Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success.

The metabolism of triglycerides (TGs) is regulated, among others, by the lipoprotein lipase (LPL) that hydrolyses the TGs on endothelial cells. In turn, LPL is inhibited by the ANGPTLs family of proteins, such as ANGPTL3, 4, and, 8; the latter is the least known. In this work, we have tried to establish the expression and localisation of the Angiopoietin-like 8 (ANGPTL8) protein in the visceral adipose tissue (VAT) of morbid-obese and non-obese patients. 109 subjects (66 women and 43 men) undergoing laparoscopic surgery participated in this study. A blood sample and a portion of the VAT were obtained, and the patients were classified according to their Body Mass Index (BMI) as non-obese (19.5–30 kg/m2) and morbid-obese (40–50 kg/m2). No significant changes in ANGPTL8 plasma levels were determined by EIA in obese patients. The immunocytochemistry and Western blotting showed the presence of increased ANGPTL8 in morbid-obese patients (p < 0.05). In-situ hybridisation and a real time polymerase chain reaction (RT-PCR) confirmed that the mRNA that encodes ANGPTL8 was present in adipocytes, without differences in their nutritional state (p = 0.89), and even in the endothelial cells. Our data suggests that ANGPT8 plasmatic levels do not change significantly in patients with morbid obesity, although there is a modest difference related to gender. Besides, we demonstrate that in visceral adipose tissue, ANGPTL8 is well defined in the cytoplasm of adipocytes coexisting with perilipin-1 and its mRNA, also is present in endothelial cells. These findings suggest the possibility that among other functions, ANGPTL8 could perform either a paracrine and/or an endocrine role in the adipose tissue.

Previously we demonstrated, in rats, that treatment with growth hormone (GH) and rehabilitation, carried out immediately after a motor cortical ablation, significantly improved the motor affectation produced by the lesion and induced the re-expression of nestin in the contralateral motor cortex. Here we analyze cortical proliferation after ablation of the frontal motor cortex and investigate the re-expression of nestin in the contralateral motor cortex and the role of the striatum and thalamus in motor recovery. The rats were subjected to ablation of the frontal motor cortex in the dominant hemisphere or sham-operated and immediately treated with GH or the vehicle (V), for five days. At 1 dpi (days post-injury), all rats received daily injections (for four days) of bromodeoxyuridine and five rats were sacrificed at 5 dpi. The other 15 rats (n = 5/group) underwent rehabilitation and were sacrificed at 25 dpi. GH induced the greatest number of proliferating cells in the perilesional cortex. GH and rehabilitation produced the functional recovery of the motor lesion and increased the expression of nestin in the striatum. In the thalamic ventral nucleus ipsilateral to the lesion, cells positive for nestin and actin were detected, but this was independent on GH. Our data suggest that GH-induced striatal nestin is involved in motor recovery.

The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen), and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01), by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01) after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01) following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets.

Previously we demonstrated, in rats, that the treatment with growth hormone (GH) and 20 rehabilitation, carried out immediately after a motor cortical ablation, significantly improved the 21 motor affectation produced by the lesion and induced the re-expression of nestin in the contralateral 22 motor cortex. Here we analyze cortical proliferation after ablation of the frontal motor cortex and 23 investigate the re-expression of nestin in the contralateral motor cortex and the role of the striatum 24 and thalamus in motor recovery. The rats were subjected to ablation of the frontal motor cortex in 25 the dominant hemisphere or sham-operated and immediately treated with GH or vehicle (V), for 26 five days. At 1 dpi (days after injury), all rats received daily injections (4 days) of 27 bromodeoxyuridine and were sacrificed. The other 15 rats (n = 5 / group) underwent rehabilitation 28 and were sacrificed at 25 dpi. GH induced the greatest number of proliferating cells in the 29 perilesional cortex. GH and rehabilitation produced the functional recovery of the motor lesion and 30 increased the expression of nestin in the striatum. In the thalamic ventral nucleus ipsilateral to the 31 lesion, cells positive for nestin and actin were detected, but this was independent of GH. Our data 32 suggest that GH-induced striatal nestin is involved in motor recovery. 33

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