Endogenous SO2 Controls Cell Apoptosis: The State-of-the-Art

SO2, previously known as the product of industrial waste, has recently been proven to be a novel gasotransmitter in the cardiovascular system. It is endogenously produced from the metabolism pathway of sulfur-containing amino acids in mammalians. Endogenous SO2 acts as an important controller in the regulation of many biological processes including cardiovascular physiological and pathophysiological events. Recently, the studies on the regulatory effect of endogenous SO2 on cell apoptosis and its pathophysiological significance have attracted great attention. Endogenous SO2 can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, neuron, alveolar macrophages, polymorphonuclear neutrophils and retinal photoreceptor cells, which might be involved in the pathogenesis of hypertension, pulmonary hypertension, myocardial injury, brain injury, acute lung injury, and retinal disease. Therefore, in the present study, we described the current findings on how endogenous SO2 is generated and metabolized, and we summarized its regulatory effects on cell apoptosis, underlying mechanisms, and pathophysiological relevance.

Lysophosphatidylcholine acyltransferase 1 controls the mitochondrial reactive oxygen species generation and survival of the retinal photoreceptor cells

ABSTRACTDue to the high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. Accordingly, dysregulation of lipid metabolism leads to the photoreceptor cell death and retinal degeneration. Mice with a frameshift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), which produces saturated phosphatidylcholine (PC) composed of two saturated fatty acids, has been reported to cause spontaneous retinal degeneration (rd11 mice). In this study, we performed a detailed characterization of LPCAT1 in the retina and found that genetic deletion of Lpcat1 induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 decreases saturated PC production and affects the proper cellular fatty acid flux, presumably by altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells without affecting the OS structure and trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of saturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.

cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates

Background Retinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have suggested visual improvement following retinal photoreceptor precursors transplantation, but there is limited evidence on the ability of these transplants to rescue retinal damage in higher mammals. The purpose of this study was to evaluate the therapeutic potential of photoreceptor precursors derived from clinically compliant induced pluripotent stem cells (iPSCs). Methods Photoreceptor precursors were sub-retinally transplanted into non-human primates (Macaca fascicularis). The cells were transplanted both in naïve and cobalt chloride-induced retinal degeneration models who had been receiving systemic immunosuppression for one week prior to the procedure. Optical coherence tomography, fundus autofluorescence imaging, electroretinography, ex vivo histology and immunofluorescence staining were used to evaluate retinal structure, function and survival of transplanted cells. Results There were no adverse effects of iPSC-derived photoreceptor precursors on retinal structure or function in naïve NHP models, indicating good biocompatibility. In addition, photoreceptor precursors injected into cobalt chloride-induced retinal degeneration NHP models demonstrated an ability both to survive and to mature into cone photoreceptors at 3 months post-transplant. Optical coherence tomography showed restoration of retinal ellipsoid zone post-transplantation. Conclusions These findings demonstrate the safety and therapeutic potential of clinically compliant iPSC-derived photoreceptor precursors as a cell replacement source for future clinical trials.

Paeonol Induces Protective Autophagy in Retinal Photoreceptor Cells

Background: Retinal photoreceptor (RP) cells are widely involved in retina-related diseases, and oxidative stress plays a critical role in retinal secondary damage. Herein, we investigated the effectiveness and potential mechanisms of autophagy of paeonol (Pae) in terms of oxidation resistance.Methods: The animal model was induced by light damage (LD) in vivo, whereas the in vitro model was established by H2O2 stimulation. The effectiveness of Pae was evaluated by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence, transmission electron microscopy, electroretinogram, and Western blot analysis in vivo, and the underlying mechanisms of Pae were assessed by Cell Counting Kit-8 assay, reactive oxygen species (ROS) assay, and Western blot analysis in 661W cells. We mainly evaluated the effects of Pae on apoptosis and autophagy.Results: Increased apoptosis of the LD-induced and decreased autophagy of RPs were mitigated by Pae treatment. Pea, which increased the expression of mitochondrial functional protein cytochrome c, reversed the decreased cell viability and autophagy induced by oxidative stress in 661W cells. Experiments showed that autophagy was downregulated in PINK1/Parkin dependent and the BNIP3L/Nix dependent pathways under H2O2 stimulation and was upregulated by Pae treatment. Pae increased the cell viability and reduced ROS levels through autophagy.Conclusion: Pretreatment with Pae preserved RP cells by enhancing autophagy, which protected retinal function.

Myelin regulatory factor deficiency is associated with the retinal photoreceptor defects in mice

Previously, we reported the myelin regulatory factor (MYRF) as a candidate gene for nanophthalmos. We have also produced Myrf knockdown (Myrf+/−) mouse strain to investigate the cellular and molecular phenotypes of reduced MYRF expression in the retina. Myrf+/− mouse strain was generated using the CRISPR/Cas9 system. Optomotor response system, electroretinogram (ERG), spectral-domain optical coherence tomography (SD-OCT), histology, and immunohistochemistry were performed to evaluate retinal spatial vision, electrophysiological function, retinal thickness, and pathological changes in cone or rod photoreceptors, respectively. RNA sequencing (RNA-seq) was performed to investigate the underlying molecular mechanism linking Myrf deficiency with photoreceptor defects. The genotype and phenotype of CRISPR/Cas9-induced Myrf+/− mice and their offspring were comprehensively investigated. Photoreceptor defects were detected in the retinas of Myrf+/− mice. Visual acuity and ERG responses were decreased in Myrf+/− mice compared with the control mice (Myrf+/+). The loss of cone and rod neurons was proportional to the decreased outer nuclear layer (ONL) thickness. Moreover, RNA-seq revealed that phototransduction and estrogen signaling pathways played important roles in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Myrf+/− mouse strain provides a good model to investigate the function of the MYRF gene. Photoreceptor defects with impaired functions of spatial vision and retinal electrophysiology indicate an important role played by MYRF in retinal development. Alterations in phototransduction and estrogen signaling pathways play important roles in linking Myrf deficiency with retinal photoreceptor defects.

Optical spherical dielectric resonator antenna for sensing and wireless communication

In this article, Terahertz spherical dielectric resonator antenna (DRA) is mathematically formulated and simulated at 511 THz for LiDAR and retinal photoreceptor applications. Titanate DR element is used at optical design frequency. It is validated with good S11, radiation pattern and 5.6 dBi gain plots using HFSS simulator. Unique mathematical formulation on super directivity and radiated states is formulated for the first time. The proximity coupled feed is used with laser Gaussian beam excitation. The silver nano waveguides is used to provide feed mechanism to terahertz DRA. This DR design at optical frequency can be used for wireless sensing and communication applications. It has novel geometry.

Long noncoding RNA U90926 is crucial for herpes simplex virus type 1 proliferation in murine retinal photoreceptor cells

Long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of infectious diseases, but the role of lncRNAs in herpes simplex virus 1 (HSV-1) infection remains unknown. Using RNA sequencing analysis, we explored lncRNAs that were highly expressed in murine retinal photoreceptor cell-derived 661W cells infected with HSV-1. U90926 RNA (522 nucleotides) was the most upregulated lncRNA detected post HSV-1 infection. The level of U90926 RNA was continuously increased post HSV-1 infection, reaching a 100-fold increase at 24 h. Cellular fractionation showed that U90926 RNA was located in the nucleus post HSV-1 infection. Downregulation of U90926 expression by RNA interference markedly suppressed HSV-1 DNA replication (80% reduction at 12 h post infection) and HSV-1 proliferation (93% reduction at 12 h post infection) in 661W cells. The survival rates of U90926-knockdown cells were significantly increased compared to those of control cells (81% and 21%, respectively; p < 0.0001). Thus, lncRNA U90926 is crucial for HSV-1 proliferation in retinal photoreceptor cells and consequently leads to host cell death by promoting HSV-1 proliferation.