Visual Transduction Occurs Within The

Visual Phototransduction

Phototransduction is the generation of an electrochemical signal in response to absorbance of low-cal (Baylor, 1996; Burns & Arshavsky, 2005; Gross & Burns, 2011; Stryer, 1986).

From: Basic Neurochemistry (Eighth Edition) , 2012

Retinal biochemistry, physiology, and cell biology

Victor Chong Dr. , ... Sobha Sivaprasad DM, MS, DNB, FRCS , in Retinal Pharmacotherapy, 2010

Outer segment of photoreceptors

Visual phototransduction is the photochemical reaction that take place when light (photon) is converted to an electric signal in the retina. Rhodopsin, the visual pigment in the rods, is a membrane protein located in the outer segments of the rods. It contains a chromophore (11- cis retinal) that is covalently spring to opsin. On photoactivation, eleven-cis retinal undergoes photoisomerization to all-trans retinal. While all the same covalently bound to opsin, the compound undergoes a number of conformational intermediates, collectively termed metarhodopsin. Information technology is suggested that metarhodopsin II is important in inactivation of electrical activeness.

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Phototransduction: Rhodopsin

L.P. Pulagam , One thousand. Palczewski , in Encyclopedia of the Heart, 2010

Rhodopsin, which absorbs a photon to initiate visual phototransduction, belongs to the superfamily of Thousand protein (guanine-nucleotide-bounden protein)-coupled receptors (GPCRs), encoded by ∼950 genes of the human genome. Mutations in the rhodopsin gene may crusade human diseases such as retinitis pigmentosa that usually result in late-onset blindness. Like all GPCRs, rhodopsin has vii transmembrane helices and consists of an apoprotein, the opsin, together with a covalently bound chromophore, 11- cis-retinal. The high-resolution structure of bovine rhodopsin, the offset 3-dimensional structure available for GPCR family proteins, provides a template for agreement GPCR construction/part at a molecular level.

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Biomolecular Interactions Role A

Nicole A. Perry-Hauser , ... Jonathan A. Javitch , in Methods in Cell Biology, 2021

2.1 Direct binding assay with rhodopsin

The prototypical GPCR rhodopsin, a protein involved in visual phototransduction, is one of the all-time studied GPCR systems ( Palczewski, 2006). Rhodopsin is activated via light, which enables activation of its cognate G protein, transducin. Agile receptor is after deactivated by GRK phosphorylation, which triggers arrestin recruitment. In vitro transcription and translation of radiolabeled arrestin has proved a useful system for efficient characterization of arrestin binding to purified rhodopsin (Fig. 1). This is due to the ease of detecting radiolabeled protein after gel filtration using a scintillation counter. This method can be used to screen numerous arrestin mutants without the requirement for full-scale arrestin purification (Gurevich & Benovic, 1993) and uses purified native rhodopsin (McDowell, 1993) and untagged arrestin, decreasing the possibility of binding artifacts.

In brief, this system uses four different functional forms of rhodopsin purified from bovine retinas: dark phosphorylated (P-Rh), light-activated phosphorylated (P-Rh*), dark unphosphorylated (Rh), and lite-activated unphosphorylated (Rh*) (Gurevich & Benovic, 2000). Arrestin preferentially binds to activated and phosphorylated rhodopsin, yielding at least a 10-fold higher bounden than to other forms, but can likewise recognize the activated or phosphorylated state of rhodopsin. Arrestin bounden to inactivate unphosphorylated Rh is near zero. Therefore, this assay tin can be used to study high-affinity arrestin interactions with P-Rh* in add-on to lower-affinity interactions with P-Rh and Rh*.

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Molecular Mechanisms of Retinal Toxicity Induced by Light and Chemical Damage

María Guadalupe Herrera-Hernández , ... Pere Garriga , in Advances in Molecular Toxicology, 2015

three.1.1 Photoreceptors harm

The first study on harm to the retina that was elicited by depression-intensity low-cal was reported in 1966 by Noell et al. [22]. It was constitute that the retina of albino rats was irreversibly damaged by continuous exposure to ambient light within the range of the natural light spectrum. Later, histological studies carried out by Green and Robertson examined eyes exposed to various levels of calorie-free on patients scheduled to undergo enucleation secondary to choroidal melanoma. These studies further corroborated the potential toxic effect of light on the neurosensory retina and RPE [23].

Rhodopsin photobleaching triggers the visual phototransduction process in the healthy retina. Withal, light assimilation by this visual paint—found in the rod outer segments (ROS) of photoreceptor cells—can as well issue in light-induced damage. Previous studies have shown that, after lite exposure, photoreceptor prison cell damage is initiated in the distal tips of ROS, and it progresses with time to touch on the entire ROS [24,25]. Retinal exposure to white light of low intensity, in albino rats, leads to astringent degenerative changes, with reduced thickness of the ONL and ultrastructural alterations such as fragmentation, disorientation of the ROS, and changes in the aamplitude of the electroretinogram b-wave [22,26,27].

Photoreceptors ROS are engulfed by cells of the RPE, during normal function, and replaced by newly synthesized structures at the ROS basis then that the rods length is kept relatively constant. A large number of phagosomes are constitute in the RPE and light exposure can lead to overall decrease in rod length. When it is a simple transient upshot, rod length would exist expected to return to normal size within 1–2 weeks. Still, ROS length is more permanently affected by intense lite especially in the superior half of the retina [28,29]. ROS shortening has been attributed to dumb disk synthesis [thirty]. Another crusade of localized effects on disk morphology is the faster rate of rhodopsin regeneration in the distal tips of ROS when compared to that in the proximal disks [31]. Furthermore, lite effects on ROS tips accept been associated with the gradient of membrane cholesterol content found in ROS [32]. The retina has a loftier content of long-chain polyunsaturated fatty acids and due to this specific lipid contents, and structure of the photoreceptor membranes, it is particularly susceptible to complimentary radical harm (see below for further give-and-take on this topic).

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G Protein-Coupled Receptors in Immune Response and Regulation

Mohammad M. Ahmadzai , ... Hariharan Subramanian , in Advances in Immunology, 2017

1 Introduction

1.i Overview

Mammalian cells employ a host of strategies in order to fine-tune the effects of receptor activation on cell function. One important mechanism by which this occurs involves the desensitization and downregulation of plasma membrane receptors by the arrestin family of proteins. By altering both the sensitivity and the sheer affluence of receptors on the cell surface, arrestins mitigate the deleterious effects of receptor overstimulation and thereby maintain homeostasis (Freedman & Lefkowitz, 1996; Kang, Tian, & Benovic, 2014; Moore, Milano, & Benovic, 2007; Pierce & Lefkowitz, 2001; Shenoy & Lefkowitz, 2011).

To date, three distinct subfamilies of arrestins take been described in humans: visual-arrestin, β-arrestin, and α-arrestin (Sharma & Parameswaran, 2015 ). The visual-arrestins were the outset arrestins to be discovered and were named for their pivotal function in visual phototransduction in rod and cone cells of the retina ( Craft & Whitmore, 1995; Freedman & Lefkowitz, 1996; Song, Raman, Gurevich, Vishnivetskiy, & Gurevich, 2006). Subsequently, investigations into agonist–receptor interactions unveiled an instrumental role for β-arrestins in the downregulation of Thousand poly peptide-coupled receptors (GPCRs) that fundamentally contradistinct our understanding of GPCR biology (Laporte et al., 1999; Lohse, Benovic, Codina, Caron, & Lefkowitz, 1990; Rajagopal & Shenoy, 2017; Shenoy & Lefkowitz, 2011). The α-arrestins, though relatively new additions to the arrestin family unit, are structurally similar to their visual- and β-arrestin counterparts, but regulate lipolysis and the pathogenesis of obesity (Kang et al., 2014). While each arrestin mediates some degree of receptor downregulation, it is important to note that this is largely context-specific: the expression patterns of the visual- and the α-arrestins are relatively restricted, whereas β-arrestins are ubiquitously expressed (Gurevich & Gurevich, 2006; Lefkowitz, Rajagopal, & Whalen, 2006; Shenoy, McDonald, Kohout, & Lefkowitz, 2001). Indeed, β-arrestins engage the broadest array of signaling pathways in humans and rodents, suggesting that they are physiologically indispensible and may participate in the pathogenesis of numerous diseases (Moore et al., 2007; Pierce & Lefkowitz, 2001).

The involvement of β-arrestins in GPCR desensitization and internalization is a canonical feature of these proteins that is at present widely accepted (Freedman & Lefkowitz, 1996; Lefkowitz, Ahn, Lefkowitz, & Shenoy, 2007; Pierce & Lefkowitz, 2001). Over the concluding decade, however, a growing body of evidence has shown that β-arrestins per se initiate intracellular signaling cascades that modulate a host of cellular processes, including: factor transcription, oncogenesis, apoptosis, and cell migration (Lefkowitz et al., 2006; Pierce & Lefkowitz, 2001). Indeed, the finding that this noncanonical signaling transpires in a GPCR-independent manner is striking and raises many questions, particularly with regards to its physiologic relevance and therapeutic potential. To these ends, we seek hither to provide a global overview of the approved and noncanonical signaling roles of β-arrestins, and to discuss their putative roles in the classical inflammatory response and select allowed pathologies.

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Pharmacological Aspects of Clinically Approved Factor Therapy Drugs and Products

Alireza Shahryari , ... Heiko Lickert , in Reference Module in Biomedical Sciences, 2022

two.4 Luxturna

Voretigene Neparvovec-rzyl (Luxturna) is the kickoff FDA-approved cistron therapy product for an inherited disorder. The drug was canonical by FDA and EMA in 2017 and 2018, respectively. Research in gene therapy resulted in the evolution of Luxturna for clinical awarding in individuals of Leber'south built amaurosis (LCA) with biallelic mutation in the RPE65 factor. The therapeutic method involves the delivery of a recombinant AAV vector that carries the RPE65 gene in the subretinal space (Prado et al., 2020; Darrow, 2019) (Table 1).

Knockout fauna models for the RPE65 factor were generated and the animals revealed similar phenotypes to their human counterparts. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber's congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with LCA. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade ( Weng, 2019).

Following a subretinal injection via vitrectomy, Luxturna targets RPE cells and delivers a salubrious copy of the RPE65 gene to restore the function of biallelic mutation. Therapeutic RPE65 poly peptide that functions as isomerohydrolase converts the trans-retinyl esters to xi-cis-retinal. Healthy RPE65 poly peptide led to the restoration of the visual bicycle via regeneration of the critical visual pigment component of 11-cis-retinal (Patel et al., 2019; Russell et al., 2018).

Luxturna is available in the clinic in ii-mL vials containing 0.5 mL of the drug at a concentration of v × 10¹² vg/mL. The initial concentration is diluted 1 in 10 prior to subretinal administration to produce a last concentration of 1.v × 10¹¹ vg in 0.three mL of solution. 72 h prior to surgery, individuals receive systemic corticosteroids over a seven-day period equivalent to 1 mg/kg/twenty-four hours of oral prednisone at max 40 mg per day. This government is not recommended for children less than 1 year old as they accept active retinal jail cell proliferation resulting in dilution and loss of drug efficacy. Data from 41 patients (81 eyes) demonstrated no significant allowed responses or other systemic adverse effects related to initial and repeated exposure to Luxturna through iv years. Transient Ag and Ab of AAV2 might rarely be recognized in tears and/or blood without signs of immunologic reactions. The minor ocular side effects are due to vitrectomy surgery including retinal tears (5%), cataracts (19%), increased intraocular pressure (10%), and conjunctival hyperemia (11%). Furthermore, meaning rare ocular events such as foveal thinning (2%), endophthalmitis (1%), and retinal disengagement (1%) were observed (Russell et al., 2017; Gao et al., 2020).

Injection of Luxturna into the subretinal space leads to transduction of some retinal pigment epithelial cells with a Dna harboring a good for you re-create of RPE65, thus having the potential to correct the visual cycle. Luxturna vector DNA levels in diverse tissues and/or secretions were measured using a qPCR test. Following 3 months of subretinal administration, biodistribution of Luxturna was examined in nonhuman primates. High levels of vector Deoxyribonucleic acid were recognized in intraocular fluids of drug-injected eyes. Nonetheless, its depression levels were detected in the optic nervus of the drug-injected eye, optic chiasm, and other organs such as spleen, liver, and rarely in the lymph nodes. Furthermore, vector shedding and biodistribution of Luxturna were examined in a clinical trial. Altogether, the vector was transiently shed at low levels in tears from the injected eye in 45% of the individuals. Following bilateral administrations, the vector Deoxyribonucleic acid was detected in tear samples of 13 individuals from a total of 29 individuals (45%). High levels of vector DNA were observed in the tear samples on day 1 post-injection (Maguire et al., 2019; Padhy et al., 2020).

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Co-Send Systems

Jeffrey Adijanto , Nancy J. Philp , in Electric current Topics in Membranes, 2012

2.four Photoreceptors and Retinal Pigment Epithelium

The retina is among the most glycolytically active tissues in the body, converting more than eighty% of all glucose that information technology consumes into lactic acrid (Wang, Kondo, & Bill, 1997; Wang, Tornquist, & Bill, 1997; Winkler, Starnes, Twardy, Brault, & Taylor, 2008 ). Still, not all cells in the retina are glycolytic. Photoreceptors are dependent on oxidative metabolism to satisfy the high energy demands of visual phototransduction. This is facilitated past the loftier levels of GLUT1 and MCT1 at photoreceptor inner segments ( Gospe, Baker, & Arshavsky, 2010; Philp et al., 2003), which also contain the highest density of mitochondria (Rock, van Driel, Valter, Rees, & Provis, 2008). Müller glia cells, on the other hand, are the most glycolytically active cells in the retina, consistent with their high expression of MCT4 (Chidlow, Wood, Graham, & Osborne, 2005). As shown in Fig. 3, the corresponding localization of MCT1 and MCT4 at the photoreceptors and the neighboring Müller cells suggests the existence of a lactate-shuttle mechanism similar to that in musculus and brain. In support of this model, studies have demonstrated that Müller cells metabolize glucose quickly to generate lactate (Poitry, Poitry-Yamate, Ueberfeld, MacLeish, & Tsacopoulos, 2000; Winkler, Arnold, Brassell, & Puro, 2000), which upon its extrusion into the subretinal infinite (SRS) via MCT4, can be taken upwards past photoreceptor cells for oxidative metabolism (Poitry-Yamate, Poitry, & Tsacopoulos, 1995).

The retinal pigment epithelium (RPE) is a monolayer of highly pigmented cells that grade the outer claret–retina barrier and performs many disquisitional functions that back up photoreceptor wellness and integrity (reviewed in (Strauss, 2005)). Anatomically, the RPE lies between the photoreceptor cells and their primary blood supply (choroidal vasculature), where information technology plays a cardinal role in SRS pH homeostasis by transporting backlog lactic acrid and other metabolic wastes (i.e. CO₂ and H_iiO) from the SRS to the choroidal claret supply. Each photoreceptor outer segment is ensheathed past the numerous microvillis that extend from the RPE upmost membrane. This anatomical configuration significantly enhances the total surface surface area for lactate uptake by the RPE, which limited loftier levels of MCT1 at its apical membrane to facilitate this process (Philp, Yoon, & Grollman, 1998). Upon entry into the prison cell, lactate may leave the RPE basolateral membrane via MCT3 into the choroidal blood vessels (Philp et al., 1998; Philp, Yoon, & Lombardi, 2001). This transepithelial lactate transport helps foreclose SRS acidosis, which could compromise photoreceptor health and role. The importance of MCT3 in regulating transepithelial lactate transport tin be inferred from studies of the MCT3 knockout mouse, which presented with impaired retinal function and abnormally high levels of lactate (≈fivefold) in the outer retina (Daniele, Sauer, Gallagher, Pugh, & Philp, 2008). These observations are consistent with before studies of transepithelial lactate transport, which showed that the flux of [¹⁴C]-labeled lactate tracer across native bovine RPE tin be influenced by the lactate gradient across the epithelium (Kenyon et al., 1994). Furthermore, in vivo studies demonstrated that changes in photoreceptor metabolism and lactate production can alter the lactate concentration of blood collected from the vortex vein (Wang, Tornquist et al., 1997). Collectively, these studies demonstrate that a pregnant fraction of lactate that enters the RPE from the upmost membrane is transported out of its basolateral membrane. It is besides of interest to consider the possibility that lactate may be utilized in the RPE as a substrate for oxidative metabolism. Indeed, RPE cells have a loftier chapters for oxidative metabolism—they are well oxygenated (Wangsa-Wirawan & Linsenmeier, 2003) and possess high densities of mitochondria (Maminishkis et al., 2006). However, it remains unclear whether RPE cells can utilize lactate for oxidative metabolism, and if and then, how much lactate is metabolized compared to that transported into the blood circulation.

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Biologics Medicine

50. OtvosJr., in Comprehensive Medicinal Chemistry III, 2017

6.05.4.4 Particle Delivery

Delivery by using nano- or microparticles involves the uptake of biodegradable polymers by the 1000 cells of the Peyer'southward patches. Particles currently used for oral delivery fall into two classes: (a) nanoparticles, ranging in size from x to thou nm and (b) microparticles ranging from 1 μm to 1 mm. ⁹⁸ In general, the smaller the particle, the better the peptide drug is absorbed, due to the difficulty to engulf larger particles and improved hydrophobic/hydrophilic ratio.

Insulin can be encapsulated very efficiently in oil-containing poly(isobutyl cyanoacrylate) nanocapsules, and these nanocapsules show unexpected biological activity after intragastric assistants. ⁹⁹ Salmon calcitonin is a highly water-soluble basic peptide, consisting of 32 amino acid residues. Calcitonin absorption via the gastrointestinal tract is significantly enhanced later incorporation into nanoparticles. ¹⁰⁰ In before approaches, nanoparticles were usually made by grafting the peptide drugs to the terminal positions of hydrophobic vinyl monomers.

In contrast, microparticles are almost exclusively made from copolymers of lactic acid and glycolic acid (PLG). The composition and the viscosity strongly influence the release kinetics of PLG microspheres. In our easily, a fifty:50 PLG microsphere releases peptide immunogens in a 1-calendar week period. ¹⁰¹ The successful drug delivery past the PLG microspheres was documented by oral immunization with Bordetella pertussis fimbriae proteins. ¹⁰² When mice were immunized with ten μg proteins orally, the resulting response was comparable with administering equivalent amounts of the immunogens absorbed onto Alhydrogel or administered intraperitoneally. Exenatide is formulated into 0.06 mm diameter microspheres of PLG that hydrate in situ and form amalgam. ¹⁰³ The peptide is released in multiple stages, from < 1% in the commencement few hours to equally long as 2 weeks. This conception is currently in the market with the commercial name Bydureon confronting type 2 diabetes.

In our experience, immunization of mice with 31D, a T-prison cell epitopic peptide entrapped in PLG microspheres, improved the antibody response compared with naked antigen, but did not attain the level of antibody product when the peptide was administered in complete Freund'south adjuvant. In spite of some initial success, we did not observe the PLG microspheres useful for the delivery of synthetic peptides or oligonucleotides on the long run.

6.05.4.four.i Nanoparticles every bit modern drug delivery systems

Contemporary particle delivery focuses on nanostructures equally vehicles. Uptake of nanostructures has been reported to exist 15–250 times greater than that of microparticles in the 1–10 μm range. ¹⁰⁴ Nanostructures non but are able to protect drugs from the degradation in the gastrointestinal tract merely besides allow commitment of drugs into many tissues of the body. Importantly, by bypassing the liver, biological drugs encapsulated in nanoparticles escape starting time-pass metabolism. Nanometer-size structures are easily taken upwards by cells and penetrate tissues.

Plasmid Dna-encoding cytokine genes, including mIL-12 and mIFN-gamma, show enhanced antitumor activity and improved survival time in mice compared with naked pmIL-12 when incorporated into 100 nm size poly[alpha-(4-aminobutyl)-L-glycolic acid (PAGA) particles. ¹⁰⁵ ^, ¹⁰⁶ Cholesterol conjugates of linear polyethylenimine, an effective nonviral gene carrier, 250 nm in size, induce protein expression levels college than the cistron product alone without any significant loss in prison cell viability. The differences in rates of transfection of the lipid/pDNA complexes in Renca cells are partly due to conformational changes upon interaction with the plasma membrane. ¹⁰⁷ The preferred nonviral gene delivery vectors are polycation/DNA complexes formed between cationic polymers and Dna through electrostatic interactions. ¹⁰⁸ Nanoparticles fabricated from polyamidoamine–polylysine graft copolymers appear to be promising gene vectors with low cytotoxicity, high transfection efficiency, and advantageous serum stability parameters. ¹⁰⁹ Inoculation of a dendrimeric version of these nanostructures complexed with the pVEGF165 cistron into balloon-injured rabbit carotid arteries results in inhibition of restenosis by increasing VEGF165 expression in vessels. ¹¹⁰ Dendrimers appear to be nonimmunogenic and exhibit the highest efficiency of transfection amongst other nonviral structures without the drawback characteristic for viral systems. ¹¹¹ However, the consensus is that further studies are required before the dendrimer/DNA complexes can be used in human gene therapy.

Liposomes are spherical vesicles in which the aqueous compartment is enclosed by a mixed hydrophilic/hydrophobic molecule layer. These structures greatly vary in their limerick, size, or surface accuse characteristics and used frequently every bit drug, vaccine, or nonpharmaceutical formulations as carriers. A nanosize multifunctional liposome, containing a magnetic resonance imaging probe, and paclitaxel and the targeting peptide c(RGDyk) overcame the insolubility of paclitaxel and improved drug delivery efficiency to the tumor. ¹¹² Modification of the c(RGDyk) peptide part significantly enhanced the cytotoxicity of the drug in A549 tumor cells. Isolated mouse retinas were treated with liposomes encapsulating either recoverin, an endogenous protein involved in visual phototransduction, or antibodies against it. The contents of intravitreally injected liposomes encapsulating either rhodamine B or recoverin were released in higher corporeality in the photoreceptor layer than in the other regions of the retina. ¹¹³ Remarkably, the released protein functioned in accord with the current model of phototransduction. From the vaccine field, iontophoresis of antigen peptide-loaded nanogels results in the aggregating of gp100 peptide in the epidermis and subsequent increase in the number of Langerhans cells. ¹¹⁴ As a result, tumor growth is significantly suppressed by iontophoresis of the antigen peptide-loaded nanogels, and these structures can represent an effective transdermal delivery arrangement for anticancer vaccination. It needs to be added that liposomes tin can be made from a great variety of ingredients and protocols making these a very heterogeneous group of nanostructures.

Microemulsions are also generally below 100 nm in size, only for these, the concrete properties and the thermodynamic stability of the complexes are the dominant factors. ¹¹⁵ They are composed of two phases of two immiscible liquids that are mixed together and stabilized with surfactants (a main and potentially a cosurfactant). Just like their larger (and unstable) brothers, the emulsions, microemulsions can be prepared either oil-in-h2o or water-in-oil. Mayhap even more than than dendrimers, microemulsions require more than studies to exclude some of the observed drawbacks and guarantee their potential for apply in clinic, ¹¹⁶ primarily because of stage inversion and the utilise of toxic alcohols used in the early preparations. ¹⁰³ When a paclitaxel-containing microemulsion was spiked with penetratin (see section " Competing Peptide Drug Commitment Technologies "), a large increase in transepidermal water loss (twofold) was observed suggesting that penetratin addition increases the barrier-disrupting and penetration-enhancing effects of microemulsions. ¹¹⁷ The ratio Δcutaneous/Δtransdermal delivery was the highest amid all the formulations studied, suggesting its potential for drug localization within cutaneous tumor lesions. When studying the optimal preparation protocol of these drug delivery systems, a water-in-oil microemulsion was loaded with model bovine serum albumin and cytochrome c. ¹¹⁸ In the next step, this stage was dispersed in h2o resulting in microemulsion formation with a size of approximately 620 nm. The nanostructured particles were able to control the release of the h2o-soluble proteins freeing merely < 10–15% poly peptide in a 24-hour interval.

Nanoparticles are solid colloidal particles that can be made from various macromolecules in which therapeutic drugs tin exist adsorbed, entrapped, or covalently fastened. Nanoparticles are remarkably stable systems, yet they allow controlled release of the hydrophilic biopolymer cargo. Their advantages over larger structures include their power to pass through small capillary vessels due to their very small volume and increased serum stability by avoiding phagocyte clearance and their ability to penetrate not but tissue gaps to reach distinct organs just also cells themselves. Remarkably, nanoparticles can promote mucosal uptake of incorporated peptides. ¹¹⁹ Incorporation into nanostructural carriers can improve the efficacy of antimicrobial peptides perhaps through controlled release properties. ¹²⁰ Lactic acid, glycolic acrid, cellulose acetate, and vinyl alcohol polymers can exist used for the preparation of antimicrobial compound-impregnated dressings by electrospinning. ¹²¹ Electrospinning is a uncomplicated, economical, and thus oft used technique during which small highly cationic biopolymers concentrate on the surface of the biomaterials allowing controlled but fast release upon contact with moist wound surfaces. ¹²² For case, electrospun nanofibers deliver LL-37, a cathelicidin peptide, consistently while still maintaining its antimicrobial functions. ¹²³

In a report receiving much attention, nisin-containing electrospun nanofiber wound dressings significantly reduce Southward. aureus load in a mouse skin abrasion/infection model. ¹²⁴ We incorporated a twenty-mer-modified antimicrobial peptide, called APO monomer, into polyvinyl alcohol nanofibers and polymerized the circuitous into a solid patch dressing. ¹²⁵ Mice were subjected to skin excision after which some wounds were infected with a near-lethal dose of multidrug-resistant Acinetobacter baumannii strain. When the wounds were subjected to histopathology after 3 days of single patch treatment, APO monomer-containing dressings improved wound appearance and accelerated wound healing. The wound sizes and bacterial loads were statistically significantly reduced compared with similar treatment with colistin, the leading similarly polyamide-based treatment option to Gram-negative infections. Significant to this volume commodity, the nanofiber carrier had more than pronounced in vivo efficacy compared with intramuscular administration of the same peptide drug, by using merely one-10th of the API. Because an average wartime cutaneous chafe size of < 20 cm² ¹²⁶ and even less in the civilian population, antibacterial peptide-impregnated nanofiber wound patches tin can be adult as effective and economical handling modalities to skin infections in burn and blast injuries on the streets and in military environments.

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Secretory proteostasis of the retinal pigmented epithelium: Impairment links to historic period-related macular degeneration

Luminita Paraoan , ... Ian Grierson , in Progress in Retinal and Centre Research, 2020

three.3 Dysregulated fe send and links to retinal degeneration

In the retina, iron is an essential micronutrient necessary for of import functions such as visual phototransduction cascade, synthesis of photoreceptor discs and RPE phagocytosis activity. For example, RPE65, the key isomerase responsible for the conversion of all-trans-retinyl esters to 11-cis-retinal in RPE cells, is dependent on iron for its activeness ( Moiseyev et al., 2006; Vocal and Dunaief, 2013). Photoreceptor cells shed and synthesise new disc membrane and this process is dependent on iron-containing enzymes such as fatty acid desaturase. Although iron is needed for many essential processes, excess atomic number 26 can go a source of gratis radicals that cause harm to lipid membranes, proteins and ultimately tissue.

RPE cells express proteins involved in iron regulation. An case is ceruloplasmin, which is abundantly expressed and secreted from the RPE. Ceruloplasmin is a ferroxidase enzyme that converts ferrous iron to ferric iron, the form that binds to transferrin, an iron transport poly peptide. Interestingly, transferrin is also a highly expressed transcript from the RPE/choroid database and RPE is a major site of transferrin synthesis in the body (Yefimova et al., 2000). It is probable that transferrin is secreted out of the RPE cells where it helps regulate iron levels. In addition to transferrin, RPE cells express transferrin receptors 1 and 2 on their basolateral membrane (Yefimova et al., 2000). This ascertainment indicates that the RPE plays a pivotal function in regulating the entry of transferrin-bound iron from the choroid into the retina. Interestingly, iron accumulation is observed in the aged RPE/choroid (Chen et al., 2009). This increased iron within the RPE is accompanied by expression alterations of key iron regulating proteins such as transferrin and ceruloplasmin, and contributes to a subtract in RPE phagocytosis ability and lysosomal activity (Chen et al., 2009). Furthermore, in a mouse model where a deficiency of ceruloplasmin and another ferroxidase called Hephaestin (Heph) was nowadays, an age-related accumulation of iron alongside retinal degeneration, characteristic of AMD, was observed (Hahn et al., 2004; Hadziahmetovic et al., 2008).

In addition to ceruloplasmin and transferrin, another important poly peptide involved in iron regulation is Prion protein (PrP^c). PrP^c is not a secreted poly peptide simply is found expressed on the basolateral membrane RPE cells where information technology modulates retinal iron homeostasis by transporting iron from the choroid to the neuroretina (Asthana et al., 2017). Interestingly, prion disease associated retinal degeneration is attributed to a misfolded isoform of prion protein chosen scrapie (PrP^south). The accumulation of misfolded PrP^s impairs iron uptake by the RPE and too causes inflammation that subsequently contributes to cytotoxicity (Asthana et al., 2017). Taken together, the importance of fe regulation past the RPE is evident in relation to maintenance of retinal integrity as loss of rest in age and/or due to presence of mutated proteins causes phenotypical characteristics of AMD such as retinal degeneration.

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Looking into the brain through the retinal ganglion cells in psychiatric disorders: A review of evidences

Thomas Schwitzer , ... Vincent Laprevote , in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2017

3 Anatomical and physiological properties of the retinal ganglion cells

Retinal ganglion cells constitute the final and most integrated retinal stage and, in the visual pathways, offer indirect and readily-measurable access to brain function between visual phototransduction processing in photoreceptors and thalamic and cortical visual processing ( Boycott and Wässle, 1999). Dendrites of ganglion cells contact axons of bipolar and amacrine cells within the retinal inner plexiform layer (Fig. 1), whereas their axons that form the optic nervus are projected out to the visual network via the lateral geniculate nucleus (Hoon et al., 2014). Consequently, the sensory information recorded at the ganglion cell layer is already coded and modulated by previous retinal stages. Dissimilar visual data in brain processing, it is not under the influence of high-level cognitive functions and not dependent on attentional achievement (Knight and Silverstein, 2001). Furthermore, the mapping of visual input from retina to neurons, called retinotopy, is like between the retinal ganglion cells and thalamic neurons (Wandell and Winawer, 2011). Posterior to the eyes, the transfer of visual information from ganglion cells to later on visual relays is mediated by the properties of the myelinated nerve fibers of the optic nerve formed by axons of the ganglion cells (Shum et al., 2016).

The retinal ganglion cells act every bit an anatomical and functional relay between the retina and the brain, and share similar anatomical and functional characteristics to thalamic and cortical neurons (Famiglietti and Kolb, 1976; Jeffries et al., 2014). Indeed, retinal ganglion cells are divided into several classes of specialized neurons and are normally composed of jail cell torso, axons and dendrites (Sand et al., 2012; Yu et al., 2013). Later on stimulation, ganglion cells are the start visual stage providing response in the class of action potentials, typically along higher visual centers in the brain (Famiglietti and Kolb, 1976). This post-stimulation response differs from that of other retinal stages, especially photoreceptors where the response to stimulation is a gradual variation of membrane potential (Baylor, 1996). Ganglion cells have receptor fields with concentric ON-middle and OFF-center properties, as in thalamic and cortical neurons of the visual pathways (Dacey, 2000; Famiglietti and Kolb, 1976; Masland, 2012, 2001).

Retinal ganglion cells show anatomical and functional segregation (Yoonessi and Yoonessi, 2011). The dwarf or beta ganglion cells have small-scale receptive fields and loftier spatial resolution, and can distinguish fine details, color and contrast (Yoonessi and Yoonessi, 2011). They initiate the P pathways in the retina that projects in layers 3–6 of the lateral geniculate nucleus to institute the parvocellular pathways (Jeffries et al., 2014). The parasol or alpha ganglion cells take a medium-sized receptive field, poor spatial resolution and high temporal resolution, and can distinguish movement (Yoonessi and Yoonessi, 2011). They initiate the M pathways in the retina that projects in layers i–ii of the lateral geniculate nucleus to plant the magnocellular pathways (Jeffries et al., 2014). The bistratified or gamma ganglion cells have a large receptive field and display spectral backdrop, especially a bluish-yellow antagonism (Yoonessi and Yoonessi, 2011). They initiate the K pathways in the retina that projects in the interlaminar layers of the lateral geniculate nucleus to found the koniocellular pathways (Jeffries et al., 2014). Interestingly, the initial segregation observed in the retina is conserved and projected in the thalamus.

Retinal ganglion cells function involves several complex neurotransmission signaling systems that are too detectable in the brain (Wässle, 2004). Excitation and inhibition of ganglion prison cell response is mediated through feedback and feedforward mechanisms past several neurotransmitters, such equally dopamine, serotonin, glutamate and γ-aminobutyric acid (GABA) (Hoon et al., 2014). Note that dysfunctions in these signaling pathways are idea to exist involved in the pathophysiology of many mental disorders. Briefly, dopamine is the primary catecholamine detected in the mammalian retina (Witkovsky, 2004) and is synthesized from the l-amino acrid tyrosine by tyrosine hydroxylase (Reis et al., 2007). Dopamine acts on 5 G-coupled poly peptide receptors spanning 2 subcategories, called D1 and D2 (Beaulieu and Gainetdinov, 2011; Frederick et al., 1982; Witkovsky, 2004). Dopaminergic receptors are found in ganglion cells (Nguyen-Legros et al., 1997). Dopamine is known to play a major role in light accommodation (Marshak, 2001). Serotonin is some other chemical messenger detected at a lower level than dopamine in the mammalian retina (Gastinger et al., 2006). Serotonin is synthesized from tryptophan by tryptophan hydroxylase one (Tph1), Tph2 and acid decarboxylase (Liang et al., 2004). Xiv types of serotonin receptors subdivide into 7 families from five-HT1 to v-HT7, just just v-HT3 is an ionotropic receptor, every bit the other vi are Chiliad-protein-coupled receptors (Barnes and Sharp, 1999). Serotonin receptors are too found in ganglion cells. Serotonin helps improve the light sensitivity of retinal ganglion cells and plays a central role in nighttime adaptation (Gastinger et al., 2006). Glutamate is an excitatory amino acid detected in the retina (de Souza et al., 2013; Wu and Maple, 1998). Glutamate is synthesized from glutamine by aspartate aminotransferase (Brandon and Lam, 1983). Five post-synaptic glutamatergic receptors are found in retinal synapses: kainate, AMPA and NMDA, which are ionotropic receptors, and 50-AP4 and ACPD, which are metabotropic receptors (Koulen, 1999). In darkness, a glutamate release from bipolar cells stimulates AMPA, kainate and NMDA receptors in ganglion cells (Dixon and Copenhagen, 1992). Glutamate plays a major role in the vertical transmission of the retinal betoken from photoreceptors to ganglion cells. Finally, the inhibitory neurotransmitter GABA is expressed in ganglions cells of vertebrate species (; de Souza et al., 2013; Marc et al., 1995; Wu and Maple, 1998). GABA is synthesized from glutamate by glutamate decarboxylase (Brandon and Lam, 1983). The ionotropic GABAa and GABAc receptors and the metabotropic GABAb receptors are the functional families of GABA receptors expressed in the retinal ganglion cells, and they mediate the release of intracellular transmitters (Lukasiewicz and Shields, 1998; Wu and Maple, 1998).

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