Archives of Pharmacal Research

Phytochemicals enriched in spices: a source of natural epigenetic therapy Abstract Metabolic disorders are increasing at an alarming rate due to the stressful lifestyle and inappropriate diet schedule. The unorganized habits influence multiple epigenetic mechanisms like DNA methylation, histone post-translational modifications and miRNA expression. These epigenetic modifications are reversible in nature and regulate gene expression in response to external stimuli without altering the DNA sequence. Dietary herbs are enriched in various phytochemicals which additionally provide nutrition and health benefits; and are known to target these epigenetic gene regulatory mechanisms. They have been in use since human civilization for their health-promoting effects. Culinary spices and condiments which are generally used to enhance the taste of food are rich repositories of many phytochemicals which provides them their unique aroma. Considerable attention has been given to “Nutri-epigenetics” nowadays, with a focus on evaluating the potential of phytochemicals to regulate/neutralize various epigenetic modifications. This article aims at highlighting the epigenetic regulatory roles of phytochemicals present in condiments and spices with considerable health benefits.

Correction to: Pharmacology of natural radioprotectors We apologize that there are some errors in the references for three sentences and Table 2.

Cis -element architecture of Nrf2–sMaf heterodimer binding sites and its relation to diseases Abstract Cellular detoxication is essential for health because it provides protection against various chemicals and xenobiotics. The KEAP1–NRF2 system is important for cellular defense against oxidative and electrophilic stresses as NRF2 activates the transcription of an array of cytoprotective genes, including drug-metabolizing and antioxidant enzymes, in a stress-dependent manner. The CNC family of transcription factors, including NRF2, form heterodimers with small Maf (sMaf) proteins and bind to consensus DNA sequences that have been referred to as antioxidant response element, electrophile response element, or NF-E2-binding element. These sequences are now collectively called CNC–sMaf binding element (CsMBE). In addition to forming a heterodimer with CNC proteins, sMaf proteins can form homodimers and recognize regulatory motifs called Maf recognition element (MARE). Although the CsMBE sequence substantially overlaps with that of MARE, the sequences differ. NRF2 selectively recognizes CsMBE, which is critical for cytoprotection. Recent advances in high-throughput sequencing and population-scale genome analysis provide new insights into the transcriptional regulation involved in the stress response. The integration of a genome-wide map of NRF2 occupancy with disease-susceptibility loci reveals the associations between polymorphisms in CsMBE and disease risk, information useful for the personalized medicine of the future.

Involvement of mitochondrial biogenesis during the differentiation of human periosteum-derived mesenchymal stem cells into adipocytes, chondrocytes and osteocytes Abstract Due to a rapidly expanding aging population, the incidence of age-related or degenerative diseases has increased, and efforts to handle the issue with regenerative medicine via adult stem cells have become more important. And it is now clear that the mitochondrial energy metabolism is important for stem cell differentiation. When stem cells commit to differentiate, glycolytic metabolism is being shifted to mitochondrial oxidative phosphorylation (OXPHOS) to meet an increased cellular energy demand required for differentiated cells. However, the nature of cellular metabolisms during the differentiation process of periosteum-derived mesenchymal stem cells (POMSC) is still unclear. In the present study, we investigated mitochondrial biogenesis during the adipogenic, chondrogenic, and osteogenic differentiation of POMSCs. Both mitochondrial DNA (mtDNA) contents and mitochondrial proteins (VDAC and mitochondrial OXPHOS complex subunits) were increased during all of these mesenchymal lineage differentiations of POMSCs. Interestingly, glycolytic metabolism is reduced as POMSCs undergo osteogenic differentiation. Furthermore, reducing mtDNA contents by ethidium bromide treatments prevents osteogenic differentiation of POMSCs. In conclusion, these results indicate that mitochondrial biogenesis and OXPHOS metabolism play important roles in the differentiation of POMCS and suggest that pharmaceutical modulation of mitochondrial biogenesis and/or function can be a novel regulation for POMSC differentiation and regenerative medicine.

Hesperetin ameliorates lipopolysaccharide-induced acute lung injury in mice through regulating the TLR4–MyD88–NF-κB signaling pathway Abstract Hesperetin, a major bioflavonoid in sweet oranges and lemons, exerts an anti-inflammatory effect in pulmonary diseases; however, its effect on lipopolysaccharide (LPS)-induced acute lung injury is unclear. This study investigated the effect of hesperetin on LPS-induced lung inflammatory response. Mice were intratracheally instilled with 5 mg/kg body weight LPS, and then were given hesperetin orally (10, 20, and 30 mg/kg body weight) 1 h later. Hesperetin dramatically suppressed the levels of interleukin-6 and tumor necrosis factor-α, as well as the number of inflammatory cells in bronchoalveolar lavage fluid. Besides, it reduced lung injury, wet weight/dry weight ratio, and myeloperoxidase and lactate dehydrogenase activities, and enhanced superoxide dismutase activity. In addition, hesperetin significantly downregulated the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein expression and suppressed nuclear factor-kappa B (NF-κB) activation in lung tissue. Together, these results indicated that the anti-inflammatory effect of hesperetin is associated with the TLR4–MyD88–NF-κB pathway, and that hesperetin shows therapeutic potential for LPS-induced acute lung injury.

Protective effects of 6,7,4′-trihydroxyisoflavone, a major metabolite of daidzein, on 6-hydroxydopamine-induced neuronal cell death in SH-SY5Y human neuroblastoma cells Abstract Daidzein, one of the important isoflavones, is extensively metabolized in the human body following consumption. In particular, 6,7,4′-trihydroxyisoflavone (THIF), a major metabolite of daidzein, has been the focus of recent investigations due to its various health benefits, such as anti-cancer and anti-obesity effects. However, the protective effects of 6,7,4′-THIF have not yet been studied in models of Parkinson’s disease (PD). Therefore, the present study aimed to investigate the protective activity of 6,7,4′-THIF on 6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells. Pretreatment of SH-SY5Y cells with 6,7,4′-THIF significantly inhibited 6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive oxygen species production. In addition, 6,7,4′-THIF significantly attenuated reductions in 6-OHDA-induced superoxide dismutase activity and glutathione content. Moreover, 6,7,4′-THIF attenuated alterations in Bax and Bcl-2 expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore, 6,7,4′-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2. Additionally, 6,7,4′-THIF effectively prevented 6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results suggest that 6,7,4′-THIF, a major metabolite of daidzein, may be an attractive option for treating and/or preventing neurodegenerative disorders such as PD.

The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain Abstract Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter that is required for the control of synaptic excitation/inhibition and neural oscillation. GABA is synthesized by glutamic acid decarboxylases (GADs) that are widely distributed and localized to axon terminals of inhibitory neurons as well as to the soma and, to a lesser extent, dendrites. The expression and activity of GADs is highly correlated with GABA levels and subsequent GABAergic neurotransmission at the inhibitory synapse. Dysregulation of GADs has been implicated in various neurological disorders including epilepsy and schizophrenia. Two isoforms of GADs, GAD67 and GAD65, are expressed from separate genes and have different regulatory processes and molecular properties. This review focuses on the recent advances in understanding the structure of GAD, its transcriptional regulation and post-transcriptional modifications in the central nervous system. This may provide insights into the pathological mechanisms underlying neurological diseases that are associated with GAD dysfunction.

MiR-338-5p ameliorates pathological cardiac hypertrophy by targeting CAMKIIδ Abstract Pathological cardiac hypertrophy (PCH) is characterized by an increase in cardiomyocyte size and thickening of the ventricular walls during the adaptive response to maintain cardiac function, which often progresses to a maladaptive response and, ultimately, to heart failure. Previous studies have demonstrated that miRNAs play roles in the pathogenesis of PCH. In this study, we first found that the regulation of miR-338-5p was aberrant in cardiac tissues of heart failure patients and transverse aortic constriction (TAC)-induced PCH mice. Overexpression of miR-338-5p in the heart using recombinant adeno-associated virus serotype 9 (rAAV9) ameliorated TAC-induced PCH, as indicated by a decreased heart weight/body weight (HW/BW) ratio. Furthermore, miR-338-5p mitigated the TAC-induced damage in heart contraction and relaxation function, as measured by echocardiography and a cardio hemodynamic measurement, respectively. We also identified CAMKIIδ as a direct target of miR-338-5p using bioinformatics tools and the luciferase reporter assay. Finally, we observed that the miR-338-5p-mediated downregulation of CAMKIIδ reversed the cell surface area enlargement induced by the Ang-II treatment in H9c2 cells. Therefore, we highlight a novel molecular mechanism of the miR-338-5p/CAMKIIδ axis that contributes to the pathogenesis of PCH.

Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects Abstract Zolpidem is extensively metabolized by CYP3A4, CYP2C9 and CYP1A2. Previous studies demonstrated that pharmacokinetics of zolpidem was affected by CYP inhibitors, but not by short-term treatment of clarithromycin. The objective of this study was to investigate the effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. In the control phase, 33 subjects received a single dose of zolpidem (5 mg). One week later, in the clarithromycin phase, the subjects received clarithromycin (500 mg) twice daily for 5 days to reach steady state concentrations, followed by zolpidem (5 mg) and clarithromycin (500 mg). In each phase, plasma concentrations of zolpidem were evaluated up to 12 h after drug administration by using liquid chromatography-tandem mass spectrometry method. In the clarithromycin phase, mean total area under the curve of zolpidem (AUCinf) was 1.62-fold higher and the time to reach peak plasma concentration of zolpidem (tmax) was prolonged by 1.95-fold compared to the control phase. In addition, elimination half-life (t1/2) of zolpidem was 1.40-fold longer during co-administration with clarithromycin and its apparent oral clearance (CL/F) was 36.2% lower with clarithromycin administration. The experimental data demonstrate the significant pharmacokinetic interaction between zolpidem and clarithromycin at steady-state.

Tetramethylpyrazine attenuates placental oxidative stress, inflammatory responses and endoplasmic reticulum stress in a mouse model of gestational diabetes mellitus Abstract Gestational diabetes mellitus (GDM) is a disease characterized by insufficient insulin secretion and glucose metabolic disorder during pregnancy. Tetramethylpyrazine has been reported to inhibit endoplasmic reticulum (ER) stress and high glucose-induced inflammation, which are closely associated with GDM. This study aimed to investigate the effects of tetramethylpyrazine on inflammatory responses, ER stress and oxidative stress of the placenta in a mouse model of GDM. Our results showed that tetramethylpyrazine treatment significantly alleviated the GDM symptoms characterized by low body weight and serum insulin levels, high blood glucose, and decreased β-cell function in pregnant C57BL/KsJdb/+ mice. In addition, tetramethylpyrazine reduced the level of malondialdehyde, and increased the levels of superoxide dismutase, glutathione peroxidase and glutathione. Moreover, tetramethylpyrazine decreased the total serum cholesterol, serum triglyceride, and serum low-density lipoprotein levels and increased the high-density lipoprotein level. Further, tetramethylpyrazine regulated the levels of serum and placental inflammatory factors and the expression of ER stress related proteins. Taken together, the present study demonstrated that tetramethylpyrazine attenuated placental oxidative stress, inflammatory responses and ER stress in GDM mice.