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Background Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) is closely related to the etiology of autosomal recessive Stargardt’s disease (STGD1) and dry age-related macular degeneration (AMD). N -retinylidene- N -retinylethanolamine (A2E) is a leading component of RPE lipofuscin that is highly susceptible to blue light. Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level, which plays an important role in retinal diseases. However, it remains unknown whether A2E functions as a physiological trigger for eliciting blue light-induced ferroptosis of RPE cells. Methods A2E-loaded RPE cells and Abca4 −/− Rdh8 −/− mice were exposed to blue light, respectively. Western blotting, immunofluorescence staining, reactive oxygen species (ROS) staining, intracellular iron staining, lipid peroxidation staining, fundus imaging, optical coherence tomography (OCT), hematoxylin–eosin (HE) staining, and electroretinography (ERG) were utilized to elucidate the role of blue light in A2E induced ferroptosis in the RPE and its potential mechanisms. Results Exposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe 2+ ) levels and inhibiting the solute carrier family 7 membrane 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. GPX4 inactivation and ROS generated by Fe 2+  overload and GSH depletion precipitated lipid peroxidation and subsequent ferroptosis in A2E-containing RPE cells upon exposure to blue light. In addition to GSH supplement, repressing either Fe 2+  by deferiprone (DFP) or lipid peroxidation with ferrostatin-1 (Fer-1) significantly protected RPE cells against ferroptosis caused by blue light illumination of A2E.  Abca4 −/− Rdh8 −/−  mice featured by an accelerated deposition of A2E in the RPE is an animal model for STGD1 and dry AMD. It was observed that ferroptosis was indeed present in the RPE of  Abca4 −/− Rdh8 −/−  mice following exposure to blue light. Notably, alleviating ferroptosis by intraperitoneally injected Fer-1 effectively rescued retinal function and ameliorated RPE/photoreceptor degeneration in blue light-exposed  Abca4 −/− Rdh8 −/−  mice. Conclusions Our results suggest the importance of blue light in A2E-mediated ferroptosis in the RPE, and deeply broaden the understanding of mechanisms underlying RPE atrophy arising from lipofuscin accumulation in STGD1 and dry AMD.

Objective To assess the effects of WeChat platform-based continuing care for arthritis on patients’ self-management, self-efficiency, quality of life (QoL), and medication compliance. Methods A study was conducted on arthritis patients recruited between December 2017 and February 2018 and divided into two groups. The intervention group received continuing care from the WeChat platform and regular follow-ups, while the control group only received regular follow-ups. The outcomes in both groups were assessed using questionnaires twice: before the study (T0) and eight weeks after T0 (T1), which consists of the evaluation of self-management, QoL, self-efficacy, and medication compliance. Results There were 23 people in each of the intervention and control groups completed two outcome measures. At eight weeks, participants in the intervention group showed an improvement in psychological QoL, cognitive symptom management, and self-efficacy, compared to the control group (QoL scores: mean difference in change between groups was 12.29, 95% CI: 4.51, 20.07, p < 0.001; cognitive symptom management: mean difference in change between groups was 0.65, 95% CI: 0.24, 1.05, p < 0.001; self-efficacy: mean difference in change between groups was 0.69, 95% CI: 0.14, 1.24, p < 0.05). Self-management, self-efficacy, and psychological quality of life were significantly improved in the intervention group before and after the intervention (p < 0.05). Conclusion Using the WeChat platform for continuing care is useful in improving the psychological state, self-efficacy, and self-management ability of patients with arthritis. The study is relevant to Clinical Practice.

Background Disruption of the retinoid (visual) cycle causes all- trans -retinal (atRAL) to accumulate in photoreceptors and retinal pigment epithelium (RPE), contributing to Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (dAMD). Yet, the mechanisms underlying atRAL-induced RPE degeneration are not well understood. Here, we explored whether ferroptosis, a form of regulated cell death marked by iron-dependent lipid peroxidation, mediated RPE damage by atRAL. Methods Cell and animal models of STGD1 and dAMD were established using ARPE-19 cells loaded with atRAL and Abca4 −/− Rdh8 −/− mice subjected to light exposure. Cell viability and morphology, mitochondrial morphology, ferrous iron (Fe 2+ ) levels, reactive oxygen species (ROS) production, lipid peroxidation, and ferroptosis-related gene and protein expression were assessed using MTS assay, inverted and confocal microscopy, fluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, respectively. The conditions of mouse retina were evaluated by electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunofluorescence labeling. Results atRAL triggered ferroptosis of ARPE-19 cells through Fe 2+ accumulation, ROS generation, lipid peroxidation, mitochondrial damage, and abnormal expression of typical ferroptosis-related genes and proteins. These effects were capable of being alleviated by treatment with ferrostatin-1 (Fer-1), a potent ferroptosis inhibitor. Moreover, ferroptosis was clearly observed in the RPE of light-exposed Abca4 −/− Rdh8 −/− mice that showed rapid and excessive accumulation of atRAL in the retina. Notably, intraperitoneal administration of Fer-1 effectively mitigated the degeneration of the RPE and photoreceptors and significantly ameliorated retinal function in Abca4 −/− Rdh8 −/− mice following light exposure. Conclusions Ferroptosis plays a critical role in RPE damage by atRAL. Inhibition of ferroptosis by Fer-1 may enhance RPE cell survival and prevent subsequent photoreceptor degeneration in STGD1 and dAMD.

All-trans-retinal (atRAL)-induced photoreceptor atrophy and retinal degeneration are hallmark features of dry age-related macular degeneration (AMD) and Stargardt disease type 1 (STGD1). The toxicity of atRAL is closely related to the generation of reactive oxygen species (ROS). Quercetin, a natural product, is known for its potent antioxidant properties; however, its effects in mitigating atRAL-mediated retinal damage remains unclear. This study investigated the protective effects of quercetin against atRAL-induced photoreceptor damage. Using atRAL-loaded 661W photoreceptor cells, we evaluated cell viability, ROS generation, and endoplasmic reticulum (ER) stress under quercetin treatment. Quercetin significantly restored the cell viability (to 70%) and reduced ROS generation in atRAL-treated 661W cells. Additionally, Western blot analysis demonstrated that quercetin mitigated protein kinase RNA-like ER kinase (PERK) signaling, preventing ER stress-induced apoptosis. Importantly, in Abca4−/−Rdh8−/− mice, an animal model of light-induced atRAL accumulation in the retina, quercetin treatment effectively alleviated light-exposed photoreceptor atrophy and retinal degeneration by attenuating PERK signaling. Thus, quercetin protected photoreceptor cells from atRAL-induced damage by inhibiting ROS generation and PERK signaling, which suggests its potential as a therapeutic agent for atRAL-related retinal degeneration.

Age-related macular degeneration (AMD) is a common disease contributing to vision loss in the elderly. All-trans-retinal (atRAL) is a retinoid in the retina, and its abnormal accumulation exhibits toxicity to the retina and promotes oxidative stress-induced photoreceptor degeneration, which plays a crucial role in AMD progression. Crocin is a natural product extracted from saffron, which displays significant antioxidant and anti-inflammatory effects. The present study elucidates the protective effects of crocin on photoreceptor cell damage by atRAL and its potential mechanisms. The results revealed that crocin significantly attenuated cytotoxicity by repressing oxidative stress, mitochondrial injury, and DNA damage in atRAL-loaded photoreceptor cells. Moreover, crocin visibly inhibited DNA damage-induced apoptosis and gasdermin E (GSDME)-mediated pyroptosis in photoreceptor cells after exposure to atRAL. It was also observed that crocin distinctly prevented an increase in Fe2+ levels and lipid peroxidation caused by atRAL via suppressing the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor-erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway, thereby ameliorating photoreceptor cell ferroptosis. In short, these findings provide new insights that crocin mitigates atRAL-induced toxicity to photoreceptor cells by inhibiting oxidative stress, apoptosis, pyroptosis, and ferroptosis.

Impaired clearance of all- -retinal (atRAL) due to visual cycle dysfunction contributes to photoreceptor atrophy, a key pathological hallmark of Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (AMD). Prior studies have shown that light-induced atRAL accumulation promotes ferroptosis and activates gasdermin E (GSDME) in retinal photoreceptors of mice, a model for STGD1 and dry AMD that exhibits visual cycle disorders. However, the role of GSDME in photoreceptor ferroptosis remains unclear. In this study, we revealed that GSDME activation by atRAL triggered photoreceptor ferroptosis and retinal atrophy via mitochondrial damage and oxidative stress. Knocking out GSDME significantly attenuated light-induced photoreceptor ferroptosis and retinal degeneration in mice. Moreover, deleting the gene in photoreceptor cells prevented atRAL-induced ferroptosis by inhibiting mitochondrial reactive oxygen species (mitoROS) production, iron overload, and lipid peroxidation. Notably, treatment with the mitoROS scavenger MitoTEMPO mitigated ferroptosis in atRAL-loaded photoreceptor cells and dramatically relieved photoreceptor ferroptosis and retinal degeneration in light-exposed mice. We found that both GSDME elimination and MitoTEMPO treatment repressed atRAL-induced photoreceptor ferroptosis and retinal atrophy by inactivating the mitoROS-induced oxidative stress. In conclusion, GSDME-mediated photoreceptor ferroptosis is crucial for inducing structural and functional damage of the retina in retinopathies caused by atRAL accumulation, thereby providing new therapeutic insights for the prevention and treatment of STGD1 and dry AMD.

Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4 Rdh8 mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4 Rdh8 mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4 Rdh8 mice after exposure to light, and mitigated punctate lesions in the fundus. EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.

High performance force sensors often encounter the conflicting requirements of high resolution and large measurement range. To address this problem, this paper presents a conceptual design of a novel uniaxial force sensor with large range and dual-stage force resolutions which enables us to measure forces within a wide range with satisfied resolutions. The newly developed force sensor features an aluminum alloy body with a probe to transfer external forces into the sensing element. It employs an optical linear encoder to detect the displacement of the sensing body. This sensing scheme may immunize outside electromagnetic noises and therefore enhance the performance of the sensor thanks to its digital signal output. In this paper, an accurate, analytical model for calculating the static stiffness and dynamics of the system was developed by using pseudo-rigid-body-model (PRBM) methodology. To optimize the design, finite element simulations were conducted. After a prototype sensor was fabricated, preliminary characterization tests were carried out to verify the accuracy of the theoretical model and demonstrate the effectiveness of the design. The experiment results indicate that the structure of the new sensor is compact, and it has the ability to measure both micro range and macro range forces within one setup, meanwhile keeps very fine resolutions.

Cannabinoids are a group of bioactive compounds abundantly present in Cannabis sativa plant. The active components of cannabis with therapeutic potential are known as cannabinoids. Cannabinoids are divided into three groups: plant-derived cannabinoids (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoids. These compounds play a crucial role in the regulation various physiological processes including the immune modulation by interacting with the endocannabinoid system (A complex cell-signaling system). Cannabinoid receptor type 1 (CB1) stimulates the binding of orexigenic peptides and inhibits the attachment of anorexigenic proteins to hypothalamic neurons in mammals, increasing food intake. Digestibility is unaffected by the presence of any cannabinoids in hemp stubble. Endogenous cannabinoids are also important for the peripheral control of lipid processing in adipose tissue, in addition to their role in the hypothalamus regulation of food intake. Regardless of the kind of synaptic connection or the length of the transmission, endocannabinoids play a crucial role in inhibiting synaptic transmission through a number of mechanisms. Cannabidiol (CBD) mainly influences redox equilibrium through intrinsic mechanisms. Useful effects of cannabinoids in animals have been mentioned e.g., for disorders of the cardiovascular system, pain treatment, disorders of the respiratory system or metabolic disorders. Dietary supplementation of cannabinoids has shown positive effects on health, growth and production performance of small and large animals. Animal fed diet supplemented with hemp seeds (180 g/day) or hemp seed cake (143 g/kg DM) had achieved batter performance without any detrimental effects. But the higher level of hemp or cannabinoid supplementation suppress immune functions and reduce productive performance. With an emphasis on the poultry and ruminants, this review aims to highlight the properties of cannabinoids and their derivatives as well as their significance as a potential feed additive in their diets to improve the immune status and health performance of animals.

The silent information regulator 2 homolog 1-NACHT, LRR and PYD domains-containing protein 3 (SIRT1-NLRP3) pathway has a crucial role in regulation of the inflammatory response, and is closely related to the occurrence and development of several inflammation-related diseases. NLRP3 is activated to produce the NLRP3 inflammasome, which leads to activation of caspase-1 and cleavage of pro-interleukin (IL)-1β and pro-IL-18 to their active forms: IL-1β and IL-18, respectively. They are proinflammatory cytokines which then cause an inflammatory response.SIRT1 can inhibit this inflammatory response through nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B pathways. This review article focuses mainly on how the SIRT1-NLRP3 pathway influences the inflammatory response and its relationship with melatonin, traumatic brain injury, neuroinflammation, depression, atherosclerosis, and liver damage. BPNQFHKpbhyXXVwX1GGRJd Video Abstract