Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 13, Issue 3, 2013

Among the endocrine factors able to regulate energy metabolism and body weight, thyroid hormones (THs) play important roles. 3,5,3'-triiodothyronine (T3) increases metabolic rate and leads to cholesterol reduction and loss of body weight and adiposity by increasing respiration and energy expenditure and by lowering metabolic efficiency. Because of these effects, T3 was previously tested as an anti-obesity and hypolipidemic agent. However, due to undesirable side effects, particularly within the cardiovascular system, its use was discontinued. The development of TH derivatives that retain lipid-lowering and anti-obesity efficacy while lack cardiovascular side effects would represent a potentially valuable therapeutic tool for the reduction of some important risk factors. Many laboratories have demonstrated metabolic effects of 3,5-diiodo-L-thyronine (3,5-T2), a natural TH, which can mimic biologic effects of T3 without inducing thyrotoxicosis effects. Recent studies revealed that 3,5-T2 acted as a protective/ameliorative factor against diet-induced obesity and its associated metabolic derangements (liver steatosis, hypertrigliceridemia, hypercholesterolemia, and insulin resistance). Accumulating evidence suggests that the actions of 3,5-T2 are exerted through mechanisms independent of those actuated by T3 and do not involve TH receptors. Instead, 3,5-T2 exerts marked effects on energy metabolism by acting mainly at the mitochondrial level.

Since the first human gene therapy clinical trials were proven successful in 2000, human gene therapy has witnessed setbacks as well as encouraging progress. While these first clinical trials were performed with a γ-retrovirus vector to correct X-linked severe combined immunodeficiency (SCID-X1) in children, others since then have applied similar or alternative viral vector strategies. More recently, lentiviral vectors have been used for the correction of human β- thalassaemia and adrenoleukodystrophy. They have also been successfully used in the treatment of leukaemia by modifying cytotoxic T cells directed to cancer cells. Here we describe the production of clinical grade retro- and lentiviral vectors for application in human therapy.

Backgrounds: Contrast media (CM)-induced nephropathy (CIN) affects morbidity and mortality in humans. Although CIN is mediated by several factors including the renin-angiotensin system (RAS), little is known about the pathophysiology. To clarify the mechanism, we developed a novel murine CIN model. Methods: We made 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol) intravenously into the mice 4 weeks after NTX. Mice received an angiotensin converting enzyme inhibitor (ACEI, n=6), an angiotensin II receptor blocker (ARB, n=4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, n=5) daily. Results: Serum creatinine levels were significantly elevated in the NTX group compared to the non-NTX group on day 28. A day after CM injection, creatinine levels were additionally elevated in the non-treated group. While ACEI treatment significantly suppressed the creatinine levels, ARB treatment did not decrease the levels. Hoe-140 negated ACEI’s ability to suppress renal dysfunction. Conclusion: ACEI treatment may be useful for the prevention of CM-induced nephropathy.

Background: The prevalence of obesity has increased dramatically throughout the world, and weight reduction through lifestyle management is urgently warranted. At present, numerous supplements advertised for their antioverweight property are available in the Japanese market, but most of these lack proper evidence. Thus, we investigated dietary supplements that have been tested in clinical trials. Search Strategy: We researched anti-obesity supplements in the Japanese market using the google search engine in Japanese with the key terms “anti-obesity supplements,” ”diet supplements,” and “weight reduction supplements.” Results: We listed 49 companies that supply anti-obesity supplements. Of these, 11 had published clinical evidence of the anti-obesity efficacy of their supplements. These products contain the following active ingredients: Angelica keiskei, bofutsusho- san, capsaishin, DHA/EPA, forskohlii, garcinia cambogia, lactoferrin, L-carnitine, oligonol, tea catechin, and yeast hydrolysate. Conclusion: We obtained 11 supplements for which clinical evidence was published in medical journals in English. We also found 10 products for which clinical or animal evidence was published in Japanese. We expect that many companies will produce evidence of the efficacy of their products in the near future, thereby validating the use of dietary anti-obesity supplements in Japan.

Metabolic syndrome (MS) is associated with oxidative stress, both at early and advanced stages of the disease. Studies have confirmed the important role of medicinal plants or their active components in the prevention, treatment and lowering of risk factors in MS. Others authors have observed that polyphenols from Hibiscus sabdariffa L. (HSL) calyces increase cellular antioxidant capacity. We studied rat groups: Control (C), Control plus 30 g per liter of HSL calyces infusion (C+HSL 3%), 30% Sucrose-fed (MS) in their drinking water and 30% Sucrose fed plus HSL calyces infusion (MS+HSL) at the concentration of 7.5, 15 and 30 g per liter. The administration of HSL infusion to the MS rats increased the concentration of antioxidant capacity, catalase, superoxide dismutase and peroxidases activity enzymes in a dependent way, while the activity of glutathione peroxidase decreased in the liver. Indices of lipid peroxidation and protein carbonylation decreased in the liver, and systolic blood pressure, body weight, intra-abdominal fat and serum levels of glycation, triglycerides, insulin and HOMA index also decreased. These results suggest that the treatment with HSL infusion may decrease oxidative stress in MS liver and that it could be regarded as an alternative treatment for MS.

Periodontitis is associated with several systemic disorders, such as diabetes, cardiovascular disease and chronic kidney disease (CKD). However, the pathophysiological relationship between periodontitis and CKD is yet to be elucidated. We assessed the hypothesis that periodontal bacteria influence renal dysfunction. We used C57BL/6J mice and implanted chambers subcutaneously in the back of each mouse. Two weeks after implantation, we injected Porphyromonas gingivalis (P.g.), which is a major periodontal pathogen, or phosphate-buffered saline (PBS) into the chamber. The subcutaneous injections were administered once a week for 6 weeks during the observation period. 5/6 nephrectomy (NTX) was made by a two-step surgical procedure. The levels of anti-P.g. IgG in the serum were determined with an ELISA. After the operation, we measured serum creatinine using an enzymatic method. On day 28, mice were sacrificed and pathological evaluation was also performed. The repeated bacterial injections elevated the serum level of anti-P.g. IgG significantly. NTX increased the serum creatinine level (0.35 ± 0.02mg/dl) compared to native mice (0.15 ± 0.01mg/dl). Neither infection altered creatinine levels (P.g. 0.41 ± 0.04mg/dl) (n = 15) compared to the PBS injected group (n = 20). On days 1, 3 and 7, serum creatinine levels were significantly increased in the P.g. injected group compared to the PBS injected group. Of note, P.g. infection deteriorated 28 days survival rate (46.9%, p<0.05) compared to the PBS injected group (90.9%). It was suggested that periodontal pathogens deteriorated serum creatinine levels and the survival rate after NTX.

Background: Decreased nitric oxide (NO) bioavailability and increased lipid oxidation are associated with progressive endothelial dysfunction. L-Citrulline, the effective precursor of L-arginine which is essential as a substrate for endothelial NO synthase (eNOS), is effective in enhancing NO-dependent signaling. However, little is known about the efficacy of L-citrulline supplementation on lipoprotein oxidation and endothelial dysfunction. Methods: Twenty-two patients (aged 41 - 64 years old) diagnosed with vasospastic angina with flow-mediated dilation (FMD) of the brachial artery (< 5.5%) received 800 mg/day of L-citrulline for 8 weeks. FMD (%), blood NOx, asymmetric dimethylarginine (ADMA), small dense LDL, oxidized lipids, amino acids concentrations were measured before and after supplementation. Results: Compared with baseline values, FMD (%) was significantly improved at 4 and 8 weeks as well as at 4 weeks after the end of intake. L-Citrulline supplementation caused a significant lowering of plasma ADMA levels. Plasma Larginine/ ADMA ratio and NOx levels rose markedly throughout the study period. Moreover, significant reductions of serum oxidized LDL and lectin-like oxidized LDL receptor 1 (LOX-1) ligand containing ApoB (LAB), an indicator of the biological activity of oxidized lipoprotein binding to LOX-1, were observed after L-citrulline intake. Conclusions: L-Citrulline supplementation improves endothelial dysfunction, probably due to potentiating NO-dependent reactions and decreasing the state of lipoprotein oxidation in humans.

The article describes development of a robust pharmacophore model and investigates structure activity relationship of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolone derivatives reported for DPP-IV inhibition, using PHASE module of Schrodinger software. Instant study also elaborates molecular interaction studies of 3-aminomethyl- 1,2-dihydro-4-phenyl-1-isoquinolones derivatives on maestro 8.5 workstation. The 3D-QSAR study comprises, four point pharmacophore features (APRR.9), including one hydrogen bond acceptor (A), one Positive (P) and two aromatic ring (R) with discrete geometries. The developed pharmacophore features were used to derive a predictive atom-based 3D QSAR model. Thus obtained 3D QSAR model has an excellent regression coefficient value (r2=0.9707) along with good statistical significance as shown by high Fisher ratio (F=215). The model also exhibits good predictive power, which is confirmed by high value of cross validated correlation coefficient (q2 = 0.901). The instant studied QSAR model suggests that hydrogen bond acceptor and aromatic character features are crucial for the DPP-IV inhibitory activity. The QSAR model also suggests that the inclusion of hydrophobic substituents, would enhance the DPP-IV inhibition. In addition to the hydrogen bond acceptor, hydrophobic character, electron withdrawing character features positively contribute to the DPP-IV inhibition.

Background: In patients with myocarditis, autoimmune disease is considered to be responsible for the pathogenesis. Previous studies revealed that plant polyphenols inhibit autoimmune myocarditis in mice. However, the effect of chlorogenic acid (CGA), one of the major polyphenol constituents of coffee beans is remain unknown. The purpose of this study is to investigate the effects of CGA on experimental autoimmune myocarditis (EAM) in mice. Methods: Balb/c mice were immunized with cardiac myosin peptides and complete Freund's adjuvant. CGA or vehicle (Cont) were administered orally from day 0 to day 21 (n=6 and 7, respectively). Mice were sacrificed on day 21. Results: We found that the CGA significantly suppressed intercellular adhesion molecule-1 (ICAM-1) expression in the EAM hearts. The suppressed ICAM-1 tended to reduce myocardial fibrosis compared to control EAM hearts. Conclusion: The findings suggest that the CGA influences inhibition of cell adhesion in myocarditis, the CGA treatment may have beneficial effects for progression of myocarditis.