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Introducción: el suicidio es responsable del 1,5% de las muertes mundiales, totalizando aproximadamente 800 000 muertes al año. Se estima que se convertirá en uno de los mayores contribuyentes a la carga mundial de morbilidad en las próximas 2 décadas. La formación clínica adecuada en el campo de la suicidología y la prevención de la conducta suicida resulta de especial relevancia en el contexto de la sala de internación de Psiquiatría. El presente estudio tiene como objetivo analizar los factores que contribuyen a la ideación y al comportamiento suicida en pacientes hospitalizados en la sala de internación de Psiquiatría de un hospital general universitario. Materiales y métodos: se realizó un estudio transversal de pacientes hospitalizados durante un año (octubre de 2018 a septiembre de 2019, n=254). Se examinaron las variables sociodemográficas, culturales y clínicas asociadas al suicidio. Resultados: el 39,4% de los pacientes que ingresaron en el período de estudio refería ideación suicida, el 13,4% un plan suicida y el 10,6% había presentado un intento de suicidio. Las mujeres tuvieron mayor chance de hospitalización debido a ideación suicida (OR=2,22, IC 95% [1,28-3,77]), plan suicida (OR=2,77, IC 95% [1,15-6,62]) e intento suicida (OR=3,12, IC 95% [1,13-8,47]). El 70% de los pacientes mayores de 65 años que tenían un plan suicida vivían solos, mientras que dicho porcentaje fue del 80% para quienes ingresaron luego de un intento de suicidio. Conclusiones: la mayor parte de los datos epidemiológicos en relación con la conducta suicida provienen de países desarrollados. Tratándose de un fenómeno de suma complejidad, creemos necesario incorporar al análisis aristas sociales, político-económicas, culturales y de género. La aplicación del método ideográfico podría brindar una herramienta útil para avanzar nuestro entendimiento en el campo de la suicidología, planteando un abordaje que se nutra de información tanto cuantitativa como cualitativa centrada en la persona, en un proceso iterativo que parta del individuo y luego busque elementos comunes contextualizados.

O experimento foi realizado no município de Vera Cruz (SP), no período de 1996 a 1998, com vistas em estudar a variabilidade espacial da taxa de infiltração de água em solo saturado e a espessura do horizonte A. O solo utilizado foi um Argissolo Vermelho-Amarelo eutrófico abrúptico, apresentando evidentes sinais de processos erosivos. As determinações de infiltração nos horizontes A, E e Bt, bem como da espessura do horizonte A, foram obtidas em malhas regulares de 40 x 40 m, com espaçamento de 5 x 5 m, totalizando 64 pontos, em café, pastagem e mata/capoeira. A análise das medidas de dispersão estatística revelou elevada variação das taxas de infiltração, bem como da espessura do horizonte A. Os semivariogramas indicaram a existência de dependência espacial da infiltração no horizonte E, em todos os usos amostrados. Com a utilização do semivario-grama cruzado, detectou-se a existência de correlação espacial entre a espessura do horizonte A e a infiltração, em cultivo de café e na mata/capoeira. A cobertura vegetal existente na mata/capoeira reduziu a perda do horizonte A, o que foi comprovado pela maior espessura e menor variação espacial.

Background: Compared to humans, colorectal polyps are relatively rare in dogs. Epidemiological and prognostic data remain accordingly sparse, although they could help veterinary clinicians in the management of these cases., Objectives: To report the epidemiological data of dogs with colorectal polyps and identify factors associated with recurrence and survival., Animals: Fifty-eight client-owned dogs with colorectal polyps admitted to 7 veterinary hospitals (53 dogs from France, 5 dogs from Spain, and 4 dogs from Portugal) were included., Methods: Retrospective multicentric cohort study. Medical records and long-term outcome of the dogs were reviewed. When available, histological samples were reassessed by 2 board-certified pathologists according to the revised Vienna classification (RVC)., Results: The West Highland White Terrier (WHWT) breed was significantly associated with the presence of colorectal polyps (OR: 20; 95% CI: 7.5-52; P < .001). The overall median time to recurrence was not reached after 2000 days. The overall estimated median survival time was 1640 days. WHWT breed and larger polyps were significantly associated with a shorter time of polyp recurrence after surgical removal (respectively, P = .05 and P = .01)., Conclusions and Clinical Importance: The probability of recurrence of colorectal polyps in dogs is low, but increased in WHWTs and larger polyps, which might benefit from routine screening after removal. No effective predictors of polyp recurrence and survival were identified using the RVC., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Chronic diarrhea is a clinical sign associated with canine leishmaniosis, varying from 3 % to 30 % of prevalence. However, its occurrence in dogs has been mostly associated with chronic kidney or liver disease. Leishmania organisms can cause inflammation of the digestive tract with chronic diarrhea as the only clinical manifestation, although it has been poorly documented in dogs. The aim of this retrospective observational study was to describe dogs with chronic diarrhea as the main clinical sign associated with leishmaniosis. All cases had a complete blood count, biochemistry, urinalyses, and diagnostic tests for leishmaniosis. Exclusion criteria included renal or hepatic disease and/or previous diagnosis of gastrointestinal disease. Twenty-three dogs were included. Small bowel diarrhea was present in 7/23 (30.4 %), large bowel diarrhea in 9/23 (39.2 %) and mixed diarrhea in 7/23 (30.4 %). Gastrointestinal biopsies were performed in 8/23 dogs and Leishmania amastigotes were found in all of them. In the others, leishmaniosis was diagnosed by serology in 10/15 dogs (66.7 %), serology plus blood PCR in 3/15 (20.0 %), lymph node cytology in 1/15 (6.7 %), and blood PCR in 1/15 (6.7 %). All dogs treated had a complete resolution of diarrhea with specific treatment for leishmaniosis alone, based on meglumine antimoniate (75-100 mg/kg SID SC for 1 month) plus allopurinol (10 mg/kg BID PO ≥ 6 months). This study suggests that leishmaniosis should be also included in the differential diagnosis of dogs from endemic areas presenting with the primary problem of large-bowel, small-bowel, or mixed-bowel chronic diarrhea., Competing Interests: Conflict of interest statement None of the authors has any other financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To review the clinical findings and outcome in dogs diagnosed with insulinoma, and to assess which factors are predictors of overall survival. Additionally, to describe the neurological manifestations of this population and their correlation with survival., Materials and Methods: Retrospective multicentric study of canine insulinoma cases (2009 to 2020). Signalment, clinical history, neurological examination, diagnostic findings, treatment and outcome were obtained from clinical records. Univariate and multivariate analyses were used to compare the overall survival., Results: One hundred and sixteen cases were included. Median duration of clinical signs before presentation was 1.5 months. The most common presenting clinical signs were weakness (59.5%), epileptic seizures (33.6%) and changes in consciousness or behaviour (27.6%). Three dogs were suspected to have paroxysmal dyskinesia. Thirty-two dogs had an abnormal neurological examination, most commonly showing obtundation (28.1%), decreased withdrawal reflexes (21.9%) and absent menace response (18.8%). Overall survival for dogs undergoing surgery (20 months) was significantly longer than in medically treated (8 months; adjusted hazard ratio: 0.33; 95% confidence interval: 0.18, 0.59). Presence of metastases was the only other variable associated with prognosis (adjusted hazard ratio 1.72; 95% confidence interval: 1.02, 2.91)., Clinical Significance: Clinical signs of canine insulinoma are vague and non-specific. Weakness, epileptic seizures and changes in mentation or behaviour were the most commonly reported. Obtunded mentation and forebrain neurolocalisation were the main neurological manifestations. Dogs undergoing surgery had a longer overall survival compared to medically treated cases, and dogs with metastasis had a shorter overall survival regardless of treatment modality. Abnormalities in the neurological examination did not correlate with prognosis., (© 2021 The Authors. Journal of Small Animal Practice published by John Wiley & Sons Ltd on behalf of British Small Animal Veterinary Association.)

Background: A demyelinating polyneuropathy with focally folded myelin sheaths was reported in 3 Miniature Schnauzers in France in 2008 and was predicted to represent a naturally occurring canine homologue of Charcot-Marie-Tooth (CMT) disease. A genetic variant of MTRM13/SBF2 has been identified as causative in affected Miniature Schnauzers with this polyneuropathy., Objective: To provide data on the long-term progression in affected Miniature Schnauzers from Spain confirmed with the MTRM13/SBF2 genetic variant., Animals: Twelve Miniature Schnauzers presented between March 2013 and June 2019., Methods: Only dogs presented with consistent clinical signs and homozygous for the MTRM13/SBF2 genetic variant were included. Clinical signs, age of onset and presentation, time from onset to presentation, treatment, outcome, and time from diagnosis to final follow-up were retrospectively reviewed., Results: The hallmark clinical signs at the time of presentation were regurgitation with radiologically confirmed megaesophagus (11/12) and aphonic bark (11/12) with or without obvious neuromuscular weakness despite electrodiagnostic evidence of appendicular demyelinating polyneuropathy. Age of onset and clinical presentation were 3-18 and 4-96 months, respectively. Treatment was mostly symptomatic and consisted of head elevation during meals, antacids, prokinetics, bethanechol, sildenafil, mirtazapine, or some combination of these. During the follow-up period (7-73 months), clinical signs were unchanged in (11/12) cases with aspiration pneumonia developing occasionally (6/12) and being the cause of death in 1 dog., Conclusions and Clinical Importance: Demyelinating polyneuropathy of Miniature Schnauzers tends to remain stable over the long term leading to a good prognosis with preventive feeding measures and symptomatic treatment to control aspiration pneumonia., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Brachycephalic dogs have unique upper respiratory anatomy with abnormal breathing patterns that are similar to those in humans with obstructive sleep apnea syndrome (OSAS). The objectives of this multicenter prospective study were to assess the effects of surgical correction on clinical signs in dogs with brachycephalic airway obstructive syndrome (BAOS) and to evaluate the levels of several biomarkers [C-reactive protein (CRP); haptoglobin (Hp), and cardiac troponin I (cTnI)] used to determine systemic inflammation and myocardial damage. This study was conducted on 33 dogs with BAOS that were evaluated before and 1 to 2 mo after surgical correction. Palatoplasty was carried out by means of 2 different surgical techniques: carbon dioxide (CO2) laser (n = 12) and electrical scalpel (n = 21). Biomarker levels (CRP, Hp, and cTnI) were determined before and after surgery. There was a significant reduction in respiratory and gastrointestinal signs in dogs with BAOS after surgical treatment (P < 0.001). A greater reduction in respiratory signs (P < 0.002) was obtained using the CO2 laser. No statistical differences were found between CRP and cTnI levels, either before or after surgical correction. Haptoglobin concentration did increase significantly in the postsurgical period (P < 0.008). Surgical treatment in dogs with BAOS reduces clinical signs, regardless of the anatomical components present. Surgical treatment for BAOS is not useful to reduce CRP and Hp levels, probably because BAOS does not induce as obvious an inflammatory process in dogs as in human patients with OSAS. No reduction in cTnI levels was observed 1 mo after surgery in dogs with BAOS, which suggests that some degree of myocardial damage remains.

Background: Brachycephalic dogs have unique upper respiratory anatomy with abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome (OSAS). The objective of this study was to evaluate the correlation between anatomical components, clinical signs and several biomarkers, used to determine systemic inflammation and myocardial damage (C-reactive protein, CRP; Haptoglobin, Hp; cardiac troponin I, cTnI), in dogs with brachycephalic upper airway obstructive syndrome (BAOS)., Results: Fifty brachycephalic dogs were included in the study and the following information was studied: signalment, clinical signs, thoracic radiographs, blood work, ECG, components of BAOS, and CRP, Hp and cTnI levels. A high proportion of dogs with BAOS (88%) had gastrointestinal signs. The prevalence of anatomic components of BAOS was: elongated soft palate (100%), stenotic nares (96%), everted laryngeal saccules (32%) and tracheal hypoplasia (29.1%). Increased serum levels of biomarkers were found in a variable proportion of dogs: 14% (7/50) had values of CRP > 20 mg/L, 22.9% (11/48) had values of Hp > 3 g/L and 47.8% (22/46) had levels of cTnI > 0.05 ng/dl. Dogs with everted laryngeal saccules had more severe respiratory signs (p<0.02) and higher values of CRP (p<0.044). No other statistical association between biomarkers levels and severity of clinical signs was found., Conclusions: According to the low percentage of patients with elevated levels of CRP and Hp, BAOS does not seem to cause an evident systemic inflammatory status. Some degree of myocardial damage may occur in dogs with BAOS that can be detected by cTnI concentration.

Seven cats were presented for mild-to-moderate cough and/or dyspnoea after starting bromide (Br) therapy for neurological diseases. The thoracic auscultation was abnormal in three cats showing increased respiratory sounds and wheezes. Haematology revealed mild eosinophilia in one cat. The thoracic radiographs showed bronchial patterns with peribronchial cuffing in most of them. Bronchoalveolar lavage performed in two cats revealed neutrophilic and eosinophilic inflammation. Histopathology conducted in one cat showed endogenous lipid pneumonia (EnLP). All cats improved with steroid therapy after Br discontinuation. Five cats were completely weaned off steroids, with no recurrence of clinical signs. In one cat, the treatment was discontinued despite persistent clinical signs. The cat presenting with EnLP developed secondary pneumothorax and did not recover. Br-associated lower airway disease can appear in cats after months of treatment and clinical improvement occurs only after discontinuing Br therapy.

Background & Aims: Liver fibrogenesis is sustained by myofibroblast-like cells originating from hepatic stellate cells (HSC/MFs), portal fibroblasts or bone marrow-derived cells, including mesenchymal stem cells (MSCs). Herein, we investigated the mechanistic role of intracellular generation of reactive oxygen species (ROS) and redox-sensitive signal transduction pathways in mediating chemotaxis, a critical profibrogenic response for human HSC/MFs and for MSC potentially engrafting chronically injured liver., Methods: Intracellular generation of ROS and signal transduction pathways were evaluated by integrating morphological and molecular biology techniques. Chemokinesis and chemotaxis were evaluated by wound healing assay and modified Boyden's chamber assay, respectively. Additional in vivo evidence was obtained in human specimens from HCV-related cirrhosis., Results: Human MSCs and HSC/MFs migrate in response to a panel of polypeptide chemoattractants and extracellularly generated superoxide anion. All polypeptides induced a NADPH-oxidase-dependent intracellular rise in ROS, resulting in activation of ERK1/2 and JNK1/2. Moreover, menadione or 2,3-dimethoxy-1,4-naphthoquinone, which generate intracellular superoxide anion or hydrogen peroxide, respectively, induced ERK1/2 and JNK1/2 activation and migration. JNK1 activation was predominant for migration as shown by specific silencing. Finally, activation of ERK1/2 and JNK1/2 was found in extracts obtained from HSC/MFs during the course of an oxidative stress-mediated model of liver injury and phosphorylated JNK1/2 isoforms were detected in α-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhotic livers., Conclusions: Intracellular generation of ROS, through activation of specific signaling pathways, is a critical event for directional migration of HSC/MFs and MSCs., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatic fibrosis is a dynamic process whereby the liver responds to conditions of persistent damage. This leads to deposition of fibrillar extracellular matrix, altered hepatocyte regeneration, deranged microvascular architecture and cirrhosis. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process indifferent chronic liver diseases, and attention has focused on possible links between the adipose tissue and liver repair.ADIPOCYTOKINEs are cytokines secreted primarily by adipose tissue, they are relevant for adipose tissue physiology and metabolism.Alterations in the adipocytokine pattern are involved in different obesity-related diseases, such as hypertension, atherosclerosis and type II diabetes mellitus (T2DM).Numerous recent studies have analyzed the role played by adipocytokines in the process of hepatic 'wound healing' and fibrogenesis. In particular, data have accumulated on the role of adiponectin and leptin. This review summarizes the more significant and recent findings concerning the role played by different adipocytokines in hepatic fibrogenesis, discussing the actions of adipocytokines on the biology of liver cells, and their effects in different animal models. The variations in the circulating levels and intrahepatic expression of different adipocytokines in patients with fibrogenic liver diseases are also discussed.

Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases.

Background/aims: Hepatic fibrogenesis, a consequence of chronic liver tissue damage, is characterized by activation of the hepatic stellate cells (HSC). Silybin has been shown to exert anti-fibrogenic effects in animal models. However, scant information is available on the fine cellular and molecular events responsible for this effect. The aim of this study was to assess the mechanisms regulating the anti-fibrogenic and anti-inflammatory activity of Silybin., Methods: Experiments were performed on HSC isolated from human liver and activated by culture on plastic., Results: Silybin was able to inhibit dose-dependently (25-50 microM) growth factor-induced pro-fibrogenic actions of activated human HSC, including cell proliferation (P < 0.001), cell motility (P < 0.001), and de novo synthesis of extracellular matrix components (P < 0.05). Silybin (25-50 microM), inhibited the IL-1-induced synthesis of MCP-1 (P < 0.01) and IL-8 (P < 0.01) showing a potent anti-inflammatory activity. Silybin exerts its effects by directly inhibiting the ERK, MEK and Raf phosphorylation, reducing the activation of NHE1 (Na+/H+ exchanger, P < 0.05) and the IkBalpha phosphorylation. In addition, Silybin was confirmed to act as a potent anti-oxidant agent., Conclusion: The results of the study provide molecular insights into the potential therapeutic action of Silybin in chronic liver disease. This action seems to be mostly related to a marked inhibition of the production of pro-inflammatory cytokines, a clear anti-oxidant effect and a reduction of the direct and indirect pro-fibrogenic potential of HSC.

Liver fibrosis is a dynamic process consisting of the chronic activation of the wound healing reaction in response to reiterated liver damage, leading to the excessive deposition of fibrillar extracellular matrix into the liver and eventually, if the cause of injury is not removed, to liver cirrhosis. The term "adipokines" identifies a group of polypeptide molecules secreted primarily by adipose tissue, which exert local, peripheral and/or central actions. Additionally to their well-established role in controlling adipose tissue physiology, adipokines have been shown to be involved in different obesity-related diseases, such as hypertension, atherosclerosis and type 2 diabetes. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process in different chronic liver diseases. Therefore, numerous recent studies have analyzed the role played by adipokines in the hepatic wound healing process, identifying novel roles as modulators of liver pathophysiology. This review summarizes the more significant and recent findings concerning the role played by adipocyte-derived molecules, such as leptin, adiponectin and resistin, in the liver fibrogenic process. The actions of different adipokines on the biology of liver resident cells, as well as their effects in different animal models of liver injury are discussed. The variations in the circulating levels and in the intrahepatic expression of these molecules occurring in patients with different chronic liver diseases will be also analyzed.

Unlabelled: Adiponectin limits the development of liver fibrosis and activates adenosine monophosphate-activated protein kinase (AMPK). AMPK is a sensor of the cellular energy status, but its possible modulation of the fibrogenic properties of hepatic stellate cells (HSCs) has not been established. In this study, we investigated the role of AMPK activation in the biology of activated human HSCs. A time-dependent activation of AMPK was observed in response to a number of stimuli, including globular adiponectin, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), or metformin. All these compounds significantly inhibited platelet-derived growth factor (PDGF)-stimulated proliferation and migration of human HSCs and reduced the secretion of monocyte chemoattractant protein-1. In addition, AICAR limited the secretion of type I procollagen. Knockdown of AMPK by gene silencing increased the mitogenic effects of PDGF, confirming the negative modulation exerted by this pathway on HSCs. AMPK activation did not reduce PDGF-dependent activation of extracellular signal-regulated kinase (ERK) or Akt at early time points, whereas a marked inhibition was observed 24 hours after addition of PDGF, reflecting a block in cell cycle progression. In contrast, AICAR blocked short-term phosphorylation of ribosomal S6 kinase (p70(S6K)) and 4E binding protein-1 (4EBP1), 2 downstream effectors of the mammalian target of rapamycin (mTOR) pathway, by PDGF. The ability of interleukin-a (IL-1) to activate nuclear factor kappa B (NF-kappaB) was also reduced by AICAR., Conclusion: Activation of AMPK negatively modulates the activated phenotype of HSCs.

Background/aims: Administration of carbon tetrachloride determines liver injury, inflammation and oxidative stress, but the molecular mechanisms of damage are only partially understood. In this study, we investigated the development of acute toxic damage in mice lacking monocyte chemoattractant protein-1 (MCP-1), a chemokine which recruits monocytes and activated lymphocytes., Methods: Mice with targeted deletion of the MCP-1 gene and wild type controls were administered a single intragastric dose of carbon tetrachloride. Serum liver enzymes, histology, expression of different chemokines and cytokines, and intrahepatic levels of oxidative stress-related products were evaluated., Results: Compared to wild type mice, peak aminotransferase levels were significantly lower in MCP-1-deficient animals. This was paralleled by a delayed appearance of necrosis at histology. In addition, MCP-1-deficient mice showed a shift in the pattern of infiltrating inflammatory cells, with a predominance of polymorphonuclear leukocytes. Lack of MCP-1 was also accompanied by reduced intrahepatic expression of cytokines regulating inflammation and tissue repair. The increase in tissue levels of reactive oxygen species and 4-hydroxy-nonenal following administration of the hepatotoxin was also significantly lower in animals lacking MCP-1., Conclusions: Lack of MCP-1 affords protection from damage and development of oxidative stress in a toxic model of severe acute liver injury.

Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.

Leptin upregulates collagen expression in hepatic stellate cells (HSCs), but the possible modulation of other actions has not been elucidated. The aim of this study was to investigate the expression and function of leptin receptors (ObR) in human HSCs and the biological actions regulated by leptin. Exposure of HSCs to leptin resulted in upregulation of monocyte chemoattractant protein 1 (MCP-1) expression. Leptin also increased gene expression of the proangiogenic cytokines vascular endothelial growth factor (VEGF) and angiopoietin-1, and VEGF was also upregulated at the protein level. Activated HSCs express ObRb and possibly other ObR isoforms. Exposure to leptin increased the tyrosine kinase activity of ObR immunoprecipitates and resulted in activation of signal transducer and activator of transcription 3. Several signaling pathways were activated by leptin in HSCs, including extracellular-signal-regulated kinase, Akt, and nuclear factor kappaB, the latter being relevant for chemokine expression. Leptin also increased the abundance of hypoxia-inducible factor 1alpha, which regulates angiogenic gene expression, in an extracellular-signal-regulated kinase- and phoshatidylinositol 3-kinase-dependent fashion. In vivo, leptin administration induced higher MCP-1 expression and more severe inflammation in mice after acute liver injury. Conversely, in leptin-deficient mice, the increase in MCP-1 messenger RNA and mononuclear infiltration was less marked than in wild-type littermates. Finally, ObR expression colocalized with VEGF and alpha-smooth muscle actin after induction of fibrosis in rats. In conclusion, ObR activation in HSCs leads to increased expression of proinflammatory and proangiogenic cytokines, indicating a complex role for leptin in the regulation of the liver wound-healing response.

Non-alcoholic steatohepatitis has been recognized as a significant cause of end-stage liver disease and hepatic decompensation. Despite the growing interest in this condition, the molecular mechanisms underlying the development of fibrosis in this setting are only partially understood. In this article, the cellular and molecular basis of fibrosis in chronic liver disease are briefly outlined. In addition, mechanisms specifically operating in the context of fatty liver and steatohepatitis are examined, including: insulin resistance, oxidative stress, and inflammation. Finally, recent developments indicating the possible contribution of cytokines derived from adipose tissue (adipokines) to liver fibrosis is discussed.

Liver fibrosis involves different cell types, and should be regarded as a "wound healing" response that occurres in conditions of chronic liver injury and is characterized by inflammation, activation of matrix-producing cells, matrix deposition and remodeling, and epithelial cell regeneration or an attempt thereof. Liver damage may be caused by several agents or conditions, resulting in different degrees and types of tissue inflammation and in activation of matrix-producing cells, such as the hepatic stellate cells (HSC). HSC undergo a phenotypic transition (known as "activation") to myofibroblast-like cells that synthesize different extracellular matrix components. Obesity is associated with the development of NASH, and has been indicated as an independent factor for the progression to fibrosis. In liver diseases, the biologic actions of the adipokines, such as leptin, adiponectin and resistin, released by adipocytes or locally produced by liver and/or inflammatory cells, may contribute to clarify the mechanisms of progression in NASH. The clinical and experimental findings accumulating on this class of molecules could represent the basis to devise a better management strategy for the patients with chronic liver disease.

Hepatic stellate cells (HSC) coordinate the liver wound-healing response through secretion of several cytokines and chemokines, including CCL2 (formerly known as monocyte chemoattractant protein-1). In this study, we evaluated the role of different proteins of the MAPK family (ERK, p38(MAPK), and JNK) in the regulation of CCL2 expression by HSC, as an index of their proinflammatory activity. Several mediators activated all three MAPK, including TNF, IL-1, and PDGF. To assess the relative role of the different MAPKs, specific pharmacological inhibitors were used; namely, SB203580 (p38(MAPK)), SP600125 (JNK), and PD98059 (MEK/ERK). The efficacy and specificity of the different inhibitors in our cellular system were verified analyzing the enzymatic activity of the different MAPKs using in vitro kinase assays and/or testing the inhibition of phosphorylation of downstream substrates. SB203580 and SP600125 dose-dependently inhibited CCL2 secretion and gene expression induced by IL-1 or TNF. In contrast, inhibition of ERK did not affect the upregulation of CCL2 induced by the two cytokines. Finally, activin A was also found to stimulate CCL2 expression and to activate ERK, JNK, p38, and their downstream targets. Unlike in cells exposed to proinflammatory cytokines, all three MAPKs were required to induce CCL2 secretion in response to activin. We conclude that members of the MAPK family differentially regulate cytokine-induced chemokine expression in human HSC.