Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss

Molecular Pharmaceutics, Journal Year: 2023, Volume and Issue: 20(8), P. 3987 - 4006

Published: July 28, 2023

Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress the acidification of inner ear microenvironment. Effective treatment SNHL often requires multifaceted approach due complex pathology, drug combination therapy expected be at forefront modern treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness multidrug simultaneous delivery capability were constructed then loaded various including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), ammonia borane (AB) provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate–chitosan (CCC) NPs monomethoxy poly(ethylene glycol)–PLGA (mPP) rendezvous dock primarily by hydrogen bonding, electrostatic forces may involved. Moreover, CCC@mPP crossed round window membrane (RWM) entered through endocytosis paracellular pathway. The docking state was basically maintained during this process, created favorable conditions for delivery. This nanosystem highly sensitive pH reactive oxygen species (ROS) changes, evidenced restricted release payload alkaline condition (pH 7.4) without ROS, while significantly promoting in acidic 5.0 6.0) ROS. TSIIA/PNS/AB-loaded almost completely preserved hair cells remained threshold shift within normal limits aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated protective mechanisms involved direct indirect scavenging excessive reduced pro-inflammatory cytokines. Both vitro vivo showed high biocompatibility NPs, even after long-term administration. Collectively, work suggests an ideal multi-drug-delivery vehicle open new avenues disease therapies.

Language: Английский

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In vivo screening for toxicity-modulating drug interactions identifies antagonism that protects against ototoxicity in zebrafish

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: March 7, 2024

Introduction: Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms action, many which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation drug-drug interactions that might impact ototoxicity would facilitate design safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations potentially cause adverse monitoring. They may also identify protective agents antagonize ototoxic injury. Methods: To address this need, we have developed novel workflow call Parallelized Evaluation Protection Injury Toxicity Assessment (PEPITA), empowers high-throughput, semi-automated quantification otoprotection in zebrafish larvae via microscopy. We used PEPITA confocal microscopy characterize vivo the consequences on drug uptake cellular damage lateral line hair cells. Results discussion: By applying measure interaction outcomes, discovered antagonistic between macrolide aminoglycoside antibiotics confer protection against aminoglycoside-induced cells larvae. Co-administration either azithromycin or erythromycin protected from broad panel aminoglycosides, at least part inhibiting into mechanism independent cell mechanotransduction. Conversely, combining macrolides aminoglycosides bacterial inhibition assays does not show antagonism antimicrobial efficacy. The proof-of-concept otoprotective suggests combinatorial interventions can protect other forms toxicity without hindering on-target

Language: Английский

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Establishment and characterization of a continuous marine fish fin cell line from Epinephelus fuscoguttatus and viral susceptibility to crustacean CMNV

Journal of Oceanology and Limnology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Language: Английский

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Chemical screen in zebrafish lateral line identified compounds that ameliorate neomycin-induced ototoxicity by inhibiting ferroptosis pathway

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 5, 2024

Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug available currently. The zebrafish has recently become valuable model to investigate AG-induced hair cell toxicity an expanding list compounds that block the uptake AGs have been identified from zebrafish-based screening; however, it remains be established whether inhibiting intracellular death pathway(s) constitutes effective strategy protect against ototoxicity. We as well in vitro cell-based assays found ferroptosis dominant type induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway blocking effectively protects neomycin-induced death. screened alkaloid natural compound library seven small ototoxicity targeting pathway: six them are radical-trapping agents (RTAs) while other one (ellipticine) regulates iron homeostasis, which essential for generation ROS stimulate ferroptosis. Our study demonstrates alternative ameliorate provides multiple hit further development.

Language: Английский

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Protective Effect of Marine Peptide from Netunea arthritica cumingii Against Gentamicin-Induced Hair Cell Damage in Zebrafish

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(11), P. 519 - 519

Published: Nov. 16, 2024

Auditory hair cell damage induced by aminoglycoside antibiotics (AmAn) leads to hearing loss, which has a serious effect on people's mental and physical health. This ototoxicity is thought be related with the excessive accumulation of reactive oxygen species (ROS) in cells. However, therapeutic agents that protect cells are limited. Marine peptides have been shown excellent potential applications disease prevention treatment. Therefore, this study investigated protective effects an active peptide from

Language: Английский

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In vivoscreening for toxicity-modulating drug interactions identifies antagonism that protects against ototoxicity in zebrafish

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 11, 2023

Abstract Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms action, many which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation drug interactions that might impact ototoxicity would facilitate design safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations potentially cause adverse monitoring. They may also identify protective agents antagonize ototoxic injury. To address this need, we have developed novel workflow call Parallelized Evaluation Protection Injury Toxicity Assessment (PEPITA), empowers high-throughput, semi-automated quantification otoprotection in zebrafish larvae. By applying PEPITA characterize interaction outcomes, discovered antagonistic between macrolide aminoglycoside antibiotics confer protection against aminoglycoside-induced damage lateral line hair cells Co-administration either azithromycin or erythromycin protected from broad panel aminoglycosides, at least part via inhibiting uptake into mechanism independent cell mechanotransduction. Conversely, combining macrolides aminoglycosides bacterial inhibition assays does not show antagonism antimicrobial efficacy. The proof-of-concept otoprotective suggests combinatorial interventions can protect other forms toxicity without hindering on-target

Language: Английский

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HIF signaling overactivation inhibits lateral line neuromast development through Wnt in zebrafish

Gene, Journal Year: 2023, Volume and Issue: 898, P. 148077 - 148077

Published: Dec. 12, 2023

Language: Английский

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In preprints: theme and variations on hair-cell regeneration in zebrafish

Development, Journal Year: 2024, Volume and Issue: 151(14)

Published: July 15, 2024

Imagine reaching old age and still being able to engage effortlessly in conversations (Cheslock De Jesus, 2023). This possibility hinges on preserving the mechanosensory hair cells we are born with, which mammals exceptionally long-lived but, with very few exceptions, cannot be replaced once lost (Kirkegaard Jørgensen, 2000; Savas, In humans, loss of these results chronic hearing deficits, making everyday activities such as conversing noisy settings or talking phone overwhelming challenges (Reynard Thai-Van, 2024). For many, this impairment not only isolates them from social interactions but also aggravates mental health issues anxiety depression (Luppa et al., Most insights into maintaining function come studying non-mammalian vertebrates, can regenerate naturally throughout their lives (Choi 2024; Denans 2019; Pinto-Teixeira 2013; Benkafadar Emerging research is revealing that multiple mechanisms regulate hair-cell regeneration, even within same species, offering hope for future breakthroughs treating humans.Among most studied hair-cell-bearing organs neuromasts lateral line, enable fishes amphibians detect low-frequency mechanical fluctuations surrounding water (Valera 2021; Tidswell These aquatic vertebrates use line orient relative flow direction, escape predators locate prey, develop avoidance reactions. The take a more prominent role when vision limited (Montgomery 2000). Fishes have ears, constituent control balance high-frequency signals (Liu Bagnall, Importantly, ears must remain functional life animal, despite persistent environmental insult cells. zebrafish has always offered researchers two key advantages (Barrallo-Gimeno Llorens, 2022; Plazas Elgoyhen, Holmgren Sheets, Pickett Raible, 2019). First, unparalleled accessibility high-resolution microscopy, chiefly thanks its superficial location availability many lines expressing various genetically encoded fluorescent makers label different cell types (Pinto-Teixeira 2015; Hewitt Second, quickly easily eliminated using pharmacological, genetic physical approaches. ensuing recovery occurs days, enabling high temporal-resolution recording entire regenerative process 2013). recent years, advances single-cell transcriptomics added above (Lush Baek Kozak 2020). Single-cell RNA sequencing (scRNA-seq) hairpin chain reaction-based situ hybridization (HCR-FISH) helped molecularly characterize cellular sub-populations (Shi Moreover, easy production mutant animals gives access molecular components drive regeneration (Parvez 2024).The initial discovery resident progenitors took place almost decades ago (López-Schier Hudspeth, 2006). Every study followed agreed general mechanism follows series steps start birth new pairs mitotic division unipotent (UHCP; Thomas Mackenzie 2012). Although it been established how supporting re-enter mitosis after death, direct UHCP behavior remained obscure (Kozak preprint, Bell colleagues evidence scRNA-seq experiments showing gene foxg1a expressed during (Bell 2024 preprint). They allele find reduced number neuromast formation. Using nls-Eos transgenic photoconvertible protein disentangle effect fox1ga mutants neuromast, they conclude Foxg1a controls proliferation population isl1a-expressing central progenitor cells.However, nagging issue field found ear zebrafish, readily (Jimenez 2022). There currently no known marker specific UHCP, unambiguous identification achieved live videomicroscopy Therefore, one explanation finding much difficult image live. Another described simply do exist ear. another Beaulieu show robust through markedly differs neuromasts, resembling closely birds (Beaulieu preprint; Bhave 1995). Here, ablation, arise transdifferentiation pool Transdifferentiation identity conversion without an immediate intervening (Wang traditionally term reserved interconversion between belonging lineages, agree authors preprint sensu lato would entail any postmitotic another. transient wave precursor otherwise depleted by continuous maintain stable preprint) used data HCR-FISH distinguish location: cabp1b-positive recently differentiated peripheral, whereas scn5lab-expressing located centrally ear's crista. A clever combination capsaicin-mediated ablation system allowed measure possible alternative interpretation inner produces pairs, does, progenitor. Then, identically birds, immediately takes mature identity, sibling remains hidden dormant immature state until further death induces emergence (Stone Rubel, Regardless, interesting what mammalian and, therefore, may clinically relevant humans.Together, preprints highlight need combine studies understand regeneration. will benefit taking advantage scRNA-seq-derived data, together newly-developed phiC31 Integrase Genomic Loci Engineered Transgenesis (pIGLET) generate diverse reproducible expression patterns compare populations behave (Lalonde Brown 2023).Beaulieu al. (2024 now accepted as: Beaulieu, M. O., Thomas, E. D. W. (2024). temporally uncoupled expansion Development 151, dev202944. doi:10.1242/dev.202944.

Language: Английский

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Experimental Studies in Otology and Audiology

Published: Jan. 1, 2024

Language: Английский

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REGENERATIVE WEAKNESS OF THE INNER EAR AND BIOENGINEERED HEARING RESTORATION: A BRIEF PROBLEM OVERVIEW

OTORHINOLARYNGOLOGY, Journal Year: 2023, Volume and Issue: unknown, P. 91 - 100

Published: Jan. 1, 2023

The structure of the hearing organ combines simplicity and depth, remaining in many issues subject active scientific research. ontogenesis this exquisite mechanism is regulated by complex still incompletely understood mechanisms. technological tools modern biomedical science allow not only to study, but also work at cellular molecular level. In article, we review data on realism restoring population human auditory receptors promising ways solve problem. addition, offer an answer a fundamental question – why, with small number relatively simply arranged receptor cells inner ear, their self-restored. Key words: spiral organ, stem cells, progenitors, impairments, regeneration, bioprosthetics, bioengineering.

Language: Английский

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