Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa

Опубликована: Март 27, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Язык: Английский

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Retinal Organoids: Innovative Tools for Understanding Retinal Degeneration

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3263 - 3263

Опубликована: Апрель 1, 2025

Retinal degenerative diseases (RDDs) comprise diverse genetic and phenotypic conditions that cause progressive retinal dysfunction cell loss, leading to vision impairment or blindness. Most RDDs lack appropriate animal models for their study, which affects understanding disease mechanisms delays the progress of new treatment development. Recent advances in stem engineering, omics, organoid technology are facilitating research into there no previously existing models. The development organoids produced from human cells has impacted study as well vitro diseases, opening possibilities applications regenerative medicine, drug discovery, precision medicine. In this review, we recapitulate RDD, mentioning some main pathways underlying neurodegeneration can be studied these models, limitations future challenges rapidly advancing field.

Язык: Английский

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Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa

eLife, Год журнала: 2025, Номер 14

Опубликована: Апрель 15, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Язык: Английский

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Reserpine Ameliorates 1,2-Dimethylhydrazine-induced Colon Cancer Through Regulating Xenobiotic Enzymes and Bax/Caspases/Bcl-2-mediated Apoptotic Mechanisms in Rats

Pharmacognosy Magazine, Год журнала: 2025, Номер unknown

Опубликована: Апрель 17, 2025

Background Colon cancer is a significant public health issue, known as major cause of cancer-associated mortalities globally. Understanding the underlying molecular mechanisms that direct onset colon necessary to develop novel therapeutic targets. Purpose This study was dedicated studying anti-cancer properties reserpine against 1,2-dimethylhydrazine (DMH)-treated in rats. Methods In present work, triggered rats by administration DMH and thereafter treated with prior throughout administration. After completing treatments, alterations body weight were assessed. The levels inflammatory cytokines, oxidative markers, xenobiotic-metabolizing enzymes, tumor apoptotic proteins carefully analyzed using commercial kits. mucosa subjected histopathological studies. Results current results proved significantly increased DMH-administered substantially diminished stress, regulated cytokine levels, inhibited AKT/mTOR axis DMH-induced Furthermore, also activities enzymes protein reduced markers analysis witnessed roles reserpine. Conclusion work shows exhibits effects These findings demonstrate has capacity an agent treat cancer.

Язык: Английский

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Recent Advances on Modeling Retinal Disease: Towards Efficient Gene/Drug Therapy

Experimental Eye Research, Год журнала: 2025, Номер unknown, С. 110416 - 110416

Опубликована: Май 1, 2025

Язык: Английский

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Cell type-focused compound screen in human organoids reveals molecules and pathways controlling cone photoreceptor death

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 10, 2023

SUMMARY Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds protect disease-affected or damage healthy cell types. However, such have not yet been performed. Here, we generated 20,000 human retinal with GFP-labeled cone photoreceptors. Since degeneration of cones is a leading cause blindness, induced death and screened 2,707 known targets, those saved further damaged cones. We identified kinase inhibitors protected both the short longer term, HSP90 term but them broad HDAC inhibition by many significantly This resource provides database cone-damaging compounds, it describes can be starting points develop neuroprotection diseases as macular degeneration.

Язык: Английский

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Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Human Molecular Genetics, Год журнала: 2024, Номер 33(10), С. 860 - 871

Опубликована: Фев. 7, 2024

Abstract Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number genes, including electron transport components, in large forward genetic screen for mutations causing age-related neurodegeneration context proteostasis dysfunction. created model complex I deficiency Drosophila retina to probe role protein degradation abnormalities encephalomyopathies. Using our model, we found that regulates both ubiquitin/proteasome autophagy/lysosome arms machinery. further performed an vivo kinome uncover new potentially druggable mechanisms contributing related failure. Reduction RIOK kinases innate immune signaling kinase pelle prevented animals. Genetically targeting oxidative stress, but not RIOK1 or knockdown, normalized markers. Our findings outline distinct pathways controlling introduce experimentally facile which study these debilitating currently treatment-refractory disorders.

Язык: Английский

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Clinical and Molecular Aspects of C2orf71/PCARE in Retinal Diseases

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 10670 - 10670

Опубликована: Июнь 26, 2023

Mutations in the photoreceptor-specific C2orf71 gene (also known as photoreceptor cilium actin regulator protein PCARE) cause autosomal recessive retinitis pigmentosa type 54 and cone-rod dystrophy. No treatments are available for patients with retinal ciliopathies exhibiting a severe clinical phenotype. Our understanding of disease process role PCARE healthy retina significantly limits our capacity to transfer recent technical developments into viable therapy choices. This study summarizes current C2orf71-related diseases, including their manifestations an unclear genotype-phenotype correlation. It discusses molecular functional studies on ciliary PCARE, focusing cell its axoneme. is proposed that actin-associated interacts WASF3 regulate actin-driven expansion membrane during development new outer segment disk cells. review also introduces various cellular animal models used model these diseases provides overview potential treatments.

Язык: Английский

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Addressing Key Questions in Organoid Models: Who, Where, How, and Why?

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 16014 - 16014

Опубликована: Ноя. 6, 2023

Organoids are three-dimensional cellular structures designed to recreate the biological characteristics of body's native tissues and organs in vitro. There has been a recent surge studies utilizing organoids due their distinct advantages over traditional two-dimensional vitro approaches. However, there is no consensus on how define organoids. This literature review aims clarify concept address four fundamental questions pertaining organoid models: (i) What constitutes organoids?-The material. (ii) Where do grow?-The extracellular scaffold. (iii) How maintained vitro?-Via culture media. (iv) Why suitable models?-They represent reproducible, stable, scalable models for applications. Finally, this provides an update employed within female reproductive tract, underscoring relevance both basic biology clinical

Язык: Английский

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Eye Diseases: When the Solution Comes from Plant Alkaloids

Planta Medica, Год журнала: 2024, Номер 90(06), С. 426 - 439

Опубликована: Март 7, 2024

Abstract Plants are an incredible source of metabolites showing a wide range biological activities. Among these, there the alkaloids, which have been exploited for medical purposes since ancient times. Nowadays, many plant-derived alkaloids main components drugs used as therapy different human diseases. This review deals with providing overview to treat eye diseases, describing historical outline, plants from they extracted, and clinical molecular data supporting their therapeutic activity. that found application in medicine so far, atropine pilocarpine most characterized ones. Conversely, caffeine berberine proposed treatment disorders, but further studies still necessary fully understand value. Lastly, alkaloid managing hypertension, reserpine, has recently identified potential drug ameliorating retinal disorders. Other important aspects discussed this solutions production. Given industrial production relies on extraction plants, chemical synthesis can be highly expensive poorly efficient, alternative methods need found. Biotechnologies offer multitude possibilities overcome these issues, spanning genetic engineering synthetic biology microorganisms bioreactors plant cell cultures. However, efforts needed completely satisfy pharmaceutical demand.

Язык: Английский

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