Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 13, Issue 2, 2013

Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress degradation of active glucagon-like peptide-1 and promote insulin secretion from pancreatic β cells in a blood glucose-dependent manner to decrease the blood glucose level. They lower the risk of hypoglycemia without causing weight gain and may protect pancreatic β cells; thus, DPP-4 inhibitors may overcome the challenges faced by conventional diabetes treatments. In particular, linagliptin, which has been shown to prevent cardiovascular events in meta-analyses of randomized studies and phase III studies performed, might extend healthy life expectancy, which is the goal of diabetes treatment. Given that one goal of diabetes treatment is prevention of cardiovascular events, glycemic control alone does not suffice; thus, expectations are placed on DPP-4 inhibitors with more potent effects regarding cardiovascular events. In fact, the greatest risk factor for cardiovascular events in patients with diabetes is a high LDL cholesterol level, followed by a high triglyceride level and a low HDL cholesterol level. Thus, future DPP-4 inhibitors must serve to effectively control diabetes and eliminate other risk factors. In addition to its hypoglycemic effect, linagliptin suppresses hepatic steatosis and has beneficial effects on lipid metabolism. Because of these favorable properties, linagliptin may be ascribed as a second-generation DPP-4 inhibitor.

Gene association studies are very appealing in autoimmune diseases. In recent years, access to other human gene sequences prompted investigators to focus on genes encoding the immune regulatory proteins such as the costimulatory, adhesion molecules, cytokines and chemokines and their receptors. Among them, cytotoxic T-lymphocyte antigen-4 (CTLA-4) has been extensively studied for its pivotal role in autoimmunity. As a central regulatory element of the immune responses magnitude, CTLA-4 could act as a double-edged sword and only the optimal expression ensures an effective, but at the same time, safe immune response. Thus, we can argue that CTLA-4 alleles associated with abnormal membrane expression could make a person more susceptible to tumor growth and/or manifestation of autoimmune diseases. Unfortunately, the relationship between the presence of SNP conferring susceptibility/protection to autoimmune disease and the genetic regulation/modification of CTLA-4 is the not yet fully clarified, and in some aspects conflicting.

Statins have been shown to have beneficial effects on preventing myocardial infarction, revascularization, and stroke, and decreasing cardiovascular mortality in numerous clinical trials. Statins are well tolerated and have been extensively studied all over the world. Physicians should not hesitate in prescribing statins to patients not only with hypercholesterolemia, but also those with high risk for atherosclerotic diseases although statins may have adverse effects such as muscle disease, liver dysfunction, and diabetes, because the incidence of these adverse effects is quite low. Physicians often need to treat patients with hypercholesterolemia and hepatic and renal disease or at the extremes of age with statins to prevent cardiovascular disease. Even in such patients, statins can be safely used with appropriate precautions. Statins sometimes need to be used with other lipid-lowering drugs to reach the recommended LDL-C goal and to improve atherogenic lipid profiles. Combination therapy is generally safe as well, if the drugs are prescribed appropriately and carefully.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons. Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, and has neurotrophic and neuroprotective activities. To examine the efficacy of VEGF electro-gene therapy for ALS, intramuscular mouse VEGF 164 gene transfer was performed by electroporation to treat a mouse model of ALS, transgenic Cu/Zn superoxide dismutase (SOD1) (G93A) mice. VEGF electro-gene therapy delayed the onset of decline in hindlimb function by more than 1 week, but did not significantly prolong survival in SOD1 transgenic mice, suggesting that continuous release of VEGF 164 by intramuscular electro-gene therapy is partially effective in the treatment of SOD1 transgenic mice.

Increasing age and replicative senescence with critical shortening of telomeres is associated with endothelial dysfunction followed by atherosclerosis. Although human telomerase reverse transcriptase (hTERT) is suggested to play an important role in endothelial cells, the precise effect of hTERT is still uncertain. In this study we investigated telomerase- independent hTERT function against oxidative stress using a primary culture of endothelial cells in which telomerase enzymatic activity was inhibited by addition of 3'-azido-3'-deoxythymidine (AZT). Overexpression of hTERT attenuated H2O2-induced endothelial apoptosis, assessed by cell viability assay and flow cytometry, accompanied by significant reduction of caspase-3 activity. Of importance, it was suggested that this effect was independent of telomerase enzymatic activity because hTERT expression did not alter telomere length under addition of AZT. Also, suppression of human telomerase-associated protein 1 (TEP-1) by introduction of TEP-1-specific small interfering RNA (siRNA) did not affect the anti-apoptotic effect of hTERT, suggesting that hTERT does not cooperate with TEP-1, another component of telomerase. Moreover, the anti-apoptotic effect of hTERT was through attenuation of H2O2-induced upregulation of p53, followed by reduction of Bax and induction of Bcl-xL. Also, overexpression of hTERT resulted in activation of the transcription factor, NFκB, which is an anti-apoptotic factor. Altogether, the present study demonstrated the anti-apoptotic effect of not telomerase but hTERT itself on cultured endothelial cells under oxidative stress, independent of telomere elongation, followed by acquired replicative ability. Also, this function of hTERT did not require another protein component of telomerase. Moreover, the anti-apoptotic effect of hTERT on endothelial cells was mediated by two pathways; reduction of p53/Bax and activation of NFκB.

Conventional therapies for idiopathic inflammatory bowel diseases (IBD), which are chronic nonspecific inflammatory disorders, are still insufficient. Recently, there has been a focus on acupuncture, one of the major complementary and alternative interventions, and some clinical trials have suggested efficacy of acupuncture for IBD. However, the therapeutic mechanism and effect of acupuncture are still unknown and are controversial because of not only lack of clinical trials but also poor experimental investigation. To prevent patients receiving ineffectual therapy, evaluation of its efficacy and elucidation of its mechanisms are important. In this study, we employed mice with dextran sulfate sodium (DSS)-induced colitis and investigated the effect of electro-acupuncture on disease activity and colonic inflammation. We performed electro-acupuncture every other day. Mice with colitis showed an increase in disease activity after DSS treatment, whereas in mice treated with electro-acupuncture, scores of disease activity, stool consistency and bloody bowel discharge were significantly reduced, consistent with improvement in pathological findings. In addition, recruitment of macrophages and expression of ICAM were inhibited, accompanied by a significant reduction of DSS-induced expression of interleukin (IL)-1β and IL-6. Of importance, acceleration of giant migrating contraction (peristalsis) induced by vagostigmin attenuated these effects of electro-acupuncture. Overall, these data demonstrated that electro-acupuncture suppressed disease activity and colonic inflammation in DSS-induced colitis through a reduction in propagated colonic peristalsis mediated by sympathetic overactivity, suggesting the potential of acupuncture as a relief therapy for IBD.

The mechanism of peripheral neuropathy has not been sufficiently clarified, and medical therapy for peripheral neuropathy is not established. Only a few reports have evaluated the analgesic effects of pregabalin in different diseases. In the present study, the effects of pregabalin in both orthopedic patients and surgical patients were compared, and the improvement of peripheral neuropathy was quantified. A questionnaire-based study was performed on numbness and the intensity of pain in orthopedic patients with organic diseases like spinal canal stenosis and in surgical patients with neuropathy from anti-cancer treatment. The data for patients who were prescribed pregabalin were examined using a numerical rating scale (NRS). Improvement of symptoms was observed in categories such as numbness, pain with numbness, and pain without numbness in orthopedic patients. NRS value decreased by 33% in all patients who were prescribed pregabalin. Drowsiness, a side effect of pregabalin, mostly disappeared over 4 weeks after pregabalin administration. Further, when combining drugs with pregabalin, the frequency of numbness and pain with numbness tended to be decreased by two agents (pregabalin + NSAID), and was significantly decreased by three agents (pregabalin + NSAID + muscle relaxant), as compared with pregabalin-only treatment. The present study revealed the analgesic effect of pregabalin with regards to pain both with and without numbness. The data suggest that pregabalin is effective especially in orthopedic patients with organic injury of nerves.

Background: Limonoids are highly oxygenated triterpenoid compounds abundantly contained in citrus fruits. It has been reported that limonoids have several pharmacological activities such as anti-cancer, anti-malarial, and antimicrobial activities. Moreover, recent reports have indicated that limonoids may have a preventive effect on cardiovascular disease and metabolic disorders. However, very little information is available about the effects of limonoids on cognitive impairment due to Alzheimer disease and vascular dementia. In the present study, we investigated whether limonin, one of the major limonoids, has a preventive effect on cognitive dysfunction in a mouse vascular dementia model induced by chronic cerebral hypoperfusion. Materials and Methods: Ten-week-old C57BL/6J male mice were subjected to bilateral common carotid artery stenosis (BCAS) using external microcoils. Mice were administered limonin (10 mg/kg/day) from 8 to 16 weeks of age. Spatial working memory was evaluated by the Morris water maze test at 16 weeks of age. Blood pressure was measured by tailcuff method. Cerebral blood flow was assessed by 2D laser speckle flowmetry. Results: Chronic cerebral hypoperfusion induced by BCAS significantly impaired cognitive function compared with that of the control group. However, administration of limonin did not ameliorate cognitive dysfunction induced by BCAS. Moreover, cerebral blood flow was reduced by BCAS, but this reduction was not improved by limonin treatment. There was no significant change in blood pressure in each mouse. Conclusion: Limonin had no apparent effect on cognitive impairment attributed to chronic cerebral hypoperfusion.

Obesity and metabolic syndrome are major risk factors for the development of atherosclerosis or chronic kidney disease. In this paper, we investigated the effect of rosuvastatin and atorvastatin on endothelial function, and liver and kidney function in obese fa/fa Zucker diabetic fatty (ZDF) rats. ZDF rats were administered rosuvastatin (10 mg/kg/day p.o.) or atorvastatin (10 mg/kg/day p.o.) for 12 weeks. Rosuvastatin treatment decreased body weight and fat weight. Neither statin affected the blood sugar and total cholesterol levels, whereas they led to a significant decrease in triglyceride and liver markers (AST and ALT). Rosuvastatin, but not atorvastatin, markedly reduced elevated urinary protein excretion after 12 weeks of treatment. Endothelial function, which was evaluated by EC50 values for acetylcholine-induced relaxation of mesenteric artery rings, was altered after 12 weeks of treatment with rosuvastatin, but not atorvastatin. Our findings suggest that rosuvastatin treatment may improve obesity, proteinuria and endothelial function compared with treatment with atorvastatin.

Recent epidemiological studies have demonstrated that diabetes mellitus (DM) is a risk factor for bone fracture. Both hyperglycemia and oxidative stress induce a reduction in enzymatic beneficial cross-links and the accumulation of disadvantageous non-enzymatic cross-linking by advanced glycation end products (AGEs) such as pentosidine in bone. On the other hand, some antihypertensive drugs have been reported to improve peripheral conditions such as retinopathy or kidney dysfunction induced by DM. In this study, ovariectomized rats with a high-fructose diet were treated with or without olmesartan, for investigating aspects of bone and mineral metabolism derangement in DM. High-fructose loading increased insulin resistance and serum pentosidine concentration. Immunohistochemical analysis also demonstrated pentosidine accumulation in bone. These results were in accordance with the results of a three point bending test, which revealed fragility of bone. Of interest, treatment with olmesartan improved insulin resistance and decreased the accumulation of the AGE pentosidine. Three point bending test also revealed improvement in fragility of bone induced by a highfructose diet. Overall, olmesartan treatment might be a useful approach in the treatment of hypertensive patients with DM.