Metallic Nanocarriers for Therapeutic Peptides: Emerging Solutions Addressing the Delivery Challenges in Brain Ailments.

Peptides and proteins have recently emerged as efficient therapeutic alternatives to conventional therapies. Although they emerged a few decades back, extensive exploration of various ailments or disorders began recently. The drawbacks of current chemotherapies and irradiation treatments, such as drug resistance and damage to healthy tissues, have enabled the rise of peptides in the quest for better prospects. The chemical tunability and smaller size make them easy to design selectively for target tissues. Other remarkable properties include antifungal, antiviral, anti-inflammatory, protection from hemorrhage stroke, and as therapeutic agents for gastric disorders and Alzheimer and Parkinson diseases. Despite these unmatched properties, their practical applicability is often hindered due to their weak susceptibility to enzymatic digestion, serum degradation, liver metabolism, kidney clearance, and immunogenic reactions. Several methods are adapted to increase the half-life of peptides, such as chemical modifications, fusing with Fc fragment, change in amino acid composition, and carrier-based delivery. Among these, nanocarrier-mediated encapsulation not only increases the half-life of the peptides in vivo but also aids in the targeted delivery. Despite its structural complexity, they also efficiently deliver therapeutic molecules across the blood-brain barrier. Here, in this review, we tried to emphasize the possible potentiality of metallic nanoparticles to be used as an efficient peptide delivery system against brain tumors and neurodegenerative disorders. SIGNIFICANCE STATEMENT: In this review, we have emphasized the various therapeutic applications of peptides/proteins, including antimicrobial, anticancer, anti-inflammatory, and neurodegenerative diseases. We also focused on these peptides' challenges under physiological conditions after administration. We highlighted the importance and potentiality of metallic nanocarriers in the ability to cross the blood-brain barrier, increasing the stability and half-life of peptides, their efficiency in targeting the delivery, and their diagnostic applications.

Chemical sensor thin film-based carbon quantum dots (CQDs) for the detection of heavy metal count in various water matrices.

Rising pollution of heavy metals is one of the greatest concerns, especially in water resources globally and has led to significant adverse effects to human health. To uplift the status of human health, detection of heavy metals is of key importance. This study establishes the ability of carbon quantum dot (CQD)-based thin films for the detection of total heavy metal counts based on a fluorescence-based mechanism in various water resources using a fiber optic spectrometer (FOS) device. CQDs and CQD thin films were characterized using various techniques, such as X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), X-ray diffraction (XRD), and confocal laser scanning microscopy (CLSM), and the sensing capability was evaluated for the detection of heavy metals using an optical fiber system. The analytical parameters of the CQD-based thin film were compared with the estimation carried out using a micro plasma-atomic emission spectroscopy (MP-AES) method. The sensing performances of CQD thin films indicate that they are able to detect five heavy metals individually (lead, nickel, manganese, cobalt and chromium) in combination with a response time of 1 minute. The CQD thin films were able to detect heavy metals with a detection limit of 0.006-0.019 ppm for the analyzed heavy metals with a linear range of estimation analyzed as 0-100 µM. The accuracy of the estimation of all five heavy metals when spiked in various real water samples lies in the range of 100-103%. The result of the study clearly indicates that CQD thin films associated with a fiber optic device have the potential to play a role in point-of-care devices for total heavy metal count detection in complex matrices of water.

Recombinant Organophosphorus acid anhydrolase (OPAA) enzyme-carbon quantum dot (CQDs)-immobilized thin film biosensors for the specific detection of Ethyl Paraoxon and Methyl Parathion in water resources.

Organophosphates pesticide (OP) toxicity through water resources is a large concern globally among all the emerging pollutants. Detection of OPs is a challenge which needs to be addressed considering the hazardous effects on the health of human beings. In the current research thin film biosensors of recombinant, Organophosphorus acid anhydrolase (OPAA) enzyme along with carbon quantum dots (CQDs) immobilized in thin films were developed. OPAA-CQDs thin film biosensors were used for the specific detection of two OPs Ethyl Paraoxon (EP) and Methyl Parathion (MP) in river water and household water supply. Recombinant OPAA enzyme was expressed in E. Coli, purified and immobilized on the CQD containing chitosan thin films. The CQDs used for this purpose were developed by a one-pot hydrothermal method from phthalic acid and Tri ethylene diamine. The properties of CQDs, OPAA and thin films were characterized using techniques like XPS, TEM, XRD, enzyme activity and CLSM measurements. Biosensing studies of EP and MP were performed by taking fluorescence measurements using a fiber optic spectrometer. The analytical parameters of biosensing were compared against an estimation carried out using the HPLC method. The biosensing performance indicates that the OPAA-CQDs thin film-based biosensors were able to detect both EP and MP in a range of 0-100 µM having a detection limit of 0.18 ppm/0.69 ppm for EP/MP, respectively with a response time of 5 min. The accuracy of estimation of EP/MP when spiked in water resources lie in the range of ∼100-102% which clearly indicates the OPAA-CQD based thin film biosensors can function as a point-of-use method for the detection of OP pesticides in complex water resources.

Bioremediation and bioscavenging for elimination of organophosphorus threats: An approach using enzymatic advancements.

Organophosphorus compounds (OP) are highly toxic pesticides and nerve agents widely used in agriculture and chemical warfare. The extensive use of these chemicals has severe environmental implications, such as contamination of soil, water bodies, and food chains, thus endangering ecosystems and biodiversity. Plants absorb pesticide residues, which then enter the food chain and accumulate in the body fat of both humans and animals. Numerous human cases of OP poisoning have been linked to both acute and long-term exposure to these toxic OP compounds. These compounds inhibit the action of the acetylcholinesterase enzyme (AChE) by phosphorylation, which prevents the breakdown of acetylcholine (ACh) neurotransmitter into choline and acetate. Thus, it becomes vital to cleanse the environment from these chemicals utilizing various physical, chemical, and biological methods. Biological methods encompassing bioremediation using immobilized microbes and enzymes have emerged as environment-friendly and cost-effective approaches for pesticide removal. Cell/enzyme immobilized systems offer higher stability, reusability, and ease of product recovery, making them ideal tools for OP bioremediation. Interestingly, enzymatic bioscavengers (stoichiometric, pseudo-catalytic, and catalytic) play a vital role in detoxifying pesticides from the human body. Catalytic bioscavenging enzymes such as Organophosphate Hydrolase, Organophosphorus acid anhydrolase, and Paraoxonase 1 show high degradation efficiency within the animal body as well as in the environment. Moreover, these enzymes can also be employed to decontaminate pesticides from food, ensuring food safety and thus minimizing human exposure. This review aims to provide insights to potential collaborators in research organizations, government bodies, and industries to bring advancements in the field of bioremediation and bioscavenging technologies for the mitigation of OP-induced health hazards.

Insights in detection and analysis of organophosphates using organophosphorus acid anhydrolases (OPAA) enzyme-based biosensors.

The human population is dependent on agriculture for its food requirements and survival. Several insecticides and pesticides have found their use for improvements in agricultural yields. Organophosphates (OP) are one of the many compounds used as insecticides and pesticides. OPs have also been used to develop G and V-series chemicals which act as highly toxic nerve agents that can severely influence the normal function of the nervous system in all living beings. Thus, OP compounds utilized as insecticides/pesticides and nerve agents are hazardous to the environment, lethal for humans and other non-target animals. To avoid their toxicity, approaches to detect and neutralize them have become essential. A variety of analytical procedures such as electrochemical processes and chromatography methods, namely liquid and gas chromatography, have been employed to detect OPs. Though these techniques are sensitive and highly accurate they suffer from drawbacks, for instance: their bulky nature and expensive instrumentation, the difficulty of operation, long detection times, and they can yield unpredictable results with variable sample complexities. With the advent of several types of biosensors, the assay of OP compounds has become simpler, faster, cost-effective with improved sensitivity, and provides the capability for onsite detection. OP biosensor assays typically utilize several enzymes with the capability to hydrolyze/degrade OP compounds, such as organophosphate hydrolase (OPH) and organophosphate acid hydrolase (OPAA). This review focuses on discussing various aspects of OPAA as biological recognition unit in terms of its: structure, properties, activity enhancement methods, and utilization for developing OPAA-based biosensing technologies for insecticides, pesticides, and nerve agents.

Fluorescent fiber-optic device sensor based on carbon quantum dot (CQD) thin films for dye detection in water resources.

Industrialization, especially in textile industries, has led to increased use of dyes and pigments to impart colours to fabrics. Textile dyes are one of the chief emerging pollutants of water resources as industrial effluents. In the current research, we report the development and utilization of pH-sensitive carbon quantum dots (CQDs) immobilized in polymer thin films acting as sensors for textile dye detection. The CQDs and CQD-containing polymer films were characterized by various techniques like XRD, TEM, XPS, and CLSM. The synthesized CQD thin films possess a unique pH-sensitive property that can be used to detect various model acidic and basic dyes that are important components of industrial effluents from textile dyes. The detection capability of the sensor films was evaluated by spiking dyes in various water matrices, like household tap water and river water. The results indicate that pH-sensitive CQD thin film was able to detect three acidic dyes, namely methyl red, methyl orange, and bromocresol green, and one basic dye, methylene blue, in a linear range of 0-100 µM with a response time of 1 minute. The CQD thin-film sensors have a limit of detection of 26.4 ppb, 214.5 ppb, 46.2 ppb, and 29.7 ppb for methyl red, methyl orange, bromocresol green and methylene blue, respectively. The accuracy of detection performed by spiking studies in water resources indicated an ∼100% recovery value in all tested acidic and basic dyes. The sensor films were compared for analytical parameters using UV-visible-fluorescence spectroscopy and HPLC.

Changes of microbiome in response to supplements with silver nanoparticles in cotton rhizosphere.

The current study focuses on analyzing the effects of supplements containing silver nanoparticles (AgNPs) on plant growth and rhizospheric bacterial communities. Specifically, the impact of AgNP supplements was assessed on both plant growth promoting traits and bacterial communities in the soil. To do this, a screening process was conducted to select bacteria capable of synthesizing AgNPs through extracellular biosynthesis. UV-Visible spectrophotometer, Fourier transform infrared, X-ray diffraction, scanning electron microscope, and field emission scanning electron microscopy all confirmed, produced AgNPs is in agglomerates form. The resulting AgNPs were introduced into soil along with various supplements and their effects were evaluated after 10 days using next generation sequencing (Illumina-16S rDNA V3-V4 region dependent) to analyze changes in bacterial communities. Seed germination, root-shoot biomass and chlorophyll content were used to assess the growth of the cotton plant, whereas the bacterial ability to promote growth was evaluated by measuring its culturable diversity including traits like phosphate solubilization and indole acetic acid production. The variance in Bray-Curtis ß diversity among six selected combinations including control depends largely on the type of added supplements contributing to 95%-97% of it. Moreover, seed germination improves greatly between 63% and 100% at a concentration range of 1.4 to 2.8 mg/L with different types of supplements. Based on the results obtained through this study, it is evident that using AgNPs along with fructose could be an effective tool for promoting Gossypium hirsutum growth and enhancing plant growth traits like profiling rhizospheric bacteria. The results that have been obtained endorse the idea of boosting the growth of rhizospheric bacteria in a natural way when AgNPs are present. Using these supplements in fields that have been contaminated will lead to a better understanding of how ecological succession occurs among rhizospheric bacteria, and what effect it has on the growth of plants.

Biosensors for detection of prostate cancer: a review.

Diagnosis of prostate cancer (PC) has posed a challenge worldwide due to the sophisticated and costly diagnostics tools, which include DRE, TRUS, GSU, PET/CT scan, MRI, and biopsy. These diagnostic techniques are very helpful in the detection of PCs; however, all the techniques have their serious limitations. Biosensors are easier to fabricate and do not require any cutting-edge technology as required for other imaging techniques. In this regard, point-of-care (POC) biosensors are important due to their portability, convenience, low cost, and fast procedure. This review explains the various existing diagnostic tools for the detection of PCs and the limitation of these methods. It also focuses on the recent studies on biosensors technologies as an alternative to the conventional diagnostic techniques for the detection of PCs.

Microalgae and bio-polymeric adsorbents: an integrative approach giving new directions to wastewater treatment.

This review analyses the account of biological (microalgae) and synthetic (bio-polymeric adsorbents) elements to compass the treatment efficiencies of various water pollutants and mechanisms behind them. While considering pollutant removal, both techniques have their own merits and demerits. Microalgal-based methods have been dominantly used as a biological method for pollutant removal. The main limitations of microalgal methods are capacity, scale, dependence on variables of environment and duration of the process. Biopolymers on the other hand are naturally produced, abundant in nature, environmentally safe and biocompatible with cells and many times biodegradable. Algal immobilization in biopolymers has promoted the reuse of cells for further treatment and protected cells from toxic environment monitoring and controlling the external factors like pH, temperature and salinity can promote the removal process while working with the mentioned technologies. In this review, a mechanistic view of both these techniques along with integrated approaches emphasizing on their loopholes and possibilities of improvement in these techniques is represented. In addition to these, the review also discusses the post-treatment effect on algal cells which are specifically dependent on pollutant type and their concentration. All these insights will aid in developing integrated solutions to improve removal efficiencies in an environmentally safe and cost-effective manner.Novelty statement The main objective of this review is to thoroughly understand the role of micro-algal cells and synthetic adsorbents individually as well as their integrative effect in the removal of pollutants from wastewater. Many reviews have been published containing information related to either removal mechanism by algae or synthetic adsorbents. While in this review we have discussed the agents, algae and synthetic adsorbents along with their limitations and explained how these limitations can be overcome with the integration of both the moieties together in process of immobilization. We have covered both the analytical and mechanistic parts of these technologies. Along with this, the post-treatment effects on algae have been discussed which can give us a critical understanding of algal response to pollutants and by-products obtained after treatment. This review contains three different sections, their importance and also explained how these technologies can be improved in the future aspects.

Recombinant organophosphorus hydrolase (OPH) expression in E. coli for the effective detection of organophosphate pesticides.

Accumulation and exposure of organophosphate pesticides are of great concern today owing to their abundant usage and potential health hazards. Harmful effects of organophosphate pesticide exposure and limitations of the available treatment methods necessitate the development of reliable, selective, cost-effective, and sensitive methods of detection. We developed a novel biosensor based on the enzymatic action of recombinant organophosphorus hydrolase (OPH) expressed in E. coli. We report the development of colorimetric biosensors made of His-Nus-OPH as well as His-Nus-OPH loaded alginate microspheres. The colorimetric detection method developed using solution-phase and alginate-encapsulated His-Nus-OPH exhibited detection limits of 0.045 and 0.039 mM, respectively, for ethyl paraoxon, and 0.101 and 0.049 mM, respectively, for methyl parathion. Additionally, fluorescence measurement using pH-sensitive fluorescein isothiocyanate (FITC) was used to sense the quantity of organophosphorus pesticides. The fluorometric detection method using solution-phase His-Nus-OPH, with ethyl paraoxon and methyl parathion as the substrate, reveals the lower limit of detection as 0.014 mM and 0.044 mM, respectively. Our results demonstrate the viability of His-Nus-OPH for OP detection with good sensitivity, LOD, and linear range. We report the first use of N-terminal His-NusA-tagged OPH, which enhances solubility significantly and presents a significant advance for the scientific community.

Impact of drug formulations on kinetics and toxicity in a preclinical model of paclitaxel-induced neuropathy.

Peripheral neuropathy is a common side effect of paclitaxel. Clinical studies suggest that different paclitaxel formulations influence the severity and time course of paclitaxel-induced peripheral neuropathy. We compared two paclitaxel formulations, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and Cremophor EL paclitaxel (CreEL-paclitaxel), for their toxicity, distribution, and clearance in the peripheral nervous system. Neuronal F11 cells were used to detect changes in morphology, cell nuclei size, and cell viability after nab- or CreEL-paclitaxel treatment via MTT Assay and immunohistochemistry. C57BL/6 mice were treated with 50 mg/kg of nab-paclitaxel or CreEL-paclitaxel. Paclitaxel levels in serum, liver, dorsal root ganglia (DRG), and sciatic nerve (SCN) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Accumulation of paclitaxel in DRG neurons and SCN was visualized by immunostainings. Neurotoxicity was evaluated after a 4-week treatment regime with nab- or CreEL-paclitaxel by nerve morphology, behavioral, and functional assays. In vitro cell nuclei size and morphology were similar between the two treatment groups. Viability was increased in neurons exposed to nab-paclitaxel compared to CreEL-paclitaxel. In vivo paclitaxel mostly accumulated in DRG. SCN displayed lower paclitaxel uptake. The two paclitaxel formulations mainly accumulated in neurofilament 200-positive large-caliber neurons and less in Isolectin B4-, or calcitonin gene-related peptide-positive small-caliber neurons. Sensory nerve conduction studies demonstrated increased sensory latencies after 11 days in nab-paclitaxel treated animals, while an increase occurred after 22 days in CreEL-paclitaxel treated animals. Behavioral testing did not reveal significant differences between the different groups. Skin denervation, axon count, myelin thickness, and F4/80-positive cell accumulation were comparable between the two treatment groups. Our findings indicate that different drug formulations impact the severity of neuropathy induced by paclitaxel via different tissue uptake. Neurotoxicity was comparable between the two paclitaxel formulations.

A novel biosensor for the detection of organophosphorus (OP)-based pesticides using organophosphorus acid anhydrolase (OPAA)-FL variant.

Indiscriminate use of organophosphorus (OP)-based insecticides is a great concern to human health because of bioaccumulation-induced health hazards. Potentially fatal consequences and limited treatment methods of OP poisoning necessitate the need for the development of reliable, selective, cost-effective, and sensitive methods of OP detection. To tackle this issue, the development of effective devices and methods is required to sensitively detect as well as degrade OPs. Enzymatic sensor systems have gained popularity due to high catalytic activity, enhanced detection limits, and high sensitivity with the environmentally benign operation. Organophosphorus acid anhydrolase (OPAA) from Alteromonas sp. JD6.5 is capable of hydrolyzing the P-F, P-O, P-S, and P-CN bonds, in OPs, including nerve agents of the G/V-series. Several mutants of OPAA are reported which have greater activity against various OPs. In this study, recombinant expression of the OPAA-FL variant in Escherichia coli was performed, purified, and subsequently tested for activity against ethyl paraoxon. OPAA-FL variant showed its optimum activity at pH 8.5 and 50 °C. Colorimetric and fluorometric assays were used for estimation of ethyl paraoxon based on p-nitrophenol and fluorescein isothiocyanate (FITC) fluorescence intensity, respectively. Colorimetric and fluorometric assay estimation indicates that ethyl paraoxon can be estimated in the linear range of 0.01 to 1 mM and 0.1 to 0.5 mM, with LOD values 0.04 mM and 0.056 mM, respectively. Furthermore, the OPAA-FL variant was immobilized into alginate microspheres for colorimetric detection of ethyl paraoxon and displayed a linear range of 0.025 to 1 mM with a LOD value of 0.06 mM. KEY POINTS: • Biosensing of paraoxon with purified and encapsulated OPAA-FL variant. • Colorimetric and fluorometric biosensing assay developed using OPAA-FL variant for paraoxon. • First report on alginate encapsulation of OPAA-FL variant for biosensing of paraoxon. Graphical abstract.

Complete genome sequence of plant growth promoting Pseudomonas aeruginosa AJ D 2 an isolate from monocropic cotton rhizosphere.

A plant growth promoting Pseudomonas aeruginosa AJD 2 was isolated from monocropic cotton rhizosphere of Maharashtra state, India. The strain was identified as per physiological, biochemical and 16S rRNA gene sequencing (Accession number MG234531). The strain possess multiple functional plant growth promoting traits and antifungal activity. The genome was extracted, purified and library of avg.515 bp was prepared and sequenced by over Illumina platform. The sequenced genome was studied by using CLC workbench and NCBI pipeline using Pseudomonas aeruginosa PAO1 and Pseudomonas aeruginosa YL84 as reference assembler. The size of the genome is 6.1 Mb with 5802 genes within it. The study over strain may give an insight into its plant growth promotion mechanism.

Advances in detection of hazardous organophosphorus compounds using organophosphorus hydrolase based biosensors.

Agricultural advancements focusing on increasing crop production have led to excessive usage of insecticides and pesticides, resulting in leaching and accumulation of these highly toxic chemicals in soil, water, and the food-chain. Organophosphorus (OP) compounds are the most commonly used insecticides and pesticides, which cause a wide range of long-lasting and life-threatening conditions. Due to the acute toxicity and long-term side effects of OP compounds, their timely, on-the-spot and rapid detection has gained importance, for efficient healthcare management. In this respect, several OP degrading enzymes have gained the spotlight in developing the enzyme-based biosensors, owing to their high activity and broad specificity. Among these enzymes, organophosphorus hydrolase (OPH) has emerged as a promising candidate for the detection of OP compounds, due to its ability to act on a broad range of substrates having a variety of bonds, like P─F, P─O, P─S, and P─CN. Various techniques employing OPH in free/immobilized/conjugated forms into sensing devices were reported to accurately detect OP compounds. The transduction mechanisms of bio-sensing are electrochemical, optical as well as novel methods like magnetoelastic/surface plasmon resonance. Furthermore, to improve the detection limits and sensitivity, nanoparticles and quantum dots are often employed in conjunction with OPH. Here, we highlight the recent advances in sensing OP compounds using OPH based biosensors, compare specifications of sensing methods, and evaluate the influence of different materials used in developing sensors. This review will also enable researchers to design and configure highly sensitive and accurate sensing systems, leading to the development of point-of-care devices for real-time analysis.

The interplay between activity and filament flexibility determines the emergent properties of active nematics.

Active nematics are microscopically driven liquid crystals that exhibit dynamical steady states characterized by the creation and annihilation of topological defects. Motivated by differences between previous simulations of active nematics based on rigid rods and experimental realizations based on semiflexible biopolymer filaments, we describe a large-scale simulation study of a particle-based computational model that explicitly incorporates filament semiflexibility. We find that energy injected into the system at the particle scale preferentially excites bend deformations, reducing the apparent filament bend modulus. The emergent characteristics of the active nematic depend on activity and flexibility only through this activity-renormalized bend 'modulus', demonstrating that apparent values of material parameters, such as the Frank 'constants', depend on activity. Thus, phenomenological parameters within continuum hydrodynamic descriptions of active nematics must account for this dependence. Further, we present a systematic way to estimate these parameters from observations of deformation fields and defect shapes in experimental or simulation data.

Loss of Schwann cell plasticity in chronic inflammatory demyelinating polyneuropathy (CIDP).

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is often associated with chronic disability, which can be accounted to incomplete regeneration of injured axons. We hypothesized that Schwann cell support for regenerating axons may be altered in CIDP, which may account for the poor clinical recovery seen in many patients. METHODS: We exposed human and rodent Schwann cells to sera from CIDP patients and controls. In a model of chronic nerve denervation, we transplanted these conditioned Schwann cells intraneurally and assessed their capacity to support axonal regeneration by electrophysiology and morphometry. RESULTS: CIDP-conditioned Schwann cells were less growth supportive for regenerating axons as compared to Schwann cells exposed to control sera. The loss of Schwann cell support was associated with lower levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CIDP sera and correlated with altered expression of c-Jun and p57kip2 in Schwann cells. The inactivation of these regulatory factors resulted in an altered expression of neurotrophins including BDNF, GDNF, and NGF in CIDP-conditioned Schwann cells in vitro. CONCLUSIONS: Our study provides evidence that pro-regenerative functions of Schwann cells are affected in CIDP. It thereby offers a possible explanation for the clinical observation that in many CIDP patients recovery is incomplete despite sufficient immunosuppressive treatment.

Toxicity to sensory neurons and Schwann cells in experimental linezolid-induced peripheral neuropathy.

OBJECTIVES: Peripheral neuropathy is a common side effect of prolonged treatment with linezolid. This study aimed to explore injurious effects of linezolid on cells of the peripheral nervous system and to establish in vivo and in vitro models of linezolid-induced peripheral neuropathy. METHODS: C57BL/6 mice were treated with linezolid or vehicle over a total period of 4 weeks. Animals were monitored by weight, nerve conduction studies and behavioural tests. Neuropathic changes were assessed by morphometry on sciatic nerves and epidermal nerve fibre density in skin sections. Rodent sensory neuron and Schwann cell cultures were exposed to linezolid in vitro and assessed for mitochondrial dysfunction. RESULTS: Prolonged treatment with linezolid induced a mild, predominantly small sensory fibre neuropathy in vivo. Exposure of Schwann cells and sensory neurons to linezolid in vitro caused mitochondrial dysfunction primarily in neurons (and less prominently in Schwann cells). Sensory axonopathy could be partially prevented by co-administration of the Na(+)/Ca(2+) exchanger blocker KB-R7943. CONCLUSIONS: Clinical and pathological features of linezolid-induced peripheral neuropathy can be replicated in in vivo and in vitro models. Mitochondrial dysfunction may contribute to the axonal damage to sensory neurons that occurs after linezolid exposure.

Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit.

BACKGROUND: S0597 is a novel glucocorticosteroid that was formulated as an intranasal spray to treat seasonal allergic rhinitis (SAR). In a previous phase 2 study, doses of 100 to 400 µg twice daily were well tolerated and more effective than placebo for improving nasal symptoms induced by grass pollen. OBJECTIVE: To assess the clinical efficacy and safety of a once-daily S0597 nasal spray for treatment of SAR induced by ragweed pollen in an environmental exposure unit (EEU). METHODS: A single-center, phase 2, randomized, double-blind study in 222 adults with SAR and a positive skin prick test result to short ragweed. Participants underwent ragweed pollen challenge in the EEU at the screening or priming visit and on days 1, 7, and 14 and received 50, 200, or 400 µg of S0597 or placebo in the evening for 13 days. The primary efficacy end point was change in total nasal symptom score (TNSS) from baseline to day 14. RESULTS: Improvement in TNSS from baseline to day 14 was statistically significant in all S0597 groups compared with placebo. Least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200-, and 400-µg/d S0597 groups, respectively (P < .05). The 200-µg group demonstrated statistically significant improvements in all TNSS subscales (rhinorrhea, nasal congestion, sneezing, nasal itching) compared with placebo at days 7 and 14. CONCLUSION: Treatment with 50 to 400 µg of S0597 once daily was well tolerated and significantly more effective than placebo in relieving nasal symptoms of SAR associated with ragweed pollen. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01940146.

Paclitaxel inhibits mRNA transport in axons.

Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy.