Hedgehog signalling pathway in adult liver: A major new player in hepatocyte metabolism and zonation?

Metabolic Zonation, i.e. the heterogeneous distribution of different metabolic pathways in different zones of the lobules, forms the basis of proper function of the liver in metabolic homeostasis and its regulation. According to recent results, Metabolic Zonation is controlled by the Wnt/β-catenin signalling pathway. Here, we hypothesize that hedgehog signalling via Indian hedgehog ligands plays an equal share in this control although, up to now, hedgehog signalling is considered not to be active in healthy adult hepatocytes. We provide broad evidence taken mainly by analogy from other mature organs that hedgehog signalling in adult hepatocytes may particularly control liver lipid and cholesterol metabolism as well as certain aspects of hormone biosynthesis. Like Wnt/β-catenin signalling, it seems to act on a very low level forming a porto-central gradient in the lobules opposite to that of Wnt/β-catenin signalling with which it is interacting by mutual inhibition. Consequently, modulation of hegdehog signalling by endogenous and exogenous agents may considerably impact on liver lipid metabolism and beyond. If functioning improperly, it may possibly contribute to diseases like non-alcoholic fatty liver disease (NAFLD) and other diseases such as lipodystrophy.     

Evaluation of the antiparasitic activities of imidazol-2-ylidene–gold(I) complexes

A series of cationic gold(I)–carbene complexes with various 4,5-diarylimidazolylidene ligands were either newly prepared or repurposed for testing against protozoal Leishmania major, Toxoplasma gondii, and Trypanosoma brucei parasites. The syntheses of the new complexes 1b and 1c were described. Ferrocene compound 1a showed the highest activities against L. major amastigotes and T. gondii and distinct selectivity for T. gondii cells when compared with the activity against nonmalignant Vero cells. The ferrocene derivatives 1a–c are generally more active against the L. major amastigotes and the T. gondii tachyzoites than the other tested anisyl gold complexes and the approved drugs atovaquone and amphotericin B. Compounds 1a and 1e showed the highest selectivities for L. major amastigotes. Compounds 1d and 1f showed the highest selectivities for L. major promastigotes; 1f was the most active compound against L. major promastigotes of this series of compounds. The 3,4,5-trimethoxyphenyl analog 1b also exhibited a much greater selectivity for T. b. brucei cells when compared with its activity against human HeLa cells.     

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma

Introduction

Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM.

Methods

Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m² on days 1 and 2, bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15–59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min).

Results

A median number of two (range 1–5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively.

Summary

These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.     

Age-specific transcriptional response to stroke

Increased age is a major risk factor for stroke incidence and post-ischemic mortality. To develop age-adjusted therapeutic interventions, a clear understanding of the complexity of age-related post-ischemic mechanisms is essential. Transient occlusion of the middle cerebral artery—a model that closely resembles human stroke—was used to induce cerebral infarction in mice of 4 different ages (2, 9, 15, 24 months). By using Illumina cDNA microarrays and quantitative PCR we detected a distinct age-dependent response to stroke involving 350 differentially expressed genes. Our analyses also identified 327 differentially expressed genes that responded to stroke in an age-independent manner. These genes are involved in different aspects of the inflammatory and immune response, oxidative stress, cell cycle activation and/or DNA repair, apoptosis, cytoskeleton reorganization and/or astrogliosis, synaptic plasticity and/or neurotransmission, and depressive disorders and/or dopamine-, serotonin-, GABA-signaling. In agreement with our earlier work, aged brains displayed an attenuated inflammatory and immune response (Sieber et al., 2011) and a reduced impairment of post-stroke synaptic plasticity. Our data also revealed a distinct age-related susceptibility for post-ischemic depression, the most common neuropsychiatric consequence of stroke, which has a major influence on functional outcome.