Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 12, Issue 2, 2012

Sjogren’s syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands, in particular the salivary and lachrymal glands. The etiology and pathogenic mechanisms of SS remain largely unknown. Accordingly there are no treatments that completely reverse the disease in patients. The purpose of this invited review is not to provide a comprehensive overview of treatment approaches for SS, but rather to comment on emerging molecular targeted therapies and cell-based therapies. Although a number of molecular-targeted therapies are currently available for autoimmune diseases, very few but Rituximab and Epratuzumab appear to be efficacious for patients with SS, suggesting the importance of an enhanced understanding of SS pathogenesis. Cell-based therapy has been demonstrated as a promising approach to treat salivary gland dysfunction in SS mouse models. Further assessment for functional restoration of damaged salivary glands in organotypic culture or in SS patients is necessary to translate the cellbased therapies into the clinic.

Recognized in 2006 as a global health priority by the United Nations, type 2 diabetes (T2D) is a major disease affecting 300 million individuals worldwide and directly responsible for at least 4 million deaths every year. About 10% of global health care spending is already related to T2D or to its complications, and this is steeply increasing, for instance in France, where diabetes costs have been growing by 9% per year in the last decade. Furthermore, as a consequence of the obesity epidemics, which affects nearly 1 billion individuals today, the number of diabetic people is expected to double in the next twenty years. It is now believed that 1 in 3 children born in the US since 2000 will develop T2D and its late complications and comorbidities during lifetime. As a consequence, for the first time in the last 200 years the life expectancy of this US generation could be shorter than that of previous ones. Similar trends are expected in other western countries. The root cause of metabolic diseases is the interaction among several genes and between these genes and the patient’s environment and lifestyle. For more than a decade much expenditure has been spent to identify disease genes that predispose to T2D and obesity. A comprehensive map of interacting disease genes would lead to an unprecedented understanding of their pathogenesis. This would lead to targets for new and better drugs to fill depleted pharma pipelines with drug candidates that directly address the root causes of the disease or to diagnostics that are predictive of the disease or drug response. The Holy Grail arising from such discoveries could result in the combination of a drug tailored to patients with a particular genetic profile and a molecular diagnostic for selecting patients with that profile. This “individualized” or “personalized” drug would have a high probability of producing an optimal response and a low probability of causing an adverse reaction. This article summarizes current strategies and experimental efforts for the identification of those drugs, including their underlying molecular targets, as well as diagnostic tools for the therapy and prediction of T2D and obesity with emphasis on energy uptake and expenditure, low-grade inflammation, lipotoxicity, lipid metabolism, white and brown adipose tissue, microvesicles, circadian clock, gut flora and somatic gene therapy. The opportunities and challenges for future personalized therapy of T2D and obesity are discussed.

Diabetic retinopathy (DR) is one of the common microvascular complications of diabetes, resulting in visual deterioration in working populations. Even in the early stage of DR, increased permeability can occur and is known to be associated with the disruption of the blood-retinal barrier (BRB). In this regard, studies on the pathogenesis of DR have been focused on the alteration of the BRB, however, detailed and unifying mechanisms and pathogenesis-based treatment of DR are yet to be elucidated. In this review, we discussed the pathogenesis of DR associated with the disruption of the BRB and reviewed novel therapeutic options. We expect that this review will help to form a consensus for pathogenesisbased treatments of DR in consideration with the disruption of the BRB.

Lipoprotein(a) [Lp(a)] is known as an independent risk factor for cardiovascular diseases (CVD). Lp(a) is a unique lipoprotein consisting of the glycoprotein apolipoprotein(a) [apo(a)] covalently linked to apolipoproteinB-100 (apoB) in low-density lipoprotein (LDL) by a single disulfide bond. Although Lp(a) level is hugely variable and under strict genetic control, largely by apo(a) gene with kringle-4 type2 repeats, elevated level of plasma Lp(a) is correlated with CVD. Smaller isoforms with fewer kringle-4 repeats are associated with higher plasma Lp(a) level, leading to an increased risk for CVD. Lipid lowering agents (i.e. statins) have little or no effect on plasma Lp(a) level. Although it was reported that administration of niacin or estrogen may reduce the Lp(a) levels, there are no specific agents for the reduction of plasma Lp(a). In this review, we put together recent evidence and describe the overview of Lp(a) with the future direction.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of morphogenic tissue interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed not only in hepatocyte but also in vascular cells, cardiac myocytes, skeletal muscle, kidney cells, neuronal cell, and fibroblasts. On the other hand, vascular endothelial growth factor (VEGF) is also a growth factor for endothelial cells. The signal transduction of VEGF and HGF is quite similar in physiological condition, but differs in pathological condition. To investigate this difference between HGF and VEGF, we showed that HGF but not VEGF prevents the senescence EPC due to oxidative stress through the inhibition of rac1. Moreover, we reported that HGF promotes SHIP-2 translocation from epithelial growth factor receptor (EGFR) to c-Met, and protects oxidative stress through EGFR degradation. By this anti-oxidative and anti-senescence effects of HGF would maintain the vessels long enough in patients receiving much oxidative stress. Another unique effect of HGF is anti-fibrosis. HGF does not inhibit TGF-β1 in physiological condition, but reduces it in pathological, we discuss the potential effect of condition by promoting the myofibroblast apoptosis, and inhibits the vicious cycle of TGF-β1 and angiotensin II through the inhibition of PTEN activity. In this report HGF on pathological condition in cardiovascular diseases and chronic kidney disease (CKD).

Background: Established therapies against chronic heart failure (CHF) like beta-blockade or renin-angiotensin inhibition still remain insufficient to conquer CHF, mainly because of the presence of non-responder or intolerability because of extremely low cardiac output. Recent report including ours revealed that transient administration of phosphodiesterase- 3 (PDE-III) inhibitor and subsequent PKA activation mimic preconditioning, reduce infarct size and restore cardiac function after myocardial infarction. Since PDE-III inhibition increases cardiac output, we tested whether intermittent transient PDE-III inhibition is also applicable to preventing non-ischemic cardiac remodeling and failure. Methods and Results: Male Wistar-Kyoto rats underwent inhibition of nitric oxide synthase by L-NAME for 8 weeks, in the presence or absence of PDE-III inhibitor olprinone by gavage once a day, 3 times a week. L-NAME specifically increased blood pressure, promoted LV hypertrophy and remodeling. Hydralazine totally canceled blood pressure increase but unaffected LV remodeling and reduced contraction, as reported previously. Olprinone was well tolerated and reduced LV hypertrophy, fibrosis and wet lung weight/body weight ratio but unchanged high blood pressure afforded by L-NAME, suggesting that olprinone inhibited the progression of cardiac remodeling and failure beyond blood pressurelowering. Furthermore, LV infiltration of polymorphic neutrophils induced by L-NAME was eliminated by olprinone. Conclusion: The intermittent transient PDE-III inhibition elicits cardioprotection against non-ischemic heart failure beyond hemodynamic effects, and the inhibition of inflammatory change might be involved in pathophysiology. Since PDE-III inhibition provides positive inotropic effect, this therapy might be a widely acceptable option for patients even with poor response to conventional therapies or severely low cardiac output.

Background: Myocardial infarction (MI) frequently causes left ventricular (LV) dysfunction, and this is involved in inflammatory reactions and fibrosis of myocardium. Several studies have demonstrated that NF-κB is substantially related to inflammation and LV remodeling. However, the effects of the continuous inhibition of NF-κB for the prevention of LV dysfunction after MI are still controversial. IMD-1041, which inhibits phosphorylation of IκB via inhibition of IKK-β, is under clinical trials. The aim of this study was to investigate effects of IMD-1041 for myocardial remodeling after infarction. Methods and Results: To analyze the effects of IMD-1041 to ischemic heart, we administered IMD-1041 (low dose; 30mg/kg/day, high dose; 100mg/kg/day) or vehicle orally to mice with ligation of the left anterior coronary artery. After 28 days of ligation, MI mice exhibited left ventricular (LV) dilatation and contractile dysfunction. However, IMD-1041 treatment significantly improved cardiac function as indicated by the preservation of fractional shortening (30mg/kg of IMD-1041, 25.8±0.8%, n=12; 100mg/kg of IMD-1041, 29.3±0.6%, n=12; vehicle, 21.6±1.6%, n=11; P<0.05). Histological analysis also showed that IMD-1041 treatment impressively reduced fibrosis area (30mg/kg of IMD-1041,21.5±2.0%, n=12; 100mg/kg of IMD-1041, 24.0±1.7%, n=12; vehicle, 33.2±3.6%, n=11; P<0.05). Although LV gelatinolytic activity of pro- and active-MMP-2 and -9 increased in the vehicle group, IMD-1041 treatment significantly inhibited the activity of MMPs. Conclusion: These results suggest that IMD-1041 treatment is effective for the prevention of myocardial dysfunction after MI through attenuation of myocardial fibrosis.

Background: Although COX-2 inhibitors are known to have adverse effects on myocardial ischemia, the effects of COX-2 inhibitors on cardiovascular diseases are still controversial. Thus, we hypothesized that COX-2 inhibitors affect pressure overloaded myocardial hypertrophy. Methods and Results: To clarify the role, we used meloxicam in a murine transversal aortic banding (TAC) model. Meloxicam (0.5mg/kg) was given orally twice a day and the mice were sacrificed on day 28 (n=10) after TAC. The drugfree vehicle was used as control (n=7). Echocardiogram revealed that left ventricular (LV) wall thickness was significantly decreased in the meloxicam-treated group compared with the control group. Heart per body weight ratio of the meloxicam-treated group was substantially less than that of the non-treated group. Pathologically, hearts in the meloxicam- treated group showed significantly less LV wall thickness and area of myocardium than those in the control group. RT-PCR showed that COX-2 mRNA levels in hearts increased in the non-treated group, while meloxicam treatment suppressed the levels. Conclusion: Meloxicam may be useful for preventing pressure overloaded myocardial hypertrophy.

Background: Left ventricular (LV) hypertrophy is a natural adaption of the heart to pressure overloading and results in life-threatening heart failure. Matrix metalloproteinase (MMP) activity is upregulated in hearts with LV hypertrophy and its activation is the main cause of change in the LV wall. Clarithromycin (CAM), a major macrolide antibiotic, has various biologic effects including MMP regulation. However, little is known about the effect of CAM on LV hypertrophy. Methods and Results: To clarify the role of CAM on LV hypertrophy, we used the transverse aortic constriction (TAC) model. The mice were randomly assigned into three groups; (a) CAM administration with TAC (CAM-treated group, n=10); (b) vehicle administration with TAC (non-treated group, n=10); (c) vehicle administration with sham-operation (control group, n=10). M-mode echocardiograms showed that LV end-diastolic posterior wall (LVPWd) thickness increased progressively from week 1 to 3 after TAC in the non-treated group. However, it was attenuated in the CAMtreated group. Furthermore, heart to body weight ratio increased in the non-treated group (15.8±1.7%); this increase was negated by CAM administration (10.2±1.4%). Histpathologically, LV wall thickness increased in the non-treated group (18.0±4.0%); this increase was also negated in the CAM-treated group (-8.5±3.5%). Real-time RT-PCR demonstrated that CAM treatment tended to suppress MMP-9 and elevate TIMP-2 mRNA levels compared to the non-treated group. Conclusion: CAM attenuates the progression of LV hypertrophy via MMP suppression after pressure overload in mice. It might be a basic solution for LV hypertrophy.

Several types of Ca channel blockers (CCBs) which have unique organ protective effects are commercially available all over the world. However, the hypotensive and pleotropic effect in CCBs are not sufficiently assessed in the diabetic patient with refractory hypertension for angiotensin receptor blocker (ARB). We conducted a pilot study to compare the efficacy of two different CCBs (azelnidipine and nifedipine controlled release (CR)) in 55 hypertensive patients with type 2 diabetes who had not achieved their target blood pressure (BP) with ARB monotherapy. Patients were randomly assigned to receive azelnidipine (8–16 mg/day) or nifedipine CR (10–40 mg/day) concomitantly with valsartan (80 mg/day). There were no significant differences in baseline characteristics between the two groups. The final dose of azelnidipine and nifedipine CR was 13.3±3.9 and 17.1±9.4 mg/day, respectively. However the target BP (<130/80mmHg) achievement rate was higher in the earlier phase of the combination therapy with nifedipine CR than that of the azelnidipine group, the rates after 6 months were comparable between the groups (83 vs. 66%). The systolic blood pressure was significantly lower in the nifedipine CR group from 2 to 6 months after the combination therapy (P<0.05, respectively). Both groups showed no significant changes in blood glucose and hemoglobin A1c. There were no significant differences in the urinary albumin/creatinine ratio and estimated Glomerular Filtration Rate (eGFR). In conclusion, the adjunctive therapy of nifedipine CR was superior to that of azelnidipine for decreasing blood pressure and achieving the target blood pressure, especially in the earlier phase of the diabetic patient with refractory hypertension for ARB. However the nephroprotective effect of nifedipine CR combination therapy was comparable to that of azelnidipine.