleus in almost all eukaryotic cells. There is evidence that CTCF plays a critical role during spermatogenesis as its depletion produces abnormal sperm and infertility. However, defects produced by its depletion throughout spermatogenesis have not been fully characterized. In this work, we performed single cell RNA sequencing in spermatogenic cells with and without CTCF. We uncovered defects in transcriptional programs that explain the severity of the damage in the produced sperm. In the early stages of spermatogenesis, transcriptional alterations are mild. As germ cells go through the specialization stage or spermiogenesis, transcriptional profiles become more altered. We found morphology defects in spermatids that support the alterations in their transcriptional profiles. Altogether, our study sheds light on the contribution of CTCF to the phenotype of male gametes and provides a fundamental description of its role at different stages of spermiogenesis.

RESUMEN

Alcohol-induced pancreas damage remains as one of the main risk factors for pancreatitis development. This disorder is poorly understood, particularly the effect of acetaldehyde, the primary alcohol metabolite, in the endocrine pancreas. Hepatocyte growth factor (HGF) is a protective protein in many tissues, displaying antioxidant, antiapoptotic, and proliferative responses. In the present work, we were focused on characterizing the response induced by HGF and its protective mechanism in the RINm5F pancreatic cell line treated with ethanol and acetaldehyde. RINm5F cells were treated with ethanol or acetaldehyde for 12 h in the presence or not of HGF (50 ng/ml). Cells under HGF treatment decreased the content of reactive oxygen species and lipid peroxidation induced by both toxics, improving cell viability. This effect was correlated to an improvement in insulin expression impaired by ethanol and acetaldehyde. Using a specific inhibitor of Erk1/2 abrogated the effects elicited by the growth factor. In conclusion, the work provides mechanistic evidence of the HGF-induced-protective response to the alcohol-induced damage in the main cellular component of the endocrine pancreas.

Asunto(s)

Acetaldehído , Etanol , Acetaldehído/toxicidad , Acetaldehído/metabolismo , Línea Celular , Etanol/toxicidad , Factor de Crecimiento de Hepatocito , Páncreas/metabolismo , Sistema de Señalización de MAP Quinasas

RESUMEN

Hepatocyte growth factor (HGF) has been proved to protect the liver against α-naphthylisothiocyanate (ANIT)-induced cholestasis by acting as an antioxidant agent and redirecting toxic biliary solutes towards blood for urinary excretion. However, this may represent an additional potential risk for kidney integrity, which is already compromised by the cholestatic process itself (cholemic nephropathy). Therefore, in the present work, we studied the renal damage caused by ANIT-induced cholestasis and whether it is aggravated or, on the contrary, counteracted by HGF; if the latter holds, the involvement of its antioxidant properties will be ascertained. ANIT-induced cholestatic deleterious renal effects were corroborated by the presence of urine bile salts, impairment of renal function, and the alterations of renal damage markers, such as HSP72, creatinine clearance, and albuminuria. HGF fully reverted all these, and the cast formation in the tubules was significantly decreased. These findings were associated with the control of renal oxidative stress. In summary, despite HGF enhancing the overload of potentially harmful biliary constituents that the kidney should remove from the bloodstream as an alternative depuration organ in cholestasis, it simultaneously protects the kidney from this damage by counteracting the prooxidant effects resulting from this harmful exposure.

Asunto(s)

Colestasis/tratamiento farmacológico , Factor de Crecimiento de Hepatocito/farmacología , Enfermedades Renales/fisiopatología , 1-Naftilisotiocianato/efectos adversos , 1-Naftilisotiocianato/farmacología , Animales , Antioxidantes/farmacología , Ácidos y Sales Biliares/metabolismo , Conductos Biliares/fisiopatología , Colestasis/sangre , Colestasis/metabolismo , Modelos Animales de Enfermedad , Factor de Crecimiento de Hepatocito/metabolismo , Riñón/metabolismo , Enfermedades Renales/metabolismo , Hígado/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

ZO-2 is a peripheral tight junction (TJ) protein whose silencing in renal epithelia induces cell hypertrophy. Here, we found that in ZO-2 KD MDCK cells, in compensatory renal hypertrophy triggered in rats by a unilateral nephrectomy and in liver steatosis of obese Zucker (OZ) rats, ZO-2 silencing is accompanied by the diminished activity of LATS, a kinase of the Hippo pathway, and the nuclear concentration of YAP, the final effector of this signaling route. ZO-2 appears to function as a scaffold for the Hippo pathway as it associates to LATS1. ZO-2 silencing in hypertrophic tissue is due to a diminished abundance of ZO-2 mRNA, and the Sp1 transcription factor is critical for ZO-2 transcription in renal cells. Treatment of OZ rats with metformin, an activator of AMPK that blocks JNK activity, augments ZO-2 and claudin-1 expression in the liver, reduces the paracellular permeability of hepatocytes, and serum bile acid content. Our results suggest that ZO-2 silencing is a common feature of hypertrophy, and that ZO-2 is a positive regulator of the Hippo pathway that regulates cell size. Moreover, our observations highlight the importance of AMPK, JNK, and ZO-2 as therapeutic targets for blood-bile barrier dysfunction.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Hígado Graso , Proteína de la Zonula Occludens-2/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Vía de Señalización Hippo , Hipertrofia , Ratas , Ratas Zucker , Proteínas de Uniones Estrechas

RESUMEN

The mechanism of damage of the biliary epithelium remains partially unexplored. However, recently many works have offered new evidence regarding the cholangiocytes' damage process, which is the main target in a broad spectrum of pathologies ranging from acute cholestasis, cholangiopathies to cholangiocarcinoma. This is encouraging since some works addressed this epithelium's relevance in health and disease until a few years ago. The biliary tree in the liver, comprised of cholangiocytes, is a pipeline for bile flow and regulates key hepatic processes such as proliferation, regeneration, immune response, and signaling. This review aimed to compile the most recent advances on the mechanisms of cholangiocellular damage during cholestasis, which, although it is present in many cholangiopathies, is not necessarily a common or conserved process in all of them, having a relevant role cAMP and PKA during obstructive cholestasis, as well as Ca2+-dependent PKC in functional cholestasis. Cholangiocellular damage could vary according to the type of cholestasis, the aggressor, or the bile ducts' location where it develops and what kind of damage can favor cholangiocellular carcinoma development.

Asunto(s)

Procedimientos Quirúrgicos del Sistema Biliar/efectos adversos , Sistema Biliar/patología , Colestasis/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Animales , Sistema Biliar/metabolismo , Proliferación Celular , Colestasis/metabolismo , Colestasis/cirugía , Humanos , Ligadura , Transducción de Señal

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a; Fabp5; Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis.

RESUMEN

INTRODUCTION AND OBJECTIVES: It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. MATERIALS AND METHODS: Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. RESULTS: Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. CONCLUSION: Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.

Asunto(s)

Grupo Citocromo b/fisiología , Factor de Crecimiento de Hepatocito/fisiología , Hepatocitos/metabolismo , NADPH Oxidasas/fisiología , Proteínas Proto-Oncogénicas c-met/fisiología , Transducción de Señal/fisiología , Animales , Técnicas de Cultivo de Célula , Hepatocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Biosíntesis de Proteínas , Transcripción Genética

RESUMEN

Cholestasis is a clinical syndrome common to a large number of hepatopathies, in which either bile production or its transit through the biliary tract is impaired due to functional or obstructive causes; the consequent intracellular retention of toxic biliary constituents generates parenchyma damage, largely via oxidative stress-mediated mechanisms. Hepatocyte growth factor (HGF) and its receptor c-Met represent one of the main systems for liver repair damage and defense against hepatotoxic factors, leading to an antioxidant and repair response. In this study, we evaluated the capability of HGF to counteract the damage caused by the model cholestatic agent, α-naphthyl isothiocyanate (ANIT). HGF had clear anti-cholestatic effects, as apparent from the improvement in both bile flow and liver function test. Histology examination revealed a significant reduction of injured areas. HGF also preserved the tight-junctional structure. These anticholestatic effects were associated with the induction of basolateral efflux ABC transporters, which facilitates extrusion of toxic biliary compounds and its further alternative depuration via urine. The biliary epithelium seems to have been also preserved, as suggested by normalization in serum GGT levels, CFTR expression and cholangyocyte primary cilium structure our results clearly show for the first time that HGF protects the liver from a cholestatic injury.

Asunto(s)

1-Naftilisotiocianato/toxicidad , Colestasis Intrahepática/inducido químicamente , Colestasis Intrahepática/prevención & control , Factor de Crecimiento de Hepatocito/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Animales , Colestasis Intrahepática/patología , Factor de Crecimiento de Hepatocito/farmacología , Masculino , Ratones , Estrés Oxidativo/fisiología

RESUMEN

Tuberculosis (TB) is one of the deadliest infectious diseases in humankind history. Although, drug sensible TB is slowly decreasing, at present the rise of TB cases produced by multidrug-resistant (MDR) and extensively drug-resistant strains is a big challenge. Thus, looking for new therapeutic options against these MDR strains is mandatory. In the present work, we studied, in BALB/c mice infected with MDR strain, the therapeutic effect of supra-pharmacological doses of the conventional primary antibiotics rifampicin and isoniazid (administrated by gavage or intratracheal routes), in combination with recombinant human hepatocyte growth factor (HGF). This high dose of antibiotics administered for 3 months, overcome the resistant threshold of the MDR strain producing a significant reduction of pulmonary bacillary loads but induced liver damage, which was totally prevented by the administration of HGF. To address the long-term efficiency of this combined treatment, groups of animals after 1 month of treatment termination were immunosuppressed by glucocorticoid administration and, after 1 month, mice were euthanized, and the bacillary load was determined in lungs. In comparison with animals treated only with a high dose of antibiotics, animals that received the combined treatment showed significantly lower bacterial burdens. Thus, treatment of MDR-TB with very high doses of primary antibiotics particularly administrated by aerial route can produce a very good therapeutic effect, and its hepatic toxicity can be prevented by the administration of HGF, becoming in a new treatment modality for MDR-TB.

Asunto(s)

Antibióticos Antituberculosos/toxicidad , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Factor de Crecimiento de Hepatocito/farmacología , Tuberculosis Resistente a Múltiples Medicamentos , Animales , Quimioterapia Combinada , Humanos , Isoniazida/toxicidad , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis , Rifampin/toxicidad

RESUMEN

Osteoarthritis (OA) is the gradual loss of articular cartilage and decrease in subchondral space. One of the risk factors Exposure to cadmium (Cd) through tobacco smoke has been identified as a major OA risk factor. There are no reports addressing the role of Cd in OA progression at the molecular level. Our findings revealed that Cd can promote the activation of metalloproteinases (MMP1, MMP3, MMP9 y MMP13), affecting the expression of COL2A1 and ACAN, and decreasing the presence of glycosaminoglycans and proteoglycans through an inflammatory response related to IL-1ß y a IL-6, as well as oxidative by producing ROS like O2-• and H2O2. In conclusion, our findings suggest a cytotoxic role of Cd in the articular cartilage, which could affect OA development.

Asunto(s)

Cadmio/toxicidad , Cartílago Articular/efectos de los fármacos , Sustancias Peligrosas/toxicidad , Osteoartritis , Animales , Humanos , Interleucina-1beta , Metaloproteasas

RESUMEN

Growth Differentiation Factor 11 (GDF11), a member of the super family of the Transforming Growth Factor ß, has gained more attention in the last few years due to numerous reports regarding its functions in other systems, which are different to those related to differentiation and embryonic development, such as age-related muscle dysfunction, skin biology, metabolism, and cancer. GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina, among others. GDF11 circulating levels and protein content in tissues are quite variable and are affected by pathological conditions or age. Although, GDF11 biology had a lot of controversies, must of them are only misunderstandings regarding the variability of its responses, which are independent of the tissue, grade of cellular differentiation or pathologies. A blunt fact regarding GDF11 biology is that its target cells have stemness feature, a property that could be found in certain adult cells in health and in disease, such as cancer cells. This review is focused to present and analyze the recent findings in the emerging research field of GDF11 function in cancer and metabolism, and discusses the controversies surrounding the biology of this atypical growth factor.

RESUMEN

INTRODUCTION/OBJECTIVES: Articular cartilage is the target tissue of osteoarthritis (OA), and because it lacks capillary networks, the microenvironment is hypoxic. Hypoxia inducible factor-1 alpha (HIF-1α) regulates the homeostasis of this tissue. The aim of this study was to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. METHOD: We performed a case-control association study and genotyped 134 knee OA patients and 267 healthy controls. All participants were genotyped in order to evaluate 42 SNPs from 22 genes involved in the HIF-1α signaling pathway using the OpenArray technology. Gene-gene interactions (epistasis) were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: The MDR analysis showed epistasis between AKT2 (rs8100018) and IGF1 (rs2288377), AKT2 (rs8100018) and IGF1 (rs35767), IGF1 (rs35767) and COL2A1 (rs1793953), and between GSK3B (rs6438552) and IGF1 (rs35767) polymorphisms, with information gain values of 21.24%, 8.37%, 9.93%, and 5.73%, respectively. Additionally, our model allowed us to identify high- and low-risk genotypes among COL2A1 rs1793953, GSK3B rs6438552, AKT2 rs8100018, and IGF1 rs35767 polymorphisms. CONCLUSIONS: Knowing the interactions of these polymorphisms involved in HIF-1α signaling pathway could provide a new diagnostic support tool to identify individuals at high risk of developing knee OA.

Asunto(s)

Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/fisiopatología , Polimorfismo de Nucleótido Simple , Transducción de Señal , Adulto , Capilares/patología , Estudios de Casos y Controles , Colágeno Tipo II/genética , Epistasis Genética , Femenino , Genotipo , Glucógeno Sintasa Quinasa 3 beta/genética , Haplotipos , Homeostasis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , México , Persona de Mediana Edad , Modelos Genéticos , Proteínas Proto-Oncogénicas c-akt/genética , Riesgo

RESUMEN

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features, despite some controversies in age-related studies. GDF11 has been poorly investigated in cancer, particularly in those with stemness capacity, such as hepatocellular carcinoma (HCC), one of the most aggressive cancers worldwide. Here, we focused on investigating the effects of GDF11 in liver cancer cells. GDF11 treatment significantly reduced proliferation, colony and spheroid formation in HCC cell lines. Consistently, down-regulation of CDK6, cyclin D1, cyclin A, and concomitant upregulation of p27 was observed after 24 h of treatment. Interestingly, cell viability was unchanged, but cell functionality was compromised. These effects were potentially induced by the expression of E-cadherin and occludin, as well as Snail and N-cadherin repression, in a time-dependent manner. Furthermore, GDF11 treatment for 72 h induced that cells were incapable of sustaining colony and sphere capacity in the absent of GDF11, up to 5 days, indicating that the effect of GDF11 on self-renewal capacity is not transient. Finally, in vivo invasion studies revealed a significant decrease in cell migration of hepatocellular carcinoma cells treated with GDF11 associated to a decreased proliferation judged by Ki67 staining. Data show that exogenous GDF11 displays tumor suppressor properties in HCC cells.

Asunto(s)

Proteínas Morfogenéticas Óseas/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Factores de Diferenciación de Crecimiento/farmacología , Neovascularización Patológica/prevención & control , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Ciclina A/genética , Ciclina A/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Factores de Diferenciación de Crecimiento/genética , Factores de Diferenciación de Crecimiento/metabolismo , Células Hep G2 , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ocludina/genética , Ocludina/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología

RESUMEN

Among hepatic diseases, cholestatic ductopenic cholangiopathies are poorly studied, and they are rarely given the importance they deserve, especially considering their high incidence in clinical practice. Although cholestatic ductopenic cholangiopathies have different etiologies and pathogenesis, all have the same target (the cholangiocyte) and similar mechanistic basis of cell death. Cholestatic cholangiopathies are characterized, predominantly, by obstructive or functional damage in the biliary epithelium, resulting in an imbalance between proliferation and cholangiocellular death; this leads to the progressive disappearance of bile ducts, as has been shown to occur in primary sclerosing cholangitis, primary biliary cholangitis, low-phospholipid-associated cholelithiasis syndrome, cystic fibrosis-related liver disease, and drug-induced ductopenia, among other biliary disorders. This review summarizes the features of the more common ductopenic syndromes and the cellular mechanisms involved in cholengiocellular death, with focus on the main forms of cholangiocyte death described so far, namely apoptosis, autophagy, necrosis, and necroptosis. It also emphasizes the importance to study in depth the molecular mechanisms of cholengiocyte death to make possible to counteract them with therapeutic purposes. These therapeutic strategies are limited in number and efficacy at present, and this is why it is important to find complementary, safe strategies to stimulate cholangiocellular proliferation in order favor bile duct replenishment as well. Successful in finding appropriate treatments would prevent the patient from having liver transplantation as the only therapeutic alternative.

Asunto(s)

Apoptosis , Enfermedades de los Conductos Biliares/tratamiento farmacológico , Enfermedades de los Conductos Biliares/patología , Colagogos y Coleréticos/uso terapéutico , Animales , Humanos

RESUMEN

Dibutyl phthalate (DBP) is a plasticizer, whose presence in the environment as a pollutant has attained a great deal of attention due to its reported association with endocrine system disturbances on animals. Growth parameters, glucose uptake, percentage of removal efficiency (%E) of DBP, biodegradation constant of DBP (k) and half-life of DBP biodegradation (t1/2) were evaluated for Pleurotus ostreatus grown on media containing glucose and different concentrations of DBP (0, 500 and 1000 mg l-1). P. ostreatus degraded 99.6 % and 94 % of 500 and 1000 mg of DBP l-1 after 312 h and 504 h, respectively. The k was 0.0155 h-1 and 0.0043 h-1 for 500 and 1000 mg of DBP l-1, respectively. t1/2 was 44.7 h and 161 h for 500 and 1000 mg of DBP l-1, respectively. Intermediate compounds of biodegraded DBP were identified by GC-MS and a DBP biodegradation pathway was proposed using quantum chemical calculation. DBP might be metabolized to benzene and acetyl acetate, the first would be oxidated to muconic acid and the latter would enter into the Krebs cycle. P. ostreatus has the ability to degrade DBP and utilizes it as source of carbon and energy.

Asunto(s)

Dibutil Ftalato/metabolismo , Contaminantes Ambientales/metabolismo , Pleurotus/metabolismo , Biodegradación Ambiental , Pleurotus/crecimiento & desarrollo

RESUMEN

Acute pancreatitis is a multifactorial disease associated with profound changes of the pancreas induced by release of digestive enzymes that lead to increase in proinflammatory cytokine production, excessive tissue necrosis, edema, and bleeding. Elevated levels of hepatocyte growth factor (HGF) and its receptor c-Met have been observed in different chronic and acute pancreatic diseases including experimental models of acute pancreatitis. In the present study, we investigated the protective effects induced by the recombinant human HGF in a mouse model of cerulein-induced acute pancreatitis. Pancreatitis was induced by 8 hourly administrations of supramaximal cerulein injections (50 µg/kg, ip). HGF treatment (20 µg/kg, iv), significantly attenuated lipase content and amylase activity in serum as well as the degree inflammation and edema overall leading to less severe histologic changes such as necrosis, induced by cerulein. Protective effects of HGF were associated with activation of pro-survival pathways such as Akt, Erk1/2, and Nrf2 and increase in executor survival-related proteins and decrease in pro-apoptotic proteins. In addition, ROS content and lipid peroxidation were diminished, and glutathione synthesis increased in pancreas. Systemic protection was observed by lung histology. In conclusion, our data indicate that HGF exerts an Nrf2 and glutathione-mediated protective effect on acute pancreatitis reflected by a reduction in inflammation, edema, and oxidative stress.

Asunto(s)

Factor de Crecimiento de Hepatocito/uso terapéutico , Pancreatitis/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Ceruletida , Modelos Animales de Enfermedad , Glutatión/biosíntesis , Factor de Crecimiento de Hepatocito/sangre , Factor de Crecimiento de Hepatocito/farmacología , Humanos , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Pancreatitis/patología , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia

RESUMEN

Dibutyl phthalate (DBP) is a widely used plasticizer, whose presence in the environment as a pollutant raises concern because of its endocrine-disrupting toxicity. Growth kinetics, glucose uptake, biodegradation constant of DBP (k), half-life of DBP biodegradation (t1/2) and percentage of removal efficiency (%E) were evaluated for Fusarium culmorum grown on media containing glucose and different concentrations of DBP (500 and 1000 mg/l). Intermediate compounds of biodegraded DBP were identified by GC-MS and a novel DBP biodegradation pathway was proposed on the basis of the intermolecular flow of electrons of the intermediates identified using quantum chemical modeling. F. culmorum degraded 99% of both 1000 and 500 mg of DBP/l after an incubation period of 168 and 228 h, respectively. %E was 99.5 and 99.3 for 1000 and 500 mg of DBP/l, respectively. The k was 0.0164 and 0.0231 h-1 for 500 and 1000 mg of DBP/l, respectively. DBP was fully metabolized to fumaric and malic acids, which are compounds that enter into the Krebs cycle. F. culmorum has a promising ability for bioremediation of environments polluted with DBP because it efficiently degrades DBP and uses high concentrations of this compound as carbon and energy source.

RESUMEN

Di(2-ethyl hexyl) phthalate (DEHP) is a plasticizer that interfere with endocrine systems in mammals. Growth parameters for Pleurotus ostreatus grown on media containing glucose and different concentrations of DEHP (0, 500 and 1000mg/L) were evaluated. The highest biomass production was observed in medium supplemented with 1000mg of DEHP/L. Half-life of DEHP biodegradation, biodegradation constant of DEHP, and percentage of removal efficiency (%E) were also determined. P. ostreatus degraded 100% of DEHP after 504h. %E was 99.3% and 98.4% for 500 and 1000mg of DEHP/L, respectively. Intermediate compounds of biodegraded DEHP were identified by GC-MS and a DEHP biodegradation pathway was proposed using quantum chemical investigation. DEHP might be metabolized through three pathways; a de-esterification pathway, an oxidation pathway and an oxidation-hydrolysis pathway, forming phthalic acid, acetic acid and butanediol, respectively. P. ostreatus degrades and uses (as carbon and energy source) high concentrations of DEHP.

Asunto(s)

Dietilhexil Ftalato/análisis , Disruptores Endocrinos/análisis , Plastificantes/análisis , Pleurotus/metabolismo , Animales , Biodegradación Ambiental , Biomasa , Biotransformación , Dietilhexil Ftalato/metabolismo , Disruptores Endocrinos/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Semivida , Plastificantes/metabolismo , Pleurotus/crecimiento & desarrollo