Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury

Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-beta and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy

Оценка воздействия дамбы в д. Босоногово Бердюжского района на окружающую среду Тюменской области

В статье рассмотрена положительная и отрицательная оценка воздействия дамбы в д. Босоногово Бердюжского района на окружающую среду Тюменской области.The article considers a positive and negative assessment of the impact of a dam in the village of Bosonogovo, Berdyuga district, on the environment of the Tyumen region

Xanthohumol feeding does not impair organ function and homoeostasis in mice

Xanthohumol, the major prenylated chalcone found in hops, is known to exert several beneficial effects but only few studies evaluated the safety profile of this natural compound with in part discrepant results. Here, we fed female BALB/c mice with a standard diet supplemented with xanthohumol for 3 weeks, and thus, achieved a daily dose of approximately 1000 mg xanthohumol/kg body weight. There were no significant differences in body weight or food intake between mice on standard diet and animals receiving the same diet supplemented with xanthohumol. Histopathological examination of liver, kidney, colon, lung, heart, spleen and thymus revealed no signs of xanthohumol-toxicity, and biochemical serum analysis confirmed normal organ function. Further, xanthohumol treatment did not affect hepatic glycogen content CYP2E1 and CYP1A2 expression levels, but CYP3A11 mRNA was approximately 30% reduced. Expression of several genes indicative of early hepatic inflammation and fibrosis, a hallmark of chronic liver injury, did not differ between xanthohumol treated and control mice. In summary, these results indicate that oral administration of xanthohumol exhibits no adverse effects on major organ function and homoeostasis in mice. Particularly, hepatotoxic effects could be ruled out confirming a good safety profile of xanthohumol as prerequisite for further studies in humans

Xanthohumol feeding does not impair organ function and homeostasis in mice

Xanthohumol, the major prenylated chalcone found in hops, is known to exert several beneficial effects but only few studies evaluated the safety profile of this natural compd. with in part discrepant results. Here, the authors fed female BALB/c mice with a std. diet supplemented with xanthohumol for 3 wk, and thus, achieved a daily dose of .apprx.1000 mg xanthohumol/kg body wt. There were no significant differences in body wt. or food intake between mice on std. diet and animals receiving the same diet supplemented with xanthohumol. Histopathol. examn. of the liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of xanthohumol toxicity, and biochem. serum anal. confirmed normal organ function. Further, xanthohumol treatment did not affect hepatic glycogen content, CYP2E1 and CYP1A2 expression levels, but CYP3A11 mRNA was .apprx.30% reduced. Expression of several genes indicative of early hepatic inflammation and fibrosis, a hallmark of chronic liver injury, did not differ between xanthohumol treated and control mice. Thus, oral administration of xanthohumol exhibited no adverse effects on major organ function and homeostasis in mice. Particularly, hepatotoxic effects could be ruled out confirming a good safety profile of xanthohumol as a prerequisite for further studies in humans

Reduced expression of CYLD in human colon and hepatocellular carcinomas

CYLD was originally identified as a tumor suppressor that is mutated in familial cylindromatosis. Recent studies suggested a role for CYLD in nuclear factor-kappaB (NF-kappaB) regulation. NF-kappaB activation has been connected with multiple aspects of oncogenesis but the underlying molecular mechanisms of persistent NF-kappaB activation in tumors remain largely unknown. Thus, we evaluated CYLD transcription in different colon and hepatocellular carcinoma cell lines and tissue samples, respectively. CYLD was downregulated or lost in all tumor cell lines investigated as compared with primary human colonic epithelial cells and hepatocytes, respectively. Further, quantitative PCR analysis revealed reduced CYLD mRNA expression in most tumor samples compared with non-tumorous tissue. Analysis on protein level confirmed these findings. Functional assays with CYLD transfected cell lines revealed that CYLD expression decreased NF-kappaB activity. Thus, functional relevant loss of CYLD expression may contribute to tumor development and progression, and may provide a new target for therapeutic strategies

Histopathological parameters as predictors for the course of Crohn's disease

BACKGROUND: Recent classification systems discriminate penetrating Crohn's disease (CD) from stricturing and non-stricturing/non-penetrating CD. As yet, no easily detectable marker is known that can predict the course of CD. Individual, clinical course-specific new treatment schemes would be highly desirable for different potentially divergent pathophysiological pathways (e.g., fistula vs stenosis). METHODS: Intestinal tissue biopsies from 63 CD patients with a disease follow-up of up to 7 years were studied retrospectively. In biopsy specimens, 34 histopathological features present prior to the onset of (a) strictures or (b) fistulas were evaluated and compared with biopsies from patients with non-stricturing/non-penetrating disease. RESULTS: Five histomorphological parameters demonstrated significant associations to different disease courses when applying univariate analysis. In a multivariate logistic regression model (1) severe lymphocytic infiltration of the lamina propria, (2) presence of crypt atrophy, and (3) absence of lymphocytic infiltration of the epithelium are the best variables to predict an uncomplicated disease course (Nagelkerke R2=0.329; P=0.001). The combination of these parameters has a sensitivity of 67% and a specificity of 83% to predict non-stricturing/non-penetrating disease (positive predictive value=0.75). CONCLUSION: Histopathological parameters may help to predict complications of CD prior to their onset. The results of this study have to be confirmed prospectively