Donepezil, the most widely used drug for the treatment of Alzheimer's disease (AD), is an acetylcholinesterase (AChE) inhibitor and is thought to improve cognition by stimulating cholinergic neurotransmission. However, no correlation has yet been established between the inhibitory role of AChE inhibitors and their therapeutic effects when used in AD patients. The cleavage pathway of amyloid precursor protein (APP) includes amyloidgenic (β, γ-cleavage) and non-amyloidgenic (α-cleavage) pathways. The intracellular transportation of APP is important in determining these cleavage pathways. It has been suggested that sorting nexin (SNX) family proteins regulates the intracellular transport of APP, thereby enhancing α-cleavage. In this study, we examined the effects of donepezil on SNX33 expression changes and APP processing in primary cultures of fetal rat cortical neurons. While donepezil treatment increased the levels of SNX33 expression and soluble APPα (sAPPα) in culture media, no changes were observed regarding full-length APP expression in the cell lysate. Donepezil also reduced the release of amyloid β (Aβ) into culture media in a concentration- and time-dependent manner. This reduction was not affected by acetylcholine receptor antagonists. The membrane surface expression of APP was elevated by donepezil. Furthermore, SNX knockdown by antisense morpholino oligos prevented the effects of donepezil. These results indicated that donepezil increased APP expression at the surface of the plasma membrane by decreasing APP endocytosis through upregulation of SNX33, suggesting donepezil might stimulate the non-amyloidogenic pathway. This new mechanism of action for the currently used anti-AD drug may provide a valuable basis for future drug discovery.

Management of chemotherapy-induced adverse effects and the associated pharmaceutical interventions as well as supportive care evidence creation are the most important responsibilities of oncology pharmacists. We have evaluated the (1) efficacy of long-term and successive pharmaceutical care in outpatient chemotherapy and (2) nephroprotective effects of magnesium (Mg) against cisplatin-induced nephrotoxicity (CIN). The results revealed that the adoption rate of pharmaceutical proposals was 98%, and that approximately 70% of the proposals attenuated painful symptoms. Moreover, approximately 60% of pharmaceutical interventions were established after the third visit; in particular, approximately 20% were suggested after the tenth visit. These results have shown that long-term and successive pharmaceutical care by oncology pharmacists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation. CIN frequency and serum creatinine elevation were significantly attenuated by Mg premedication during the cisplatin, docetaxel, and fluorouracil regimen, without changes in adverse effects and response rate. Mg premedication has been suggested to exert a protective effect against CIN without influencing on adverse effects and anti-tumor efficacy. The nephroprotective effect of Mg against CIN was evaluated using Wistar rats. Cisplatin (2.5 mg/kg) was administered once or three times weekly with or without 40 mg/kg MgSO4. The results revealed that Mg regulates the expression of organic cation transporter 2, multidrug and toxin extrusion protein 1, and copper transporter 1, leading to reduced renal platinum accumulation, which results in CIN attenuation. In conclusion, evaluation of pharmaceutical care and supportive care by oncology pharmacists is necessary for advanced care of cancer patients.

Epigenetics is the study of heritable changes in gene expression that occur without alterations in the DNA sequence. Several studies have shown that environmental chemicals can alter epigenetic modifications, including histone modifications and DNA methylation. Environmental chemicals may show toxic effects via epigenetic mechanism-regulated changes in gene expression. Previously, we reported that zinc treatment rapidly decreased Lys(4)-trimethylated and Lys(9)-acetylated histone H3 in the metallothionein (MT) promoter, and also decreased total histone H3. The chromatin structure in the MT promoter may be locally disrupted by zinc-induced nucleosome removal. We also showed that chromium (VI) inhibited MT gene transcription by modifying the transcription potential of the co-activator p300. MT is a small cysteine-rich protein that is active in zinc homeostasis, cadmium detoxification, and protection against reactive oxygen species. Epigenetic changes might influence the cytoprotective function of the MT gene. In this review, I briefly summarize the results of previous studies and discuss the mechanisms and toxicological significance of metal-mediated epigenetic modifications.

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca2+ concentration ([Ca2+]cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca2+ channel blockers are only effective in very few patients with IPAH (<10%). It is unclear why dihydropyridine Ca2+ channel blockers are not therapeutically effective in a majority of IPAH patients. We have previously shown that extracellular Ca2+-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, and it contributes to enhanced [Ca2+]cyt responses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca2+ channel blockers on [Ca2+]cyt responses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca2+]cyt in IPAH-PASMCs, but not in PASMCs from normal subjects. Nicardipine (dihydropyridines) and Bay K 8644 (a dihydropyridine Ca2+ channel activator) also augmented the CaSR-mediated [Ca2+]cyt increase in IPAH-PASMCs. In contrast, non-dihydropyridine Ca2+ channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca2+]cyt response in IPAH-PASMCs. Finally, in monocrotaline-induced pulmonary hypertensive rats, nifedipine caused further increase in right ventricular systolic pressure and thus right ventricular hypertrophy. In conclusion, dihydropyridine Ca2+ channel blockers could exacerbate symptoms of pulmonary hypertension in IPAH patients with upregulated CaSR in PASMCs.

Chronic alcohol consumption is a major public health problem that frequently leads to the development of liver steatosis, fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Hyperhomocysteinemia is a pathological consequence of alcoholic liver disease (ALD) and is attributed to hepatic endoplasmic reticulum (ER) stress and insulin resistance. However, the regulatory function of nuclear receptors in ALD associated with dysregulation of homocysteine metabolism remains largely unknown. Nuclear receptor small heterodimer partner (SHP, NROB2) is a pleiotropic transcriptional repressor involved in regulating various metabolic path-ways in the liver. This study investigated a critical role of SHP in alcohol-induced hyperhomocysteinemia. . The expression and enzymatic activities of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine y -lyase (CTH) were significantly increased in the liver of SHP- knockout (SKO) mice as compared to the wild-type mice. The substrates of BHMT and CTH, such as betaine, choline and cystathionine, were decreased in SKO liver while their products including hydrogen sulfide and cysteine were increased. However, methionine and homocysteine were not altered by SHP- deficiency, suggesting that the methionine cycle is activated in SKO mice. Forkhead box A (FOXA)- binding site was identified in both the BHMT and CTH promoters. Luciferase assay demonstrated that FOXAI, but not FOXA2, activated both BHMT and CTH promoters through the FOXA-binding site. Overexpression of FOXA1 induced BHMT and CTH expression in Hepal-6 cells, which was inhibited by SHP coexpression. Consistently, alcohol-induced hyperhomocysteinemia, and homocysteine-induced hepatic ER stress and glucose intolerance were abrogated in SKO mice. These novel findings identified SHP and FOXA1 as important regulators of hepatic homocysteine metabolism. Because hyper-homocysteinemia is a risk factor for cardiovascular disease and insulin resistance, and is often associated with ALD and metabolic syndrome, SHP and FOXA1 could be used as potential targets for hyperhomocysteinemia and its related diseases. Taken together, these results shed light on the regulatory mechanism of homocysteine metabolism in the liver.

Taste disorder is one of the adverse effects of cancer chemotherapy resulting in a loss of appetite, leading to malnutrition and a decrease in the quality of life of the patient. Oxaliplatin, a platinum anticancer drug, has a critical role in colon cancer chemotherapy and is known to induce taste disorder. Here, we evaluated the taste functions in oxaliplatin-administered rats. Among the taste receptors, expression levels of T1R2, one of the sweet receptor subunits, increased in the circumvallate papillae of the oxaliplatin-administered rats. In a brief-access test, i.e., behavioral analysis of the taste response, oxaliplatin-administered rats showed a decreased response to sweet taste. However, we did not detect any differences in the plasma levels of zinc, number of taste cells, or morphology of taste buds between control and oxaliplatin-administered rats. In conclusion, the decreased response to sweet taste by oxaliplatin administration may be due to the upregulation of T1R2 expression.