Reply to: "YAP in tumorigenesis: Friend or foe?"

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Państwo i społeczeństwo w XXI wieku. Sztuka - społeczeństwo - edukacja

Ze wstępu: "Tradycyjnie Krakowska Szkoła Wyższa im. Andrzeja Frycza Modrzewskiego organizuje w pierwszych dniach czerwca Międzynarodową Konferencję Naukową. Tegorocznym przedmiotem obrad, czwartej już konferencji, było „Państwo i społeczeństwo w XXI wieku”. W tej różnorodności problemów i zagadnień związanych z życiem społecznym, ideą naszej części konferencji była wielka opowieść 0 wychowaniu przez sztukę."(...

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Thyroid hormones, thyromimetics and their metabolites in the treatment of liver disease

The signaling pathways activated by thyroid hormone receptors (THR) are of fundamental importance for organogenesis, growth and differentiation, and significantly influence energy metabolism, lipid utilization and glucose homeostasis. Pharmacological control of these pathways would likely impact the treatment of several human diseases characterized by altered metabolism, growth or differentiation. Not surprisingly, biomedical research has been trying for the past decades to pharmacologically target the 3,5,3'-triiodothyronine (T3)/THR axis. In vitro and in vivo studies have provided evidence of the potential utility of the activation of the T3-dependent pathways in metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and in the treatment of hepatocellular carcinoma (HCC). Unfortunately, supra-physiological doses of the THR agonist T3 cause severe thyrotoxicosis thus hampering its therapeutic use. However, the observation that most of the desired beneficial effects of T3 are mediated by the activation of the beta isoform of THR (THRβ) in metabolically active organs has led to the synthesis of a number of THRβ-selective thyromimetics. Among these drugs, GC-1, GC-24, KB141, KB2115, and MB07344 displayed a promising therapeutic strategy for liver diseases. However, although these drugs exhibited encouraging results when tested in the treatment of experimentally-induced obesity, dyslipidemia, and HCC, significant adverse effects limited their use in clinical trials. More recently, evidence has been provided that some metabolites of thyroid hormones (TH), mono and diiodothyronines, could also play a role in the treatment of liver disease. These molecules, for a long time considered inactive byproducts of the metabolism of thyroid hormones, have now been proposed to be able to modulate and control lipid and cell energy metabolism. In this review, we will summarize the current knowledge regarding T3, its metabolites and analogs with reference to their possible clinical application in the treatment of liver disease. In particular, we will focus our attention on NAFLD, non-alcoholic steatohepatitis (NASH) and HCC. In addition, the possible therapeutic use of mono- and diiodothyronines in metabolic and/or neoplastic liver disease will be discussed

Gender-specific interplay of signaling through β-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation

Aberrant signaling through the Wnt/β-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated β-catenin. In the present study, the interplay of β-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of β-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female β-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether β-catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists

High frequency of β-catenin mutations in mouse hepatocellular carcinomas induced by a nongenotoxic constitutive androstane receptor agonist

Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice the tumor-promoting activity of agonists of constitutive androstane receptor (CAR) occurs by selection of carcinogen-initiated cells harboring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCP) in the absence of genotoxic injury are unknown. Here, we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCP alone displayed different nucleotide substitutions compared with those found in HCCs from mice pretreated with diethylnitrosamine. Moreover, unlike those occurring in HCCs from diethylnitrosamine + TCP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2, Tbx3, Axin2, and Ccnd1, or nuclear translocation of β-catenin compared with the control liver. Remarkably, in the nontumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase–positive hepatocytes. These results show that, although chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in nontumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes

TR beta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells

International audienceBackground & Aims Thyroid hormones elicit many cellular and metabolic effects in various organs. Most of these actions, including mitogenesis, are mediated by the thyroid hormone 3,5,3′-triiodo-l-thyronine (T3) nuclear receptors (TRs). They are transcription factors, expressed as different isoforms encoded by the TRα and TRβ genes. Here, experiments were performed to determine whether (i) T3-induces hepatocyte proliferation in mouse liver and pancreas, and, (ii) which TR isoform, is responsible for its mitogenic effect. Methods Cell proliferation was measured by bromodeoxyuridine (BrdU) incorporation after T3 or the TRβ agonist GC-1 in liver and pancreas of CD-1, C57BL, or TRα0/0 mice. Cell cycle-associated proteins were measured by Western blot. Results T3 added to the diet at a concentration of 4mg/kg caused a striking increase in BrdU incorporation in mouse hepatocytes. Increased BrdU incorporation was associated with enhanced protein levels of cyclin D1 and PCNA and decreased levels of p27. Treatment with GC-1, a selective agonist of the TRβ isoform, also induced a strong mitogenic response of mouse hepatocytes and pancreatic acinar cells which was similar to that elicited by T3. Finally, treatment with T3 of mice TRα0/0 induced a proliferative response in the liver and pancreas, similar to that of their wild type counterpart. Conclusions These results demonstrate that T3 is a powerful inducer of cell proliferation in mouse liver and suggest that the β-isoform is responsible for the hepatomitogenic activity of T3. The same isoform seems to also mediate the proliferation of mouse pancreatic acinar cells