200 research outputs found
Insulin-like growth factor I (IGF-I) and liver cirrhosis
Insulin-like growth factor I (IGF-I) is a polypeptide hormone secreted
by multiple tissues in response to growth hormone (GH). It
is partly responsible for GH activity, and also has glucose-lowering
and anabolizing effects. Ninety percent of circulating IGF-I originates
in the liver and has autocrine, paracrine, and endocrine effects,
the latter on multiple tissues. Liver cirrhosis results in a progressive
decline of hepatic IGF-I output, and this factor may
become undetectable in advanced disease. Some cirrhosis complications,
mainly those nutritional and metabolic in nature (insuline
resistance, malnutrition, osteopenia, hypogonadism, intestinal disorders),
may be at least partly related to this IGF-I deficiency, since
some IGF-I effects represent a reverse image of cirrhosis complications.
Despite this, IGF-I replacement therapy has been never
suggested for cirrhosis. A number of experimental studies in cirrhotic
rats showed that therapy using low-dose recombinant IGF-I
exerts two types of effect on experimental cirrhosis: a) liver improvement
driven by improved hepatocellular function, portal hypertension,
and liver fibrosis; and b) cirrhosis-related extrahepatic disorder
improvement driven by improved food efficiency, muscle
mass, bone mass, gonadal function and structure, and intestinal
function and structure, with a normalization of sugar and amino
acid malabsorption, and improved intstinal barrier function, manifested
by reduced endotoxemia and bacterial translocation. Subsequently,
the first randomized, double-blind, placebo-controlled, pilot
clinical trial in a small number of cirrhotic patients showed
increased serum albumin and improved energy metabolism as a
result of IGF-I use. Further clinical trials are needed to identify adequate
IGF-I doses, administration duration and frequency, and the
subgroup of cirrhotic patients who will benefit most from this replacement
therapy
COVIDâ19 mitigation by digital contact tracing and contact prevention (appâbased social exposure warnings)
A plethora of measures are being combined in the attempt to reduce SARS-CoV-2 spread. Due to its sustainability, contact tracing is one of the most frequently applied interventions worldwide, albeit with mixed results. We evaluate the performance of digital contact tracing for different infection detection rates and response time delays. We also introduce and analyze a novel strategy we call contact prevention, which emits high exposure warnings to smartphone users according to Bluetooth-based contact counting. We model the effect of both strategies on transmission dynamics in SERIA, an agent-based simulation platform that implements population-dependent statistical distributions. Results show that contact prevention remains effective in scenarios with high diagnostic/response time delays and low infection detection rates, which greatly impair the effect of traditional contact tracing strategies. Contact prevention could play a significant role in pandemic mitigation, especially in developing countries where diagnostic and tracing capabilities are inadequate. Contact prevention could thus sustainably reduce the propagation of respiratory viruses while relying on available technology, respecting data privacy, and most importantly, promoting community-based awareness and social responsibility. Depending on infection detection and app adoption rates, applying a combination of digital contact tracing and contact prevention could reduce pandemic-related mortality by 20â56%.publishedVersionFil: Soldano, GermĂĄn J. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina.Fil: Soldano, GermĂĄn J. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Investigaciones en FĂsico-quĂmica de CĂłrdoba; Argentina.Fil: Fraire Juan A. Universidad Nacional de CĂłrdoba. Facultad de Ciencias Exactas, FĂsicas y Naturales; Argentina.Fil: Fraire Juan A. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Estudios Avanzados en ingenierĂa y TecnologĂa; Argentina.Fil: Fraire Juan A. Saarland University. Saarland Informatics Campus; SaarbrĂŒcken, Germany.Fil: Finochietto, Jorge M. Universidad Nacional de CĂłrdoba. Facultad de Ciencias Exactas, FĂsicas y Naturales; Argentina.Fil: Finochietto, Jorge M. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Estudios Avanzados en ingenierĂa y TecnologĂa; Argentina.Fil: Quiroga; Rodrigo. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina.Fil: Quiroga; Rodrigo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Investigaciones en FĂsico-quĂmica de CĂłrdoba; Argentina
Trasplante hepĂĄtico
Liver transplantation is an efficient therapeutic
option for terminal hepatic diseases. The principal
indications of liver transplantation are hepatic cirrhosis,
hepatic tumours (mainly, hepotocellular carcinoma)
and acute liver failure. Over the years, the
absolute contraindications for a transplant have lessened.
Surgical techniques have also undergone
changes. The results of liver transplant have improved
so that survival one year after the transplant is close to
90% and after five years some 80% of transplanted
patients continue to live
S-adenosyl-L-methionine protects the liver against the cholestatic, cytotoxic, and vasoactive effects of leukotriene D4: a study with isolated and perfused rat liver
Cysteinyl-leukotrienes can cause cholestasis and liver damage when administered at nanomolar concentrations. Using the isolated and perfused rat liver we analyzed whether S-adenosyl-L-methionine (SAMe) may protect this organ against the noxious effects of leukotriene-D4 (LTD4). We observed that a 2 nmol bolus of this compound decreased bile flow (-12.6% +/- 1.6%, P < .02), and bile salt excretion (-23.5% +/- 2.2%, P < .02; both compared with baseline values), caused the release of glutamic-oxaloacetic transaminase (GOT) and lactic dehydrogenase (LDH) to the hepatic effluent, and increased significantly the perfusion pressure as compared with a control group not receiving LTD4 (6.0 +/- 1.1 vs. 0.2 +/- 0.02 mm hg, respectively; P < .001). The cholestatic effect of LTD4 was attenuated by infusion of SAMe which, at rates of 67 and 100 microg/min, totally prevented the decrease in bile salt excretion. Likewise, in SAMe infused livers, the release to the effluent of GOT and LDH was lower than in the group receiving LTD4 only, and was even lower than in the control group. We also found that the increase in perfusion pressure induced by LTD4 was prevented by SAMe in a dose-dependent manner. Of interest, SAMe increased the biliary excretion of the eicosanoid in a dose-related fashion. We conclude that SAMe reverts the cholestatic, cytotoxic, and hemodynamic effects of LTD4 on the liver, and that these protective effects might be partly because of a stimulation of the biliary excretion of the leukotriene
The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-ÎșB and TGFÎČ pathways in hepatic stellate cells
Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture
with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic
insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the
deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver
cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic
patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate
cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit
a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of
DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits
fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks
TGFÎČ and NF-ÎșB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and
inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression,
leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion
of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs
targeting NF-ÎșB and TGFÎČ pathways and inducing ADPR expression and quiescence in these cells
Zanthosimuline and Related Pyranoquinolines as Antifungal Agents for Postharvest Fruit Disease Control
The natural product zanthosimuline and its 18 analogues were easily prepared from simple starting materials and evaluated in vitro against postharvest fruit fungal pathogens. The panel included Penicillium digitatum, Botrytis cinerea, Monilinia fructicola, and Rhizopus stolonifer; all of them causing relevant economic losses worldwide. The minimum inhibitory concentrations and minimum fungicidal concentrations of each compound were determined, and the main structure?activity relationships were established. The biological activity observed was strongly increased by maintaining the prenyl side chain of zanthosimuline in an N-demethylated derivative. In addition, the compound that is the most active in the in vitro evaluation was tested in freshly harvested peaches exhibiting a promising brown rot control profile, comparable to the commercial agent carbendazim but demonstrating less toxicity against human liver cell lines.Fil: Di Liberto, Melina Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de QuĂmica OrgĂĄnica. Ărea Farmacognosia; ArgentinaFil: Caldo, AgustĂn J.. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Quiroga, Ariel Dario. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de FisiologĂa Experimental. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de FisiologĂa Experimental; ArgentinaFil: Riveira, MartĂn Jorge. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Derita, Marcos Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de QuĂmica OrgĂĄnica. Ărea Farmacognosia; Argentin
Influence of tumor characteristics on the outcome of liver transplantation among
Hepatocellular carcinoma (HCC) may recur after liver transplantation (LT), mainly
in patients with multinodular and large tumors. However, factors predictive of
outcome after LT in patients with small tumors remain ill defined. We
investigated which factors were related to mortality or tumor recurrence among 47
liver transplant recipients with liver cirrhosis and HCC and compared them with
107 patients with liver cirrhosis without tumor who underwent LT in the same
period. Patients with HCC were older (P <.001), more frequently had cirrhosis of
a viral origin (P <.001), and had lower Child-Pugh scores (P <.001) than patients
without tumor. Survival of patients with and without tumor was not significantly
different (P =.20). Among patients with HCC, those with lower recurrence-free
survival rates had liver cirrhosis of a viral origin, vascular invasion, bilobar
disease, and tumor-node-metastasis (TNM) stage IV. At multivariate analysis, the
only factor associated with mortality or recurrence was TNM stage IV (P =.02).
Our results suggest that in patients with HCC and TNM stage IV, LT might be
contraindicate
Taurocholate-stimulated leukotriene C4 biosynthesis and leukotriene C4-stimulated choleresis in isolated rat liver
BACKGROUND/AIMS: Cysteinyl-containing leukotrienes seem to exert a cholestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for leukotrienes in bile flow formation.
METHODS: In the isolated rat liver, the effects of two different concentrations of leukotriene C4 on bile flow and bile salt excretion are analyzed, as well as the possible effect of taurocholate on the hepatic production of cysteinyl-containing leukotrienes.
RESULTS: Leukotriene C4 (0.25 fmol) increased bile salt excretion (+22.2%; P < 0.05), whereas a much higher dose (0.25 x 10(6) fmol) showed the known cholestatic effect, reducing bile salt excretion (-25.9%; P < 0.01). These dose-dependent biphasic effects were specific because they could be prevented by the simultaneous administration of cysteinyl-containing leukotriene antagonists. On the other hand, taurocholate administration induced a dose-dependent increase in biliary excretion of cysteinyl-containing leukotrienes. Furthermore, taurocholate increased messenger RNA levels of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Taurocholate increase of hepatocyte intracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism.
CONCLUSIONS: These results constitute evidence for the existence of a positive feedback mechanism by which bile salts stimulate the synthesis of leukotrienes that, in turn, stimulate bile salt excretion
Herpes Zoster After Liver Transplantation: Incidence, Risk Factors, and Complications
Herpes zoster is the consequence of the reactivation of latent varicella-zoster
infection. Immunosuppression may be a predisposing factor for herpes zoster. We
have retrospectively assessed the risk of herpes zoster, the risk factors for its
occurrence, and its evolution in a population of 209 consecutive liver transplant
recipients. Herpes zoster developed in 25 (12%) of patients. One-, 3-, 5-, and
10-year actuarial rates of herpes zoster were 3%, 10%, 14%, and 18%,
respectively. In a case-control study, patients developing herpes zoster were
younger, received a higher number of immunosuppressive drugs, and were more
frequently receiving mycophenolate mofetil or azathioprine. In multivariate
analysis, the only factor related to herpes zoster occurrence was treatment with
mycophenolate mofetil or azathioprine. Eight patients (31%) developed
postherpetic neuralgia. In conclusion, herpes zoster is a relatively common
complication after liver transplantation. It is related to immunosuppressive
therapy. Postherpetic neuralgia develops in one third of patients with
posttransplant herpes zoster
Conversion From Calcineurin Inhibitors to Mycophenolate Mofetil in Liver Transplant Recipients With Diabetes Mellitus
Diabetes mellitus, a frequent metabolic complication in liver transplant
recipients, may be produced by the diabetogenic effect of calcineurin inhibitors
cyclosporine and tacrolimus. The aim of this study was to investigate the safety
and metabolic effects of a gradual switch from cyclosporine or tacrolimus to
mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient
was withdrawn from the study due to gastrointestinal side effects. Of the 11
remaining patients, cyclosporine or tacrolimus was completely withdrawn in five
patients. Two patients developed suspected acute rejection episodes that were
controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and
C-peptide levels were significantly lower at 3 and 6 months after the initiation
of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid
levels were significantly reduced after the change of treatment. In conclusion, a
switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce
beneficial metabolic effects in diabetic liver transplant recipients, but poses a
risk of graft rejection
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