bims-mideyd 2023-01-01 papers

Issue of 2023‒01‒01
five papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Phytomedicine. 2022 Dec 15. pii: S0944-7113(22)00694-8. [Epub ahead of print]110 154606

Retinal protective effect of curcumin metabolite hexahydrocurcumin against blue light-induced RPE damage.

Yi-Hsiung Lin, Shwu-Jiuan Sheu, Wangta Liu, Yun-Tzu Hsu, Chen-Xi He, Chang-Yi Wu, Kuo-Jen Chen, Po-Yen Lee, Chien-Chih Chiu, Kai-Chun Cheng.

BACKGROUND: Age-related macular degeneration (AMD) is a disease of retinal pigment epithelium (RPE) cells. We have previously demonstrated that blue light can damage RPE cells and their underlying mechanisms. We found that hexahydrocurcumin (HHC), a metabolite of curcumin, had better retinal protection than curcumin. However, the involved mechanisms remain unclear.METHODS: By exposing ARPE-19 human RPE cells and mouse primary RPE cells to blue light, the intracellular mechanisms of HHC in cells were investigated, including the proliferation of RPE cells and the effects of HHC on activating intracellular protective mechanisms and related factors. Next-generation sequencing (NGS) RNA sequencing revealed the underlying mechanisms involved in the induction and regulation of HHC treatment following blue light exposure.
RESULTS: HHC promoted autophagy by enhancing autophagic flux, reduced oxidative stress and endoplasmic reticulum (ER) stress, and effectively reversed blue light-induced cell death. RNA sequencing-based bioinformatics approaches comprehensively analyze HHC-mediated cellular processes.
CONCLUSION: Our findings elucidate the mechanisms of HHC against blue light damage in RPE cells and are beneficial for the development of natural metabolite-based preventive drugs or functional foods.

Keywords: Age-related macular degeneration; Autophagy; Blue light damage; Curcumin metabolites; Retinal pigment epithelial; Retinal protection

DOI: https://doi.org/10.1016/j.phymed.2022.154606

Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01776-4. [Epub ahead of print]41(13): 111880

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma.

Song Li, Tatjana C Jakobs.

Aging causes an irreversible, cumulative decline in neuronal function. Using the visual system as a model, we show that astrocytes play a critical role in maintaining retinal ganglion cell health and that deletion of SPP1 (secreted phosphoprotein 1, or osteopontin) from astrocytes leads to increased vulnerability of ganglion cells to age, elevated intraocular pressure, and traumatic optic nerve damage. Overexpression of SPP1 slows the age-related decline in ganglion cell numbers and is highly protective of visual function in a mouse model of glaucoma. SPP1 acts by promoting phagocytosis and secretion of neurotrophic factors while inhibiting production of neurotoxic and pro-inflammatory factors. SPP1 up-regulates transcription of genes related to oxidative phosphorylation, functionally enhances mitochondrial respiration, and promotes the integrity of mitochondrial microstructure. SPP1 increases intracellular ATP concentration via up-regulation of VDAC1.

Keywords: CP: Neuroscience; VDAC1; aging; astrocytes; glaucoma; mitochondria; mitophagy; neurodegeneration; neuroprotection; osteopontin; secreted phosphoprotein 1

DOI: https://doi.org/10.1016/j.celrep.2022.111880

Ophthalmol Sci. 2022 Dec;2(4): 100192

Neuroprotection for Age-Related Macular Degeneration.

Jonathan B Lin, Yusuke Murakami, Joan W Miller, Demetrios G Vavvas.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.

Keywords: AD, Alzheimer disease; ALA, alpha lipoic acid; AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study; AREDS2, Age-Related Eye Disease Study 2; Age-related macular degeneration; CFH, complement factor H; CNTF, ciliary neurotrophic factor; GA, geographic atrophy; HTRA1, high-temperature requirement A1; IOP, intraocular pressure; Neuroprotection; RBP, retinol-binding protein; RGC, retinal ganglion cell; RIPK3, receptor-interacting serine/threonine-protein kinase 3; ROS, reactive oxygen species; RPE, retinal pigment epithelium; Retinal degeneration; VA, visual acuity; iPSC, induced pluripotent stem cell

DOI: https://doi.org/10.1016/j.xops.2022.100192

Sci Rep. 2022 Dec 23. 12(1): 22442

Pretreatment of human retinal pigment epithelial cells with sterculic acid forestalls fenretinide-induced apoptosis.

Samuel William, Todd Duncan, T Michael Redmond.

The ratio of saturated to monounsaturated fatty acids, thought to play a critical role in many cellular functions, is regulated by stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. Previously, we observed a decrease in both SCD protein and enzymatic activity in apoptosis induced by fenretinide, a synthetic analog of retinoic acid, in the human retinal pigment epithelial (RPE) cell line ARPE-19. Here, we investigated the effect of pretreating ARPE-19 with sterculic acid, a cyclopropenoic fatty acid inhibitor of SCD, on preventing fenretinide-induced apoptosis, given the role of SCD in cell proliferation and apoptosis. We show that sterculic acid pretreatment prevents the effects of fenretinide-induced apoptosis shown by changes in cell morphology, viability, and caspase-3 activation. Analysis of endoplasmic reticulum (ER)-associated proteins shows that sterculic acid pretreatment reduced the fenretinide-induced upregulation of heme oxygenase-1, ATF3 and GADD153 expression that are in response to reactive oxygen species (ROS) generation. Sterculic acid is as effective as allopurinol in inhibition of xanthine oxidase (XDH), and this may play a role in reducing the potential role of XDH in fenretinide-induced ROS generation. Sterculic acid pretreatment also results in a reduction in SOD2 mRNA expression. Dihydroceramide accumulation, compared to ceramide, and ROS generation indicate that a ceramide-independent pathway mediates fenretinide-induced apoptosis, and ROS mediation is borne out by activation of the NF-κBp50 and NF-κBp65 downstream signaling cascade. Its prevention by sterculic acid pretreatment further indicates the latter's antioxidant/anti-inflammatory effect. Taken together, our results suggest that sterculic acid pretreatment can mitigate ROS-mediated fenretinide-induced apoptosis. Thus, sterculic acid may serve as a potential antioxidant and therapeutic agent. These effects may be independent of its effects on SCD activity.

DOI: https://doi.org/10.1038/s41598-022-26383-9

Exp Eye Res. 2022 Dec 25. pii: S0014-4835(22)00446-8. [Epub ahead of print] 109365

Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway.

Yurun Liu, Simin Gu, Yaru Su, Shoubi Wang, Yaqi Cheng, Xuan Sang, Lin Jin, Ying Liu, Chaoyang Li, Weiqin Liu, Minghao Chen, Xiaoran Wang, Zhichong Wang.

Retinal pigment epithelial (RPE) cellular senescence is regarded as an initiator for age-related macular degeneration (AMD). We previously demonstrated that by the coculture way, embryonic stem cells (ESCs) can reverse the senescence of RPE cells, but xenograft cells can cause a plethora of adverse effects. Extracellular vesicles (EVs) derived from ESCs can act as messengers to mediate nearby cell activities and have the same potential as ESCs to reverse RPE senescence. Furthermore, ESC-EVs have achieved preliminary efficacy while treating many age-related diseases. The present study aimed to test the effect of ESC-EVs on the replicative senescence model of RPE cells as well as its mechanism. The results showed that ESC-EVs enhanced the proliferative ability and cell cycle transition of senescent RPE cells, whereas reduced the senescence-associated galactosidase (SA-β-gal) staining rate, as well as the levels of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). Moreover, classical markers of cellular senescence p21WAF1/CIP1 (p21) and p16INK4a (p16) were downregulated. The bioinformatic analysis and further study showed that the inhibition of the p38MAPK pathway by ESC-EVs played a pivotal role in RPE cellular senescence-reversing effect, which was ameliorated or even abolished when dehydrocorydaline were administrated simultaneously, demonstrating that ESC-EVs can effectively reverse RPE cellular senesence by inhibiting the p38MAPK pathway, thus highlights the potential of ESC-derived EVs as biomaterials for preventative and protective therapy in AMD.

Keywords: ESC; Extracellular vesicles; RPE; Senescence; p38MAPK

DOI: https://doi.org/10.1016/j.exer.2022.109365