Diabetes mellitus is the most common cause of blindness among working-age adults, with a prevalence of 7 - 8% of adults in the USA, and is one of the most common causes of renal failure requiring kidney transplant and the most common cause of non-traumatic lower limb amputation in developed nations  . The role of the intracellular signaling enzyme protein kinase C (PKC) in the development of diabetic complications has become a field of intense research interest. An inhibitor of the PKC-beta isoform ruboxistaurin (RBX) has in vitro and in vivo benefits in ameliorating disturbances of cell regulation and blood flow related to hyperglycemia. The benefit of RBX for peripheral neuropathy has not been successfully demonstrated in Phase III trials. Although there was a beneficial effect of RBX on nephropathy in a pilot study, there has been no further clinical development for this indication. The major cause of visual disability - diabetic macular edema - seems to respond to RBX treatment with both anatomic and functional benefits. The manufacturer, Eli Lilly Co., has received an approvable letter from the FDA for the prevention of vision loss in patients with diabetic retinopathy with RBX, pending results of additional clinical trials for this indication.
"In addition, kinases are the most frequently targeted gene class in cancer therapy, second only to the G protein-coupled receptors as therapeutic targets (Cohen, 2002; Hopkins & Groom, 2002). Kinase inhibitors have been employed as treatments for malignancies as diverse as leukemia and gastrointestinal stromal tumors (imatinib) (Druker et al., 1996, 2001), diabetic retinopathy (ruboxistaurin) (Danis & Sheetz, 2009), atopic dermatitis (safingol) (Eglen & Reisine, 2009), and cerebral ischemia (fasudil) (Yamashita et al., 2007). There is also an increasing impetus to consider the repurposing of FDA-approved kinase inhibitors for use as anti-infective therapies. "
[Show abstract][Hide abstract] ABSTRACT: Currently, there is a paucity of information regarding the molecular pathogenesis for many high-consequence pathogens (HCPs) that pose direct threats to public health and security both nationally and internationally. For example, variola virus (VARV), the etiologic agent of smallpox, was responsible for ~500 million human fatalities in the 20(th) century prior to its successful eradication in May 1980 . Following the cessation of routine vaccinia virus (VACV) vaccination, a significant portion of the global population has been left vulnerable to VARV. This has resulted in significant concerns regarding the potential release of VARV, or another closely related orthopoxvirus, such as monkeypox virus (MPXV), to an increasingly vulnerable population. This article is protected by copyright. All rights reserved.
Pathogens and Disease 03/2014; 71(2). DOI:10.1111/2049-632X.12163 · 2.40 Impact Factor
"One of the first PKC inhibitors, PKC412, reduced the effects of several isoforms of PKC and improved visual acuity when administered orally (100 mg/d) to patients with diabetic macular edema (DME) . In the diabetic retina, the isoform PKC-β is highly expressed; thus, the selective inhibition of PKC-β by ruboxistaurin mesylate has been widely studied . Eli Lilly Co., USA, has designed a specific inhibitor of the PKC-β isoform, ruboxistaurin, which has shown beneficial effects in animal models of DR . "
[Show abstract][Hide abstract] ABSTRACT: Diabetic retinopathy (DR) is the most common complication of diabetes. It causes vision loss, and the incidence is increasing with the growth of the diabetes epidemic worldwide. Over the past few decades a number of clinical trials have confirmed that careful control of glycemia and blood pressure can reduce the risk of developing DR and control its progression. In recent years, many treatment options have been developed for clinical management of the complications of DR (e.g., proliferative DR and macular edema) using laser-based therapies, intravitreal corticosteroids and anti-vascular endothelial growth factors, and vitrectomy to remove scarring and hemorrhage, but all these have limited benefits. In this review, we highlight and discuss potential molecular targets and new approaches that have shown great promise for the treatment of DR. New drugs and strategies are based on targeting a number of hyperglycemia-induced metabolic stress pathways, oxidative stress and inflammatory pathways, the renin-angiotensin system, and neurodegeneration, in addition to the use of stem cells and ribonucleic acid interference (RNAi) technologies. At present, clinical trials of some of these newer drugs in humans are yet to begin or are in early stages. Together, the new therapeutic drugs and approaches discussed may control the incidence and progression of DR with greater efficacy and safety.
Medical science monitor: international medical journal of experimental and clinical research 04/2013; 19(1):300-8. DOI:10.12659/MSM.883895 · 1.43 Impact Factor
"It is well established that chronic hyperglycemia induces abnormal activation of PKC, which contributes to diabetic cardiovascular complications (37,38). However, the PKC-signaling pathway is complicated by numerous isoforms, each with varying cellular distribution and opposing function at times (39). "
[Show abstract][Hide abstract] ABSTRACT: Protein kinase C (PKC) β2 is preferably overexpressed in the diabetic myocardium, which induces cardiomyocyte hypertrophy and contributes to diabetic cardiomyopathy, but the underlying mechanisms are incompletely understood. Caveolae are critical in signal transduction of PKC isoforms in cardiomyocytes. Caveolin (Cav)-3, the cardiomyocyte-specific caveolar structural protein isoform, is decreased in the diabetic heart. The current study determined whether PKCβ2 activation affects caveolae and Cav-3 expression. Immunoprecipitation and immunofluorescence analysis revealed that high glucose (HG) increased the association and co-localization of PKCβ2 and Cav-3 in isolated cardiomyocytes. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 siRNA transfection prevented HG-induced PKCβ2 phosphorylation. Inhibition of PKCβ2 activation by compound CGP53353 or knockdown of PKCβ2 expression via siRNA attenuated the reductions of Cav-3 expression and Akt/eNOS phosphorylation in cardiomyocytes exposed to HG. LY333531 treatment (for a duration of 4 weeks) prevented excessive PKCβ2 activation and attenuated cardiac diastolic dysfunction in rats with streptozotocin-induced diabetes. LY333531 suppressed the decreased expression of myocardial nitric oxide (NO), Cav-3, p-Akt, and p-eNOS, and also mitigated the augmentation of O2-, nitrotyrosine, Cav-1, and iNOS expression. In conclusion, hyperglycemia-induced PKCβ2 activation requires caveolae, and is associated with reduced Cav-3 expression in the diabetic heart. Prevention of excessive PKCβ2 activation attenuated cardiac diastolic dysfunction by restoring Cav-3 expression and subsequently rescuing Akt/eNOS/NO signaling.
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