Stress kinases in the development of liver steatosis and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

Every day, the body's biological processes work to an internal clock known as the circadian rhythm. This rhythm is controlled by 'clock genes' that are switched on or off by daily physical and environmental cues, such as changes in light levels. These daily rhythms are very finely tuned, and disturbances can lead to serious health problems, such as diabetes or high blood pressure. The ability of the body to cycle through the circadian rhythm each day is heavily influenced by the clock of one key organ: the liver. This organ plays a critical role in converting food and drink into energy. There is evidence that neutrophils ­ white blood cells that protect the body by being the first response to inflammation ­ can influence how the liver performs its role in obese people, by for example, releasing a protein called elastase. Additionally, the levels of neutrophils circulating in the blood change following a daily pattern. Crespo, González-Terán et al. wondered whether neutrophils enter the liver at specific times of the day to control liver's daily rhythm. Crespo, González-Terán et al. revealed that neutrophils visit the liver in a pattern that peaks when it gets light and dips when it gets dark by counting the number of neutrophils in the livers of mice at different times of the day. During these visits, neutrophils secreted elastase, which activated a protein called JNK in the cells of the mice's liver. This subsequently blocked the activity of another protein, FGF21, which led to the activation of the genes that allow cells to make fat molecules for storage. JNK activation also switched on the clock gene, Bmal1, ultimately causing fat to build up in the mice's liver. Crespo, González-Terán et al. also found that, in samples from human livers, the levels of elastase, the activity of JNK, and whether the Bmal1 gene was switched on were tightly linked. This suggests that neutrophils may be controlling the liver's rhythm in humans the same way they do in mice. Overall, this research shows that neutrophils can control and reset the liver's daily rhythm using a precisely co-ordinated series of molecular changes. These insights into the liver's molecular clock suggest that elastase, JNK and BmaI1 may represent new therapeutic targets for drugs or smart medicines to treat metabolic diseases such as diabetes or high blood pressure.

Rock Tea extract (Jasonia glutinosa) relaxes rat aortic smooth muscle by inhibition of L-type Ca2+ channels

In traditional herbal medicine, Rock Tea (Jasonia glutinosa) is known for its prophylactic and therapeutic value in various disorders including arterial hypertension. However, the mechanism by which Rock Tea exerts blood pressure-lowering actions has not been elucidated yet. Our aim was to demonstrate vasorelaxing effects of Rock Tea extract and to reveal its possible action mechanism. Isometric myography was conducted on high-K+-precontracted rings from rat thoracic aorta and tested extracts at concentrations of 0.5-5 mg/ml. Whole-cell patch-clamp experiments were performed in rat aortic vascular smooth muscle cells (line A7r5) to determine blocking effects on L-type Ca2+ channels. Rock Tea extract relaxed the aorta contracted by high [K+] concentration dependently with an EC50 of ≈2.4 mg/ml and produced ≈75 % relaxation at the highest concentration tested. The L-type Ca2+ channel blocker, verapamil (10−6 M), had similar effects. Rock Tea extract had no effect in nominally Ca2+-free high-K+ buffer but significantly inhibited contractions to re-addition of Ca2+. Rock Tea extract inhibited the contractions induced by the L-type Ca2+ channel activator Bay K 8644 (10−5 M) and by phenylephrine (10−6 M). Rock Tea extract and Y-27632 (10−6 M), Rho-kinase inhibitor, had similar effects and the respective effects were not additive. Patch-clamp experiments demonstrated that Rock Tea extract (2.5 mg/ml) virtually abolished L-type Ca2+ currents in A7r5. We conclude that Rock Tea extract produced vasorelaxation of rat aorta and that this relaxant effect is mediated by inhibition of L-type Ca2+ channels. Rock Tea extracts may be of phytomedicinal value for prevention and adjuvant treatment of hypertension and other cardiovascular diseases

Rock Tea extract (Jasonia glutinosa) relaxes rat aortic smooth muscle by inhibition of L-type Ca(2+) channels.

In traditional herbal medicine, Rock Tea (Jasonia glutinosa) is known for its prophylactic and therapeutic value in various disorders including arterial hypertension. However, the mechanism by which Rock Tea exerts blood pressure-lowering actions has not been elucidated yet. Our aim was to demonstrate vasorelaxing effects of Rock Tea extract and to reveal its possible action mechanism. Isometric myography was conducted on high-K+-precontracted rings from rat thoracic aorta and tested extracts at concentrations of 0.5-5 mg/ml. Whole-cell patch-clamp experiments were performed in rat aortic vascular smooth muscle cells (line A7r5) to determine blocking effects on L-type Ca(2+) channels. Rock Tea extract relaxed the aorta contracted by high [K+] concentration dependently with an EC50 of ≈2.4 mg/ml and produced ≈75 % relaxation at the highest concentration tested. The L-type Ca(2+) channel blocker, verapamil (10(-6) M), had similar effects. Rock Tea extract had no effect in nominally Ca(2+)-free high-K(+) buffer but significantly inhibited contractions to re-addition of Ca(2+). Rock Tea extract inhibited the contractions induced by the L-type Ca(2+) channel activator Bay K 8644 (10(-5) M) and by phenylephrine (10(-6) M). Rock Tea extract and Y-27632 (10(-6) M), Rho-kinase inhibitor, had similar effects and the respective effects were not additive. Patch-clamp experiments demonstrated that Rock Tea extract (2.5 mg/ml) virtually abolished L-type Ca(2+) currents in A7r5. We conclude that Rock Tea extract produced vasorelaxation of rat aorta and that this relaxant effect is mediated by inhibition of L-type Ca(2+) channels. Rock Tea extracts may be of phytomedicinal value for prevention and adjuvant treatment of hypertension and other cardiovascular diseases.

Calidad de vida en pacientes con esclerosis múltiple en tratamiento rehabilitador / Quality of life in multiple sclerosis patients on rehabilitation treatment

OBJETIVO: describir la mejor evidencia disponible sobre la eficacia del tratamiento rehabilitador en pacientes con esclerosis múltiple (EM). MÉTODO: se ha realizado una búsqueda en las bases de datos bibliográficas PubMed, Cinahl y Cuiden Plus. Los términos incluidos en la búsqueda fueron: "multiple sclerosis", "hospitalization", "ambulatorycare" y "rehabilitation". Para concretar la búsqueda, se aplicaron varios límites en las bases de datos: 1) fecha de publicación de los estudios (2003-actualidad), 2) el idioma de publicación (español, ingles y francés), 3) la edad (> 18 años), 4) población de estudio con diagnóstico de EM confirmado, y 5) el tipo de artículo (ensayos clínicos aleatorizados). Los estudios fueron seleccionados a partir del título y el resumen, obteniéndose a texto completo para un análisis más detallado. RESULTADOS: la búsqueda en las distintas bases de datos electrónicas dio como resultado 7.171 documentos, de los cuales, al aplicar los límites de búsqueda dieron como resultado 278 artículos. Una vez que se aplicaron los criterios de inclusión quedaron incluidos 59 artículos que fueron evaluados utilizando la parrilla el CASPe para ensayos clínicos. DISCUSIÓN Y CONCLUSIONES: cabe destacar que el tratamiento rehabilitador multidisciplinar (MD) puede mejorar la calidad de vida de los pacientes con EM, según los ensayos clínicos incluidos en esta revisión. Sin embargo, no siempre existen diferencias estadísticamente significativas a favor del mismo. También se ha podido observar la eficacia de tratamientos complementarios que pueden mejorar la calidad de vida, pero que están poco estudiados hasta ahora. Por lo tanto, será interesante incluir terapias complementarias en los tratamientos de rehabilitación de pacientes con EM para medir su efecto

OBJECTIVE: to describe the best evidence available on the efficacy of rehabilitation treatment in patients with Multiple Sclerosis (MS). METHOD: a search has been conducted in the bibliographic databases PubMed, Cinahl and Cuiden Plus. The terms included in the search were: "Multiple Sclerosis", "hospitalization", "ambulatory care" and "rehabilitation". In order to make the search more specific, various limits were applied to the databases: 1) Date of publication of the studies (from 2003 to current date), 2) language of publication (Spanish, English and French), 3) age (> 18 years), 4) study population with confirmed MS diagnosis, and 5) type of article (randomized clinical trials). Studies were selected based on their title and abstract, and the complete text was obtained for a more detailed analysis. RESULTS: the search in different electronic databases resulted in 7,171 documents; once applied the search limits, 278 articles were obtained. After implementing the inclusion criteria, 59 articles were left as included, which were assessed using the CASPe tool for clinical trials. DISCUSSION AND CONCLUSIONS: it is worth highlighting that MD rehabilitation treatment can improve the quality of life in MS patients, according to clinical trials included in this review. However, there are not always statistically significant differences in its favour. Moreover, the efficacy of complementary treatments has been observed, which might improve quality of life, but have not been sufficiently studied so far. Therefore, it would be interesting to include complementary therapies in rehabilitation treatments for patients with SM, in order to measure their effect