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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.

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Background: Hemangioma is a benign dermal or subcutaneous endothelial cell tumor composed of vascular spaces of varying sizes filled with erythrocytes and lined with a single layer of uniform endothelial cells. Although the pathogenesis is not well defined, these tumors are considered to result from an imbalance in angiogenesis, leading to uncontrolled proliferation of vascular elements. To the best of our knowledge, there are no reports of congenital cutaneous hemangioma in sheep. This report describes the clinical, laboratory, and pathological findings of a case of congenital hemangioma affecting a newborn lamb. Case: A 5-day-old crossbred (Dorper x Santa Inês) lamb presenting with an ear nodule that expanded in the right ear was necropsied. An expansive subcutaneous nodule was observed macroscopically; it occupied approximately 90% of the right ear and had a crusty, irregular surface. The cut surface had multiple cavitations delimited by firm fibrous tissue and a light yellow-to-translucent content. Microscopically, it showed focally extensive subcutaneous neoplastic proliferation and moderate cellularity; it was formed of vascular beds of varied sizes and supported by moderate fibrocollagenous stroma. Suppurative inflammation was observed in the neoplastic vascular beds with large amounts of free basophilic coccoid bacteria inside macrophages. Immunohistochemistry analysis was performed to confirm the diagnosis. Strong cytoplasmic labeling was observed in neoplastic endothelial cells for CD31 and factor VIII. The Ki67 proliferation marker was positive in approximately 5% of neoplastic cells. The cells did not express smooth muscle actin (1A4) or pan-cytokeratin (AE1AE3). Histological characteristics and immunohistochemistry findings were consistent with those of congenital cutaneous hemangioma, a rare neoplasm in sheep. Discussion: The association of clinical, anatomopathological, and immunohistochemical data enabled the diagnosis of congenital cutaneous hemangioma in the 5-day-old lamb. Reports of vascular tumors in sheep are not frequent in literature and usually involve adult animals with no anatomical site predilection. In sheep, the occurrence of nasotracheal hemangioma in a 2-year-old ewe and gingival hemangioma in a 5-year-old sheep have already been described. A cutaneous extra-neural hemangioblastoma was diagnosed in the ear of a 1-month-old lamb. IHC was also used to confirm the diagnosis of hemangioblastoma. Macroscopically, hemangiomas can present as well-delimited and encapsulated masses that when cut, show a reticulated pattern similar to honeycombs that separate the blood-filled cavities. The present case showed a similar conformation but without enough erythrocytes to result in a bloody appearance. Tumor drainage and the predominance of blood serum in the content possibly made it macroscopically translucent. Microscopically, the hemangioma was classified as cavernous. This morphological variation forms large channels separated by fibrous connective tissue stroma, which may contain inflammatory cells. IHC confirmed the endothelial lining of the cystic cavities and was crucial in excluding differential diagnoses. Thus, factor VIII-related antigen was used as a marker for normal and neoplastic cells, as well as for tumoral and reactive neovascularization, in which neoplastic cells were immuno-expressed for CD31 and Factor VIII. In domestic animals, the association between CD31 and Factor VIII is considered more specific for vascular endothelial cells, differentiating them from cells of lymphatic origin. Congenital cutaneous hemangioma occurs in sheep, and its diagnosis and differentiation can be based on histopathology associated with conventional immunohistochemical panels for vascular neoformation.

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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.

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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.

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Traumatic reticuloperitonitis combined with embolic pneumonia and hepatitis is unusual signs of foreign body syndrome in cattle. A 4-year-old Holstein bull presented decreased appetite, dry cough, progressive weight loss, sternal recumbence and reluctance to stand and move. Laboratory tests revealed leucocytosis (18.4 × 103 /µl) accompanied by neutrophilia (10.48 × 103 /µl), and monocytosis (1.28 × 103 /µl), hyperglobulinaemia (6.3 g/dl), hypoalbuminaemia (1.5 g/dl), hyperfibrinogenaemia (10 g/L) and severe increase in gamma-glutamyl transferase activity (1,216 U/L). Reticular ultrasonographical examination showed a large amount of hyperechoic and hypoechoic content between the reticular serosa and the hepatic visceral surface. The main gross findings included fibrin deposition and adhesions between the reticulum, liver and diaphragm surfaces; a 4.0 mm in diameter transmural reticular perforation; a 12.0-cm diameter and scarce small randomly abscesses in the liver's parenchyma. The lungs presented multifocal areas of suppurative embolic foci (pulmonary abscesses), interstitial emphysema and multifocal fibrin deposition on the pleural surface. Ancillary diagnostic tests, such as ultrasonography and laboratory test, associated with clinical evaluation, may increase the accuracy of the correct diagnosis and avoid wasting time and money on untreatable cases.

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Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor-suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor-suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma-derived cell lines were exposed to GDF11 (50 ng/ml), RNA-seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum-related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real-time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.

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O trabalho avalia o comportamento de risco para infecções sexualmente transmissíveis (ISTs) em estudantes do ensino médio de Urussanga-SC. A pesquisa foi observacional transversal, descritiva, com coleta de dados primários e abordagem quantitativa. A população estudada constou de alunos do ensino médio de escolas públicas e privadas de Urussanga-SC no ano de 2019. A amostra foi constituída por 178 indivíduos, sendo majoritariamente composta pelo sexo feminino (61,4%), e a média de idades foi de 16 anos (±1,04). Do total, 50% haviam iniciado as atividades sexuais. Entre o sexo feminino, 48,1% relataram um parceiro, contrapondo-se com o sexo masculino, no qual 40,7% relataram quatro ou mais. Em relação ao conhecimento sobre manifestações de ISTs, 62,4% informaram dor na região genital como sinal de alerta, todavia a presença de feridas e corrimento foi reconhecida por menos de 40% dos adolescentes. A maioria dos adolescentes já recebeu orientações sobre sexualidade e afirmou possuir conhecimento sobre ela, porém os resultados demonstram falha no entendimento, sendo evidente a importância da educação sexual nas escolas.(AU)

The assessed work examined risk behavior for sexually transmitted infections (STIs) in high school students from Urussanga-SC. A cross-sectional, descriptive observational study, using primary data collection and a quantitative approach. The population studied contained high school students from public and private schools in Urussanga- SC in 2019. The sample was mainly composed of females and the average age was 16 years. From the total, 50% already started sexual activities. Of the female sex, 48.1% refer to one partner, by contrast, 40,7% of the male sex, refer to four or more partners. Regarding manifestations, 62.4% reported pain in the genital region as a warning sign, however, the presence of wounds and discharge was registered by less than 40% of adolescents. Most adolescents have already received some guidance on sexuality and reported having knowledge about the subject. Nevertheless, the results presented a lack of understanding, highlighting the importance of sex education in schools.(AU)

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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.

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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.

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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.