scholarly journals Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1935
Author(s):  
Joseph Thomas Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Inflammatory Response ◽  
Retinitis Pigmentosa ◽  
Therapeutic Strategy ◽  
Treatment Strategies ◽  
Photoreceptor Cells ◽  
Rod Photoreceptors ◽  
Inflammatory Reactions ◽  
Environmental Light ◽  
The Stability ◽  
Visual Receptor

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP.

The Role of Inflammasomes in Atherosclerosis and Stroke Pathogenesis

2020 ◽  
Vol 26 (34) ◽  
pp. 4234-4245
Author(s):  
Deepaneeta Sarmah ◽  
Aishika Datta ◽  
Swapnil Raut ◽  
Ankan Sarkar ◽  
Birva Shah ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Treatment Strategies ◽  
Cerebrovascular Diseases ◽  
Cellular Injury ◽  
Inflammatory Reactions ◽  
Inflammatory Pathways

Inflammation is a devastating outcome of cerebrovascular diseases (CVD), namely stroke and atherosclerosis. Numerous studies over the decade have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after a stroke or a rupture of an atherosclerotic plaque. In view of this, targeting these inflammatory pathways using different pharmacological therapies may improve outcomes in patients with CVD. Here, we review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also, discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators.

Ayurvedic management of Retinitis Pigmentosa (Doshandha) - A Case Study

2017 ◽  
Vol 2 (05) ◽  
Author(s):  
Anju D. ◽  
Pushpa Raj Poudel ◽  
Ajoy Viswam ◽  
Ashwini M. J.
Keyword(s):  
Retinitis Pigmentosa ◽  
Low Vision ◽  
Symptomatic Relief ◽  
Retinal Dystrophy ◽  
Treatment Protocol ◽  
Signs And Symptoms ◽  
Photoreceptor Cells ◽  
Rod Photoreceptor ◽  
Night Time ◽  
Initial Symptoms

Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment due to the progressive degeneration of rod photoreceptor cells in retina. This form of retinal dystrophy manifests initial symptoms independentof age; thus, RP diagnosis occurs anywhere from early infancy to late adulthood. This primary pigmentary retinal dystrophy is a hereditary disorder predominantly affecting the rods more than the cones. The main classical triads of retinitis pigmentosa are arteriolar attenuation, Retinal bone spicule pigmentation and Waxy disc pallor. The main treatment of retinitis pigmentosa is by using Low vision aids (LVA) and Genetic counseling. As such a complete cure for retinitis pigmentosa is not present. So a treatment protocol has to be adopted that helps in at least the symptomatic relief. In Ayurveda, the signs and symptoms of this can be compared with the Lakshanas of Doshandha which is one among the Dristigata Roga. It is considered as a diseased condition in which sunset will obliterate the Dristi Mandala and makes the person blind at night time. During morning hours the rising sunrays will disperse the accumulated Dosas from Dristi to clear vision. This disease resembles Kaphajatimira in its pathogenesis, but the night blindness is the special feature. Since the disease is purely Kaphaja, a treatment attempt is planned in Kaphara and Brimhana line. The present paper discusses a case of retinitis pigmentosa and it’s Ayurvedic Treatment.

scholarly journals Retinitis pigmentosa is associated with shifts in the gut microbiome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oksana Kutsyr ◽  
Lucía Maestre-Carballa ◽  
Mónica Lluesma-Gomez ◽  
Manuel Martinez-Garcia ◽  
Nicolás Cuenca ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Gut Microbiome ◽  
Functional Decline ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Amplicon Sequencing ◽  
Rrna Gene ◽  
Sequencing Data ◽  
Alpha And Beta Diversity ◽  
Potential Biomarker

AbstractThe gut microbiome is known to influence the pathogenesis and progression of neurodegenerative diseases. However, there has been relatively little focus upon the implications of the gut microbiome in retinal diseases such as retinitis pigmentosa (RP). Here, we investigated changes in gut microbiome composition linked to RP, by assessing both retinal degeneration and gut microbiome in the rd10 mouse model of RP as compared to control C57BL/6J mice. In rd10 mice, retinal responsiveness to flashlight stimuli and visual acuity were deteriorated with respect to observed in age-matched control mice. This functional decline in dystrophic animals was accompanied by photoreceptor loss, morphologic anomalies in photoreceptor cells and retinal reactive gliosis. Furthermore, 16S rRNA gene amplicon sequencing data showed a microbial gut dysbiosis with differences in alpha and beta diversity at the genera, species and amplicon sequence variants (ASV) levels between dystrophic and control mice. Remarkably, four fairly common ASV in healthy gut microbiome belonging to Rikenella spp., Muribaculaceace spp., Prevotellaceae UCG-001 spp., and Bacilli spp. were absent in the gut microbiome of retinal disease mice, while Bacteroides caecimuris was significantly enriched in mice with RP. The results indicate that retinal degenerative changes in RP are linked to relevant gut microbiome changes. The findings suggest that microbiome shifting could be considered as potential biomarker and therapeutic target for retinal degenerative diseases.

The role of splicing factors in retinitis pigmentosa: links to cilia

2021 ◽  
Author(s):  
Dale W. Maxwell ◽  
Raymond T. O'Keefe ◽  
Sudipto Roy ◽  
Kathryn E. Hentges
Keyword(s):  
Retinitis Pigmentosa ◽  
Primary Cilium ◽  
Photoreceptor Cells ◽  
Genetic Mutations ◽  
Splicing Factors ◽  
Sequence Variants ◽  
Biological Functions ◽  
Progressive Degeneration

Cilia are critical to numerous biological functions, both in development and everyday homeostatic processes. Diseases arising from genetic mutations that cause cilia dysfunction are termed ciliopathies. Several ubiquitously expressed splicing factors have been implicated in the condition Retinitis Pigmentosa (RP), a group of diseases characterised by the progressive degeneration of the retina. In many types of RP the disease affects the modified primary cilium of the photoreceptor cells and thus, these types of RP are considered ciliopathies. Here, we discuss sequence variants found within a number of these splicing factors, the resulting phenotypes, and the mechanisms underpinning disease pathology. Additionally, we discuss recent evidence investigating why RP patients with mutations in globally expressed splicing factors present with retina-specific phenotypes.

Sepsis Syndrome

2014 ◽  
pp. 395-402
Author(s):  
Joshua A. Englert ◽  
Rebecca Marlene Baron
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Innate Immune System ◽  
Tissue Injury ◽  
Treatment Strategies ◽  
Sepsis Syndrome ◽  
Clinical Syndrome ◽  
High Morbidity ◽  
Early Management ◽  
Inflammatory State

Sepsis is a clinical syndrome characterized by systemic inflammation leading to tissue injury that arises as a complication of an infection. According to current paradigms, sepsis arises as a result of the infection of a normally sterile body compartment. Infection leads to activation of the innate immune system to produce a systemic inflammatory response. This response is a necessary component of the body's defense against infection under normal conditions, but it is the lack of regulation of this response that is central to the pathogenesis of sepsis. As discussed in more detail below, this dysregulated inflammatory state can lead to tissue injury and dysfunction in organs not involved in the original infectious insult. Although sepsis remains a condition with exceedingly high morbidity and mortality, recent early management and treatment strategies have demonstrated exciting improvements in overall outcomes.

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

scholarly journals Immunocytochemical localization of opsin in the cell membrane of developing rat retinal photoreceptors.

1984 ◽  
Vol 98 (5) ◽  
pp. 1788-1795 ◽  
Author(s):  
I Nir ◽  
D Cohen ◽  
D S Papermaster
Keyword(s):  
Plasma Membrane ◽  
Outer Segment ◽  
Plasma Membranes ◽  
Photoreceptor Cells ◽  
Rod Photoreceptor ◽  
Rod Photoreceptors ◽  
Retinal Photoreceptors ◽  
Retinal Rod ◽  
Ros Formation ◽  
Developing Rat

Mature retinal rod photoreceptors sequester opsin in the disk and plasma membranes of the rod outer segment (ROS). Opsin is synthesized in the inner segment and is transferred to the outer segment along the connecting cilium that joins the two compartments. We have investigated early stages of retinal development during which the polarized distribution of opsin is established in the rod photoreceptor cell. Retinas were isolated from newborn rats, 3-21 d old, and incubated with affinity purified biotinyl-sheep anti-bovine opsin followed by avidin-ferritin. At early postnatal ages prior to the development of the ROS, opsin is labeled by antiopsin on the inner segment plasma membrane. At the fifth postnatal day, as ROS formation begins opsin was detected on the connecting cilium plasma membrane. However, the labeling density of the ciliary plasma membrane was not uniform: the proximal cilium was relatively unlabeled in comparison with the distal cilium and the ROS plasma membrane. In nearly mature rat retinas, opsin was no longer detected on the inner segment plasma membrane. A similar polarized distribution of opsin was also observed in adult human rod photoreceptor cells labeled with the same antibodies. These results suggest that some component(s) of the connecting cilium and its plasma membrane may participate in establishing and maintaining the polarized distribution of opsin.

scholarly journals Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4904
Author(s):  
Gaia Pasqualetto ◽  
Martin Schepelmann ◽  
Carmine Varricchio ◽  
Elisa Pileggi ◽  
Caroline Khogali ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Small Molecules ◽  
Binding Site ◽  
Photoreceptor Cells ◽  
Structural Features ◽  
Outer Cell ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
In Silico Studies ◽  
Leber’S Congenital Amaurosis

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.

scholarly journals Cx32 mRNA in rat liver: effects of inflammation on poly(A) tail distribution and mRNA degradation

1999 ◽  
Vol 276 (5) ◽  
pp. R1249-R1257 ◽  
Author(s):  
Nicholas G. Theodorakis ◽  
Antonio de Maio
Keyword(s):  
Inflammatory Response ◽  
Mrna Stability ◽  
Actinomycin D ◽  
Mrna Degradation ◽  
Connexin 32 ◽  
Detectable Change ◽  
Final Size ◽  
Tail Distribution ◽  
The Stability ◽  
Lps Treatment

Previous studies showed that the expression of connexin 32 (Cx32), the polypeptide subunit component of the major hepatic gap junction, is reduced in liver by changes in mRNA stability during bacterial lipopolysaccharide (LPS)-induced inflammation. In this study, we examined the distribution of Cx32 mRNA poly(A) tail lengths during LPS-induced inflammation, because this is considered the first step in the degradation of many mRNAs. During LPS treatment the first detectable change in Cx32 mRNA was a gradual shortening of its poly(A) tail, which reached a final size of ∼20 nucleotides. However, the poly(A) tail did not disappear entirely before the bulk of Cx32 mRNA was degraded. Treatment with actinomycin D, which blocks the degradation of Cx32 mRNA after LPS administration, resulted in the appearance of a completely deadenylated mRNA, which otherwise could not be detected. On the contrary, treatment with cycloheximide resulted in a decrease in the stability of Cx32 mRNA without an apparent change of the poly(A) tail size. The effect of cycloheximide on Cx32 mRNA stability seems to be due indirectly to the induction of an inflammatory response by this drug. These results suggest that, similar for many mRNAs, shortening of the poly(A) tail is one of the first steps in the degradation of Cx32 mRNA during inflammation.

scholarly journals Anti-Inflammatory Cytokines: Important Immunoregulatory Factors Contributing to Chemotherapy-Induced Gastrointestinal Mucositis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Masooma Sultani ◽  
Andrea M. Stringer ◽  
Joanne M. Bowen ◽  
Rachel J. Gibson
Keyword(s):  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Financial Burden ◽  
Interleukin 1 ◽  
Treatment Strategies ◽  
Inflammatory Reactions ◽  
Anti Inflammatory

“Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.

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