The Logistical Backbone of Photoreceptor Cell Function: Complementary Mechanisms of Dietary Vitamin A Receptors and Rhodopsin Transporters.

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway.

Initially discovered by Makuto Kuro-o in 1997, Klotho is a putative aging-suppressor gene when overexpressed and accelerates aging when deleted in mice. Previously, we showed that α-Klotho regulates retinal pigment epithelium (RPE) functions and protects against oxidative stress. However, the mechanisms by which Klotho influences RPE and retinal homeostasis remain elusive. Here, by performing a series of in vitro and in vivo experiments, we demonstrate that Klotho regulates cell viability under oxidative stress, mitochondrial gene expression and activity by inducing the phosphorylation of AMPK and p38MAPK, which in turn phosphorylate and activate CREB and ATF2, respectively, triggering PGC-1α transcription. The inhibition of Klotho in human RPE cells using CRISPR-Cas9 gene editing confirmed that a lack of Klotho negatively affects RPE functions, including mitochondrial activity and cell viability. Proteomic analyses showed that myelin sheath and mitochondrial-related proteins are downregulated in the RPE/retina of Kl-/- compared to WT mice, further supporting our biochemical observations. We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.

Anorexia Nervosa and Osteoporosis: Pathophysiology and Treatment.

Anorexia nervosa (AN) affects 2.9 million people, many of whom experience bone loss and increased fracture risk. In this article, we review data on the underlying pathophysiology of AN-related osteoporosis and possible approaches to disease management. Available research suggests that low body weight and decreased gonadal function are the strongest predictors of bone loss and fractures in patients with AN. Additionally, other metabolic disturbances have been linked to bone loss, including growth hormone resistance, low leptin concentrations, and hypercortisolemia, but those correlations are less consistent and lack evidence of causality. In terms of treatment of AN-related bone disease, weight gain has the most robust impact on bone mineral density (BMD). Restoration of gonadal function seems to augment this effect and may independently improve BMD. Bisphosphonates, insulin-like growth factor 1 supplementation, and teriparatide may also be reasonable considerations, however need long-term efficacy and safety data.

Treatment of cachexia: melanocortin and ghrelin interventions.

Cachexia is a condition typified by wasting of fat and LBM caused by anorexia and further endocrinological modulation of energy stores. Diseases known to cause cachectic symptoms include cancer, chronic kidney disease, and chronic heart failure; these conditions are associated with increased levels of proinflammatory cytokines and increased resting energy expenditure. Early studies have suggested the central melanocortin system as one of the main mediators of the symptoms of cachexia. Pharmacological and genetic antagonism of these pathways attenuates cachectic symptoms in laboratory models; effects have yet to be studied in humans. In addition, ghrelin, an endogenous orexigenic hormone with receptors on melanocortinergic neurons, has been shown to ameliorate symptoms of cachexia, at least in part, by an increase in appetite via melanocortin modulation, in addition to its anticatabolic and anti-inflammatory effects. These effects of ghrelin have been confirmed in multiple types of cachexia in both laboratory and human studies, suggesting a positive future for cachexia treatments.

Partial normalization of pubertal timing in female mice with DSS colitis treated with anti-TNF-α antibody.

BACKGROUND: Inflammatory bowel disease (IBD) and resultant colitis occurring prior to puberty are frequently associated with delayed puberty and losses of growth and bone mineralization. Some of this delay may be due to colonic inflammation and associated systemic inflammation. To date no treatments for IBD have been shown to normalize the timing of puberty. Our objective in this study was to determine whether there is a normalization of the timing of puberty during treatment of colitis using monoclonal antibodies (abs) to tumor necrosis factor (TNF)-α. METHODS: We induced colitis in 23-day-old C57Bl6 female mice using 3% dextran sodium sulfate (DSS) for 7 days, followed by removal of DSS for an additional 3 days, resulting in 10 days of worsening colitis. DSS-treated mice received either TNF-α ab or Control ab on days 4 and 8 of colitis, while non-colitic Control mice received injections of TNF-α ab (Control + TNF-α ab). All groups were followed for the timing of vaginal opening until day of life 33, when they were euthanized for serum and colon collection. RESULTS: The DSS + TNF-α ab group had lower levels of systemic interleukin (IL)-6 and a partial normalization of the timing of vaginal opening compared to the DSS + Control ab group. There were no differences in weight gain, growth, or colon histological inflammatory scores between the DSS + TNFα ab and DSS + Control ab groups over the course of the experiment. CONCLUSIONS: We conclude that anti-TNF-α ab treatment causes a partial normalization of pubertal timing coincident with decreased systemic inflammation in DSS colitis. These data may have implications regarding growth and bone mineralization outcomes in pediatric IBD.