Preservation of Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) in Late Adult Mice: Implications as a Potential Biomarker for Early Onset Ocular Degenerative Diseases.

Purpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a crucial role in non-image-forming visual functions. Given their significant loss observed in various ocular degenerative diseases at early stages, this study aimed to assess changes in both the morphology and associated behavioral functions of ipRGCs in mice between 6 (mature) and 12 (late adult) months old. The findings contribute to understanding the preservation of ipRGCs in late adults and their potential as a biomarker for early ocular degenerative diseases. Methods: Female and male C57BL/6J mice were used to assess the behavioral consequences of aging to mature and old adults, including pupillary light reflex, light aversion, visual acuity, and contrast sensitivity. Immunohistochemistry on retinal wholemounts from these mice was then conducted to evaluate ipRGC dendritic morphology in the ganglion cell layer (GCL) and inner nuclear layer (INL). Results: Morphological analysis showed that ipRGC dendritic field complexity was remarkably stable through 12 months old of age. Similarly, the pupillary light reflex, visual acuity, and contrast sensitivity were stable in mature and old adults. Although alterations were observed in ipRGC-independent light aversion distinct from the pupillary light reflex, aged wild-type mice continuously showed enhanced light aversion with dilation. No effect of sex was observed in any tests. Conclusions: The preservation of both ipRGC morphology and function highlights the potential of ipRGC-mediated function as a valuable biomarker for ocular diseases characterized by early ipRGC loss. The consistent stability of ipRGCs in mature and old adult mice suggests that detected changes in ipRGC-mediated functions could serve as early indicators or diagnostic tools for early-onset conditions such as Alzheimer's disease, Parkinson's disease, and diabetes, where ipRGC loss has been documented.

Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis.

Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ10-NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ10/NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ10-NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration.

The central melanocortin system as a treatment target for obesity and diabetes: A brief overview.

The melanocortins are derived from proopiomelanocortin (POMC) and include three forms of melanocyte-stimulating hormone (α-, ß-, γ-, MSH) and adrenocorticotropic hormone. α-MSH, a potent POMC-derived neuropeptide, binds to melanocortin 4 receptor (MC4R) in the brain to reduce food intake (via appetite suppression) and increase energy expenditure (via sympathetic nervous system) after integration of central neuronal signal (e.g. serotonin, glutamate) and peripheral signals such as anorexigenic hormones (e.g. leptin, insulin) and nutrient (e.g. glucose). Mutations in POMC or MC4R can cause increase in food intake and body weight. Weight gain and obesity in turn result in a phenotypic switch of white adipose tissue, which then secretes proinflammatory cytokines that play a role in the development of insulin resistance and type 2 diabetes. Besides α-MSH's effects in decreasing food intake and body weight, α-MSH also carries protective anti-inflammatory properties in both immune cells and non-immune cells (e.g. adipocyte) that express melanocortin receptors. Since type 2 diabetic patients who have overweight or obese are recommended to lose body weight while current available anti-obesity drugs have various side effects, α-MSH-based therapeutics might be hopeful for the management of both obesity and type 2 diabetes.

Anti-inflammatory α-Melanocyte-Stimulating Hormone Protects Retina After Ischemia/Reperfusion Injury in Type I Diabetes.

Retinal ischemia/reperfusion (I/R) injury is a major cause of vision loss in many ocular diseases. Retinal I/R injury is common in diabetic retinopathy, which as a result of hyperglycemia damages the retina and can cause blindness if left untreated. Inflammation is a major contributing factor in the pathogenesis of I/R injury. α-Melanocyte-stimulating hormone (α-MSH) is an anti-inflammatory peptide hormone that has displayed protective effects against I/R-induced organ damages. Here, we aimed to investigate the protective role of α-MSH on I/R-induced diabetic retinal damage using hyperglycemic C57BL/6J Ins2Akita/+ mice. Experimental I/R injury was induced by blocking the right middle cerebral artery (MCA) for 2 h followed by 2 h or 22 h of reperfusion using the intraluminal method. Since ophthalmic artery originates proximal to the origin of the MCA, the filament also blocked blood supply to the retina. Upon treatment with α-MSH at 1 h after ischemia and 1 h after reperfusion, animals displayed significant improvement in amplitudes of b-wave and oscillatory potentials during electroretinography. α-MSH also prevented I/R-induced histological alterations and inhibited the development of retinal swelling. Loss of retinal ganglion cells as well as oxidative stress were significantly attenuated in the α-MSH-treated retinae. Level of interleukin 10 was significantly increased after α-MSH treatment. Moreover, gene expression of glutamate aspartate transporter 1, monocarboxylate transporter (MCT) 1 and MCT-2 were significantly higher after α-MSH administration. In conclusion, α-MSH mitigates the severity of I/R-induced retinal damage under hyperglycemic condition. These beneficial effects of α-MSH may have important therapeutic implications against retinal I/R injury under hyperglycemic condition.

Neuropeptide α-Melanocyte-Stimulating Hormone Promotes Neurological Recovery and Repairs Cerebral Ischemia/Reperfusion Injury in Type 1 Diabetes.

Persons with type 1 diabetes have an increased risk of stroke compared with the general population. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that has protective effects against ischemia/reperfusion (I/R) induced organ damages. In this study, we aimed to investigate the neuroprotective role of this peptide on I/R induced brain damage after experimental stroke associated with hyperglycemia using C57BL/6J Ins2Akita/+ mice. Experimental stroke was induced by blocking the right middle cerebral artery for 2 h with reperfusion for 2 and 22 h, respectively using the intraluminal method. Animals were treated intraperitoneally with or without α-MSH at 1 h after ischemia and 1 h after reperfusion. Significantly higher survival rate and lower neurological scores were recorded in animals injected with α-MSH. Similarly, neuron death, glial cells activation as well as oxidative and nitrosative stress were significantly decreased in α-MSH treated group. Relative intensities of matrix metallopeptidases 9, cyclooxygenase 2 and nuclear factor-κB were significantly decreased while intensities of Akt, heme oxygenase (HO) 1, HO-2 and B-cell lymphoma 2 were significantly increased after α-MSH treatment. In addition, gene expressions of monocarboxylate transporter (MCT) 1, MCT-2 and activity-regulated cytoskeleton-associated protein were significantly higher in brain samples treated with α-MSH, suggesting this peptide may have role in neuron survival by an involvement of lactate metabolism. In conclusion, α-MSH is neuroprotective under hyperglycemic condition against I/R induced brain damage by its anti-inflammatory, anti-oxidative and anti-apoptotic properties. The use of α-MSH analogues may be potential therapeutic agents for diabetic stroke.

Long-term lutein administration attenuates retinal inflammation and functional deficits in early diabetic retinopathy using the Ins2Akita/+ mice.

INTRODUCTION: Lutein is a carotenoid whose protective effects in the retina have been reported in various studies. The effect of lutein has not been reported in the retina of the Ins2Akita/+ mouse, a well-characterized genetic model for diabetic retinopathy (DR) in which the etiology of diabetes is better defined than the chemically induced diabetes. The objective of the present study is to investigate the effect of long-term administration of lutein in early stages of DR using the Ins2Akita/+ mouse. RESEARCH DESIGN AND METHODS: Heterozygous male Ins2Akita/+ and age-matched wild-type mice were used. Lutein was administered to the mice in drinking water starting 6 weeks old daily until analysis at 4.5, 6.5 or 9 months of age. Plain water served as non-treatment control. Microglia were immunostained with ionized calcium-binding adapter molecule 1 (Iba-1) and cluster of differentiation 68 (CD68) in retinal flat-mounts. Vascular endothelial growth factor (VEGF) level in the retina was assessed by enzyme-linked immunosorbent assay (ELISA). Vascular permeability was analyzed in retinal flat-mounts after fluorescein isothiocyanate (FITC)-dextran perfusion. Retinal occludin expression was assessed via Western blots. Retinal function was examined by electroretinography (ERG). RESULTS: Increased microglial reactivity was detected in the Ins2Akita/+ mouse retina and was suppressed by lutein. Lutein administration also reduced the upregulation of VEGF in the Ins2Akita/+ mouse retina. Increased vascular leakage and decreased occludin expression were observed in the Ins2Akita/+ mouse retina, and these alterations were attenuated by lutein treatment. ERG recordings showed reduced a-wave and b-wave amplitudes in the Ins2Akita/+ mice. With lutein treatment, the ERG deficits were significantly alleviated. CONCLUSIONS: We showed beneficial effects of long-term lutein administration in the Ins2Akita/+ mouse retina, including suppression of retinal inflammation, protection of retinal vasculature and preservation of retinal function. These results point to lutein's potential as a long-term therapeutic intervention for prevention of inflammation and retinal degeneration in patients with early DR.

Moderate intensity exercise improves heart rate variability in obese adults with type 2 diabetes.

AIM: The aim of this study was to determine the effect of moderate aerobic exercise on heart rate variability (HRV) in obese adults with type 2 diabetes. METHODS: Forty-one obese adults with type 2 diabetes participated in this study. Anthropometric and metabolic parameters were measured, and resting electrocardiogram (ECG) for the HRV analysis at spontaneous respiration was recorded for 5 min in supine position before and after six months of supervised aerobic training given thrice-a-week. RESULTS: The mean age, body mass index (BMI), and duration of diabetes of the study population were 44.1 ± 4.5 years, 30.94 ± 1.36 kg/m2, and 16.3 ± 2.7 years, respectively. In time domain variables, standard deviation of all RR intervals (SDNN), the square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD) and percentage of consecutive RR intervals that differ by more than 50 ms (pNN50) were significantly increased after exercise. In frequency domain variables, high frequency (HF) (ms2) and HF (nu) were significantly increased while low frequency (LF) (ms2) and LF/HF ratio were significantly decreased after exercise. But LF (nu) was unaffected after exercise. CONCLUSION: This study suggests that thrice-a-week moderate intensity aerobic exercise for six months improves cardiac rhythm regulation as measured by HRV in obese adults with type 2 diabetes.

Reduced parasympathetic tone in newly diagnosed essential hypertension.

AIM: The aim of the study was to compare heart rate variability (HRV) of newly diagnosed essential hypertensive subjects with controls. METHODS: The study was conducted on 120 hypertensive subjects and 120 controls. RESULTS: The time-domain measures, standard deviation of all RR intervals (SDNN), the square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD), and percentage of consecutive RR intervals that differ by more than 50ms (pNN50) which reflect parasympathetic activity were significantly less in hypertensive subjects. In frequency-domain measures, high frequency [HF (ms(2))] and [HF (nu)], which reflects parasympathetic activity, was significantly less in hypertensive subjects while LF (nu) and LF/HF (%), which reflect sympathetic activity, were comparable between the groups. CONCLUSION: These findings suggest that HRV is reduced in subjects with newly diagnosed essential hypertension and the parasympathetic dysregulation is present in the early stage of essential hypertension.

Mild-to-moderate intensity exercise improves cardiac autonomic drive in type 2 diabetes.

AIMS/INTRODUCTION: The aim of the present study was to determine the effect of moderate aerobic exercise on cardiac autonomic function in type 2 diabetic patients. MATERIALS AND METHODS: Heart rate variability of 20 patients with type 2 diabetes was assessed. Resting electrocardiogram for the heart rate variability analysis at spontaneous respiration was recorded for 5 min in the supine position before and after 6 months of supervised aerobic training given three times per week. RESULTS: In time domain measures, the square root of the mean of the sum of the squares of differences between adjacent R-R intervals (RMSSD; 29.7 [26-34.5] vs 46.4 [29.8-52.2] ms, P = 0.023) and the percentage of consecutive RR intervals that differ by more than 50 ms (pNN50; 10.7 [5.5-12.7] vs 26.1 [6.6-37.2]%, P = 0.025] were significantly increased after exercise. In frequency domain measures, low frequency (62.4 [59.1-79.2] vs 37 [31.3-43.3] nu, P = 0.003) and low frequency/high frequency (1.67 [1.44-3.8] vs 0.58 [0.46-0.59]%, P = 0.009) were significantly decreased, whereas high frequency (95 [67-149] vs 229 [98-427] ms(2), P = 0.006) and high frequency (37.6 [20.8-40.9] vs 63 [56.7-68.7] normalized units, P = 0.003) were significantly increased after exercise. In a Poincaré plot, standard deviation perpendicular to the line of the Poincaré plot (SD1; 21.3 [18.5-24.8]-33.1 [21.5-37.2] ms, P = 0.027) was significantly increased after exercise. CONCLUSIONS: These data suggest that three times per week moderate intensity aerobic exercise for 6 months improves cardiac rhythm regulation as measured by heart rate variability in type 2 diabetic patients.

Cardiovascular autonomic function and vibration perception threshold in type 2 diabetes mellitus.

OBJECTIVE: The aim of this study was to compare cardiovascular autonomic function tests (AFT) and vibration perception threshold (VPT) of patients with type 2 diabetes mellitus (T2DM) with controls. RESEARCH DESIGN/METHODS: The study was conducted on 60 diabetic patients comparing with 30 controls. The cardiovascular AFT and VPT were assessed in both groups. RESULTS: Among cardiovascular AFT, E:I ratio [1.24 (1.2-1.32) vs 1.3 (1.24-1.4), p=0.001], and Valsalva ratio [1.28 (1.22-1.4) vs 1.6 (1.5-1.73), p=0.001], the indicators of parasympathetic reactivity were reduced in T2DM. Rise in DBP during handgrip, an indicator of sympathetic reactivity was lower in T2DM [12 (10-14) vs 16 (14-18) mmHg, p=0.001] whereas, fall in SBP during head up tilt [4 (4-8) vs 5 (4-8) mmHg] was comparable. VPT (somatic sensation) was comparable between T2DM and control. CONCLUSION: Autonomic involvement is more marked than somatic, and parasympathetic involvement is more marked than the sympathetic, possibly reflecting severity and chronological pattern of their involvement.