Valsartan nano-filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds.

Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an extended-release formulation that would reduce patient burden by decreasing the frequency of daily applications. Here, we used nanotechnology to self-assemble valsartan amphiphiles into a filamentous structure (val-filaments) that would serve as a scaffold in wound beds and allow for steady, localised and tunable release of valsartan amphiphiles over 24 days. Two topical treatments of this peptide-based hydrogel on full-thickness wounds in Zucker Diabetic Fatty rats resulted in faster rates of wound closure. By day 23, all val-filament treated wounds were completely closed, as compared to one wound closed in the placebo group. Mechanistically, we observed enrichment of proteins involved in cell adhesion and energetics pathways, downregulation of Tgf-ß signalling pathway mediators (pSmad2, pSmad3 and Smad4) and increased mitochondrial metabolic pathway intermediates. This study demonstrates the successful synthesis of a sustained-release valsartan filament hydrogel, its impact on mitochondrial energetics and efficacy in treating diabetic wounds.

Concise Review: Using Stem Cells to Prevent the Progression of Myopia-A Concept.

The prevalence of myopia has increased in modern society due to the educational load of children. This condition is growing rapidly, especially in Asian countries where it has already reached a pandemic level. Typically, the younger the child's age at the onset of myopia, the more rapidly the condition will progress and the greater the likelihood that it will develop the known sight-threatening complications of high myopia. This rise in incidence of severe myopia has contributed to an increased frequency of eye diseases in adulthood, which often complicate therapeutic procedures. Currently, no treatment is available to prevent myopia progression. Stem cell therapy can potentially address two components of myopia. Regardless of the exact etiology, myopia is always associated with scleral weakness. In this context, a strategy aimed at scleral reinforcement by transplanting connective tissue-supportive mesenchymal stem cells is an attractive approach that could yield effective and universal therapy. Sunlight exposure appears to have a protective effect against myopia. It is postulated that this effect is mediated via local ocular production of dopamine. With a variety of dopamine-producing cells already available for the treatment of Parkinson's disease, stem cells engineered for dopamine production could be used for the treatment of myopia. In this review, we further explore these concepts and present evidence from the literature to support the use of stem cell therapy for the treatment of myopia.

Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker.

Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker-Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.

Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds.

Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers losartan and valsartan and the angiotensin-converting enzyme inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. The application of 1% valsartan gel compared with other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. One percent of valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated mothers against decapentaplegic homologs 2 and 3 and common mothers against decapentaplegic homolog 4, alpha-smooth muscle actin, CD31, phospho-vascular endothelial growth factor receptor 2, and p42/44 mitogen-activated protein kinase. Knockout of the angiotensin subtype 2 receptors abolished the beneficial effects of angiotensin type 1 receptor blockers, suggesting a role for angiotensin subtype 2 receptors in chronic wound healing.

Dorcas Hager Padget: neuroembryologist and neurosurgical illustrator trained at Johns Hopkins.

Dorcas Hager Padget was a pioneer in the fields of neurosurgical illustration and neuroembryology who practiced during the early 20th century at The Johns Hopkins University. Without a college degree, she trained as a medical illustrator in the Johns Hopkins School of Medicine's Department of Art as Applied to Medicine under Max Brödel. She began her career working for Walter Dandy as his medical artist, gaining worldwide recognition for her neurosurgical illustrations. With Dandy's encouragement, Hager Padget undertook her own scientific research, studying neurodevelopment and aneurysm formation in the circle of Willis by using human embryos from the world-renowned Carnegie Collection. She made lasting contributions to the field of neuroembryology, publishing the first major work on neurodevelopment of the cerebral arterial and venous systems. Following Dandy's death in 1946, Hager Padget began a full-time career as a scientific researcher, first at the Department of Embryology at the Carnegie Institution of Washington in Baltimore and later at the University of Maryland School of Medicine. She continued to make contributions to the field of congenital malformations of the brain and spine, coining the term "neuroschisis" to describe a possible mechanism of neural tube damage leading to the creation of a myelomeningocele. The authors describe Dorcas Hager Padget's contributions to neurosurgical illustration and neuroembryology, as well as her remarkable career.

The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance.

Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors-type 1 (AT1R) and type 2 (AT2R). The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT1R-NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals.

Bilateral infraoptic A1 arteries in association with a craniopharyngioma: Case report and review of the literature.

BACKGROUND: While variation within the anterior cerebrovascular circulation is common, an infraoptic course of the proximal anterior cerebral artery (ACA), or infraoptic A1, is a relatively rare cerebrovascular anomaly. Associations with suprasellar neoplasms may occur, and accurate identification of this aberrant vessel during dissection is crucial to preventing vascular injury or stroke. CASE DESCRIPTION: We present the first reported case of surgically confirmed bilateral infraoptic A1 arteries associated with a craniopharyngioma. We review the relevant magnetic resonance imaging (MRI), angiographic, and intraoperative anatomic features of the infraoptic A1 to emphasize the importance of these variables when planning and performing surgery in the region of the anterior communicating artery (AComm) complex. CONCLUSIONS: Awareness of the existence and clinical significance of this unusual anomaly can facilitate its recognition on preoperative studies and during dissection in the suprasellar space, allowing neurosurgeons to adjust operative plans accordingly.

Following mitochondrial footprints through a long mucosal path to lung cancer.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations are reported in different tumors. However, there is no information on the temporal development of the mtDNA mutations/content alteration and their extent in normal and abnormal mucosa continuously exposed to tobacco smoke in lung cancer patients. METHODOLOGY: We examined the pattern of mtDNA alteration (mtDNA mutation and content index) in 25 airway mucosal biopsies, corresponding tumors and normal lymph nodes obtained from three patients with primary lung cancers. In addition, we examined the pattern of mtDNA mutation in corresponding tumors and normal lymph nodes obtained from eight other patients with primary lung cancers. The entire 16.5 kb mitochondrial genome was sequenced on Affymetrix Mitochip v2.0 sequencing platform in every sample. To examine mtDNA content index, we performed real-time PCR analysis. PRINCIPAL FINDINGS: The airway mucosal biopsies obtained from three lung cancer patients were histopathologically negative but exhibited multiple clonal mtDNA mutations detectable in the corresponding tumors. One of the patients was operated twice for the removal of tumor from the right upper and left lower lobe respectively within a span of two years. Both of these tumors exhibited twenty identical mtDNA mutations. MtDNA content increased significantly (P<0.001) in the lung cancer and all the histologically negative mucosal biopsies except one compared to the control lymph node. CONCLUSIONS/SIGNIFICANCE: Our results document the extent of massive clonal patches that develop in lifetime smokers and ultimately give rise to clinically significant cancers. These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation. MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring. Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.

Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP.

A common feature of many advanced cancers is their enhanced capacity to metabolize glucose to lactic acid. In a challenging study designed to assess whether such cancers can be debilitated, we seeded hepatocellular carcinoma cells expressing the highly glycolytic phenotype into two different locations of young rats. Advanced cancers (2-3cm) developed and were treated with the alkylating agent 3-bromopyruvate, a lactate/pyruvate analog shown here to selectively deplete ATP and induce cell death. In all 19 treated animals advanced cancers were eradicated without apparent toxicity or recurrence. These findings attest to the feasibility of completely destroying advanced, highly glycolytic cancers.