Graphical abstract Highlights ► The distribution of GABAA receptor subunits is highly heterogeneous. ► The distribution of mRNAs corresponds to that of proteins. ► The distribution in the mouse ...correlates largely to that in rats although there are distinct differences.
GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that ...can belong to eight different subunit classes. Depending on their subunit composition, these receptors exhibit distinct pharmacological and electrophysiological properties. Recent studies on recombinant and native GABA(A) receptors suggest the existence of far more receptor subtypes than previously assumed. Thus, receptors composed of one, two, three, four, or five different subunits might exist in the brain. Studies on the regional, cellular and subcellular distribution of GABA(A) receptor subunits, and on the co-localization of these subunits at the light and electron microscopic level for the first time provide information on the distribution of GABA(A) receptor subtypes in the brain. These studies will have to be complemented by electrophysiological and pharmacological studies on the respective recombinant and native receptors to finally identify the receptor subtypes present in the brain. The distinct cellular and subcellular location of individual receptor subtypes suggests that they exhibit specific functions in the brain that can be selectively modulated by subtype specific drugs. This conclusion is supported by the recent demonstration that different GABA(A) receptor subtypes mediate different effects of benzodiazepines. Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes. Such drugs might exhibit quite selective clinical effects.
GABA
A receptors are ligand-operated chloride channels assembled from five subunits in a heteropentameric manner. Using immunocytochemistry, we investigated the distribution of GABA
A receptor ...subunits deriving from 13 different genes (α1–α6, β1–β3, γ1–γ3 and δ) in the adult rat brain. Subunit α1-, β1-, β2-, β3- and γ2-immunoreactivities were found throughout the brain, although differences in their distribution were observed. Subunit α2-, α3-, α4-, α5-, α6-, γ1- and δ-immunoreactivities were more confined to certain brain areas. Thus, α2-subunit-immunoreactivity was preferentially located in forebrain areas and the cerebellum. Subunit α6-immunoreactivity was only present in granule cells of the cerebellum and the cochlear nucleus, and subunit γ1-immunoreactivity was preferentially located in the central and medial amygdaloid nuclei, in pallidal areas, the substantia nigra pars reticulata and the inferior olive. The α5-subunit-immunoreactivity was strongest in Ammon’s horn, the olfactory bulb and hypothalamus. In contrast, α4-subunit-immunoreactivity was detected in the thalamus, dentate gyrus, olfactory tubercle and basal ganglia. Subunit α3-immunoreactivity was observed in the glomerular and external plexiform layers of the olfactory bulb, in the inner layers of the cerebral cortex, the reticular thalamic nucleus, the zonal and superficial layers of the superior colliculus, the amygdala and cranial nerve nuclei. Only faint subunit γ3-immunoreactivity was detected in most areas; it was darkest in midbrain and pontine nuclei. Subunit δ-immunoreactivity was frequently co-distributed with α4 subunit-immunoreactivity, e.g. in the thalamus, striatum, outer layers of the cortex and dentate molecular layer. Striking examples of complementary distribution of certain subunit-immunoreactivities were observed. Thus, subunit α2-, α4-, β1-, β3- and δ-immunoreactivities were considerably more concentrated in the neostriatum than in the pallidum and entopeduncular nucleus. In contrast, labeling for the α1-, β2-, γ1- and γ2-subunits prevailed in the pallidum compared to the striatum. With the exception of the reticular thalamic nucleus, which was prominently stained for subunits α3, β1, β3 and γ2, most thalamic nuclei were rich in α1-, α4-, β2- and δ-immunoreactivities. Whereas the dorsal lateral geniculate nucleus was strongly immunoreactive for subunits α4, β2 and δ, the ventral lateral geniculate nucleus was predominantly labeled for subunits α2, α3, β1, β3 and γ2; subunit α1- and α5-immunoreactivities were about equally distributed in both areas. In most hypothalamic areas, immunoreactivities for subunits α1, α2, β1, β2 and β3 were observed. In the supraoptic nucleus, staining of conspicuous dendritic networks with subunit α1, α2, β2, and γ2 antibodies was contrasted by perykarya labeled for α5-, β1- and δ-immunoreactivities. Among all brain regions, the median emminence was most heavily labeled for subunit β2-immunoreactivity. In most pontine and cranial nerve nuclei and in the medulla, only subunit α1-, β2- and γ2-immunoreactivities were strong, whereas the inferior olive was significantly labeled only for subunits β1, γ1 and γ2.
In this study, a highly heterogeneous distribution of 13 different GABA
A receptor subunit-immunoreactivities was observed. This distribution and the apparently typical patterns of co-distribution of these GABA
A receptor subunits support the assumption of multiple, differently assembled GABA
A receptor subtypes and their heterogeneous distribution within the adult rat brain.
Highlights • All PV-positive interneurons of DG-granule cell layer express GABAA receptor δ subunits. • PV-positive cells in hilus or molecular layer express δ subunits to a lower extent. • Only 8% ...of somatostatin-containing interneurons in DG express the δ subunit. • Calbindin- and calretinin-positive cells in DG seem not to express the δ subunit. • PV-positive cells in the (sub-)granule cell layer express α1, β2 and δ subunits.
Cancer and hepatic steatosis Paternostro, R.; Sieghart, W.; Trauner, M. ...
ESMO open,
08/2021, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis ...with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection.
•Non-alcoholic fatty liver disease can lead to cirrhosis with all its complications, including hepatocellular carcinoma.•Chemotherapy-associated acute steatohepatitis is a side-effect of chemotherapeutic agents and may limit treatment options.•In this review we summarize current clinical concepts of NAFLD and CASH that help clinicians in their clinical practice.
Aliment Pharmacol Ther 2012; 35: 83–91
Summary
Background Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal ...hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome.
Aim To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes.
Methods Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), RhoA, tumour necrosis factor‐alpha (TNF‐α) and placental growth factor (PlGF) were evaluated.
Results Thirteen patients (m/f = 12/1; Child–Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF‐α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43–85%) mRNA decrease of all five investigated genes.
Conclusion Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.
In this report we investigated the combination of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathway inhibition as a possible new therapeutic strategy for small ...cell lung cancer (SCLC).
EGFR, p-AKT, p-ERK, p-mTOR and p-p70s6K protein expressions were studied by immunohistochemistry in 107 small cell lung carcinomas and correlated with clinicopathological parameters. Cells of SCLC were treated with erlotinib+/-RAD001 and analysed for cell viability, proliferation, autophagy, and pathway regulation.
Epidermal growth factor receptor, p-AKT, p-ERK, p-mTOR, and p-p70s6K were expressed in 37, 24, 13, 55 and 91% of the tumour specimens of all SCLC patients, respectively, and were not associated with disease-free or overall survival. The expression of EGFR was lower in neoadjuvant-treated patients (P=0.038); mTOR pathway activation was higher in the early stages of disease (P=0.048). Coexpression of EGFR/p-mTOR/p-p70s6K was observed in 28% of all patients . EGFR immunoreactivity was associated with p-ERK and p-mTOR expression (P=0.02 and P=0.0001); p-mTOR immunoreactivity was associated with p-p70s6K expression (P=0.001). Tumour cells comprised a functional EGFR, no activating mutations in exons 18-21, and resistance to RAD001 monotherapy. We found synergistic effects of erlotinib and RAD001 combination therapy on the molecular level, cell viability, proliferation and autophagy.
The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC.
Summary
Background Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC).
Aim To identify prognostic factors in sorafenib‐treated HCC patients and to ...evaluate outcomes with respect to liver function.
Methods In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy‐eight HCC patients who received best supportive care (BSC) in the pre‐sorafenib era served as a control.
Results In sorafenib‐treated patients, low baseline α‐fetoprotein, low Child–Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP‐A patients had a median OS of 11.3 (sorafenib n = 76) vs. 6.4 (BSC n = 17) months (P = 0.010), and CP‐B patients had a median OS of 5.5 (sorafenib n = 55) vs. 1.9 (BSC n = 22) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L n = 58) vs. 3.9 (≥100 U/L n = 15) months for CP‐A patients (P = 0.127), and 6.5 (<100 U/L n = 33) vs. 2.1 (≥100 U/L n = 21) months for CP‐B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116).
Conclusions Sorafenib was associated with improved survival in both CP‐A and CP‐B patients. In CP‐B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.
Abstract Calumenin is a Ca2+ -binding protein that belongs to the CREC superfamily. It contains six EF-hand domains that exhibit a low affinity for Ca2+ as well as an endoplasmic reticulum retention ...signal. Calumenin exhibits a broad and relatively high expression in various brain regions during development as demonstrated by in situ hybridization. Signal intensity of calumenin is highest during the early development and then declines over time to reach a relatively low expression in adult animals. Immunohistochemistry indicates that at the P0 stage, calumenin expression is most abundant in migrating neurons in the zones around the lateral ventricle. In the brain of adult animals, it is expressed in various glial and neuronal cell types, including immature neurons in subgranular zone of hippocampal dentate gyrus. At the subcellular level, calumenin is identified in punctuate and diffuse distribution mostly in somatic regions where it co-localizes with endoplasmic reticulum (ER) and partially Golgi apparatus. Upon subcellular fractionation, calumenin is enriched in fractions containing membranes and is only weakly present in soluble fractions. This study points to a possible important role of calumenin in migration and differentiation of neurons, and/or in Ca2+ signaling between glial cells and neurons.
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