Specific Dose Research Articles

NANOSPONGES - A REVOLUTIONARY TARGETED DRUG DELIVERY NANOCARRIER: A REVIEW

Effective targeted drug delivery systems have long been a dream, but have been largely hampered by the complex chemistries involved in developing new systems. The creation of novel colloidal carriers known as nanosponges has the potential to resolve these issues. An innovative and developing technology called nanosponge provides regulated medication delivery for topical application. Highly porous nanosponges have a unique capacity to entrap active molecules and have the advantage of programmable release. Nanosponges are small three-dimensional porous structures about the size of nanometer that can contain many different drugs. These tiny sponges can move throughout the body until they meet a specific target site and attach to surfaces and begin to release the drug in a controlled and predictable manner. Because the drug can be delivered to a specific target site instead of circulating throughout the body, it is more effective for a given specific dose. They are easy to make and safe for biological use. Different types of cyclodextrins can be cross-linked using a carbonyl or a dicarboxylate chemical as a cross-linker to create nanosponges. This groundbreaking technology has been extensively investigated for the delivery of medications for oral, topical, and parental administrations. Vaccines, antibodies, proteins, and enzymes can all be effectively transported via Nanosponges. The current review emphasizes the methods, advantages, disadvantages, characterization, and applications of nanosponges.

Comprehensive investigation of lateral dose profile and output factor measurements in small proton fields from different delivery techniques.

As a part of the commissioning and quality assurance in proton beam therapy, lateral dose profiles and output factors have to be acquired. Such measurements can be performed with point detectors and are especially challenging in small fields or steep lateral penumbra regions as the detector's volume effect may lead to perturbations. To address this issue, this work aims to quantify and correct for such perturbations of six point detectors in small proton fields created via three different delivery techniques. Lateral dose profile and output measurements of three proton beam delivery techniques (pencil beam scanning, pencil beam scanning combined with collimators, passive scattering with collimators) were performed using high-resolution EBT3 films, a PinPoint 3D 31022 ionization chamber, a microSilicon diode 60023 and a microDiamond detector 60019 (all PTW Freiburg, Germany). Detector specific lateral dose response functions K(x,y) acting as the convolution kernel transforming the undisturbed dose distribution D(x,y) into the measured signal profiles M(x,y) were applied to quantify perturbations of the six investigated detectors in the proton fields and correct the measurements. A signal theoretical analysis in Fourier space of the dose distributions and detector's K(x,y) was performed to aid the understanding of the measurement process with regard to the combination of detector choice and delivery technique. Quantification of the lateral penumbra broadening and signal reduction at the fields center revealed that measurements in the pencil beam scanning fields are only compromised slightly even by large volume ionization chambers with maximum differences in the lateral penumbra of 0.25mm and 4% signal reduction at the field center. In contrast, radiation techniques with collimation are not accurately represented by the investigated detectors as indicated by a penumbra broadening up to 1.6mm for passive scattering with collimators and 2.2mm for pencil beam scanning with collimators. For a 3mm diameter collimator field, a signal reduction at field center between 7.6% and 60.7% was asserted. Lateral dose profile measurements have been corrected via deconvolution with the corresponding K(x,y) to obtain the undisturbed D(x,y). Corrected output ratios of the passively scattered collimated fields obtained for the microDiamond, microSilicon and PinPoint 3D show agreement better than 0.9% (one standard deviation) for the smallest field size of 3mm. Point detector perturbations in small proton fields created with three delivery techniques were quantified and found to be especially pronounced for collimated small proton fields with steep dose gradients. Among all investigated detectors, the microSilicon diode showed the smallest perturbations. The correction strategies based on detector's K(x,y) were found suitable for obtaining unperturbed lateral dose profiles and output factors. Approximation of K(x,y) by considering only the geometrical averaging effect has been shown to provide reasonable prediction of the detector's volume effect. The findings of this work may be used to guide the choice of point detectors in various proton fields and to contribute toward the development of a code of practice for small field proton dosimetry.

Terrestrial Radiation of Some Selected Active Telecommunication Sites in Port Harcourt, Rivers State, Nigeria

A study on terrestrial background ionization radiation was carried out around active selected telecommunications sites in Port Harcourt. This study was done using Radalert 100 and the geographical position system (GPS). The exposure rate ranged from 0.033 to 0.141 with a mean value of 0.123±0.20 (mR/h) which is lower than the acceptable limit of 0.0133 (mR/h). The absorbed dose ranged from 287.1 nG/h to 1226.7 nGy/hr with a mean value of 1066.64±1769.6 nGy/hr, which is quite higher than the acceptable limit of 89.0 nGy/h. The annual effective dose ranged between 0.44 and 1.88 mSv/y, with a mean value of 1.642.7 mSv/y which is quite higher than the safe limit of 1.0 mSv/y. The excess lifetime Cancer Risk (ELCR) varied from 1.54 x10-3 to 6.58x10-3 with a mean value of 5. 72±9.5 mSv/y. The result from this study is higher than the acceptable limit of 0.29 x10-3 as recommended by UNSCEAR. This means that people living within these areas may be exposed to cancer in later life. The effective dose of the various organs (ED Organs) are within the recommended safe limit of ICRP. The testes and the bone marrow are the most sensitive to radiation with the percentage distribution of 18.0% and 16.0%. Since the Annual effective dose, absorbed dose, and excess lifetime cancer risk are higher than the world standard, the chances of contracting cancer related illnesses are significant. It is recommended that monitoring of the exposure rate to ionizing radiation within the environment should be carried out. Also, individuals should on regular basis request for specific organ dose test.

Dose measurement study of the chest during a CT scan using a fabricated phantom

The purpose of this study was to evaluate radiation doses during computer tomography (CT) scans of the whole body and organs using a fabricated phantom. The Weighted Computer Tomography Dose Index (CTDIw) was evaluated and measured using a fabricated phantom, and five CT scanners were used for chest examinations from four hospitals in Najran, Saudi Arabia. The heart, lungs, esophagus, and spinal cord doses were measured with clinical whole body CT acquisition protocol using Thermoluminescent Dosimeters (TLDs). The TLDs used for measurements were selected for an accuracy of 5% and calibrated for the X-ray radiation field. The CTDIw and organ doses reported in this study were compared with results of ImPACT software for calculating organ doses. The results show good agreement with the calculations and the literature. The measured specific organ doses ranged between 1.33 mGy (lung marrow) and 1.65 mGy (esophagus). The model is easy to produce and useful for evaluating the organ doses and CTDIw.

A Comprehensive Review Article on Transdermal Patch

Transdermal drug delivery system (TDDS) established itself as an integral part of novel drug delivery systems. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal drug delivery systems are polymeric formulations which when applied to skin deliver the drug at a predetermined rate across dermis to achieve systemic effects. A transdermal patch is medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered in this method.

Aspirin prevents estrogen deficiency-induced bone loss by inhibiting osteoclastogenesis and promoting osteogenesis

BackgroundAspirin is a commonly used antipyretic, analgesic, and anti-inflammatory drug. Numerous researches have demonstrated that aspirin exerts multiple biological effects on bone metabolism. However, its spatiotemporal roles remain controversial according to the specific therapeutic doses used for different clinical conditions, and the detailed mechanisms have not been fully elucidated. Hence, in the present study, we aimed to identify the dual effects of different aspirin dosages on osteoclastic activity and osteoblastic bone formation in vitro and in vivo.MethodsThe effects of varying doses of aspirin on osteoclast and osteoblast differentiation were evaluated in vitro. The underlying molecular mechanisms were detected using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence techniques. An ovariectomized rat osteoporosis model was used to assess the bone-protective effects of aspirin in vivo.ResultsAspirin dose-dependently suppressed RANKL-induced osteoclasts differentiation and bone resorption in vitro and reduced the expression of osteoclastic marker genes, including TRAP, cathepsin K, and CTR. Further molecular analysis revealed that aspirin impaired the RANKL-induced NF-κB and MAPK signaling pathways and prevented the nuclear translocation of the NF-κB p65 subunit. Low-dose aspirin promoted osteogenic differentiation, whereas these effects were attenuated when high-dose aspirin was administered. Both low and high doses of aspirin prevented bone loss in an ovariectomized rat osteoporosis model in vivo.ConclusionAspirin inhibits RANKL-induced osteoclastogenesis and promotes osteogenesis in a dual regulatory manner, thus preventing bone loss in vivo. These data indicate that aspirin has potential applications in the prevention and treatment of osteopenia.

Maslinic acid attenuates UVB-induced oxidative damage in HFF-1 cells.

Oxidative damage is one of the major mechanisms of ultraviolet B (UVB)-induced damage to the skin. Maslinic acid (MA) is a natural compound of pentacyclic triterpene acids. It has been proved to have anti-inflammatory and antioxidant properties. This study aimed to explore the effects of MA on oxidative damage in human foreskin fibroblast cells (HFF-1) and the potential molecular mechanisms. A specific dose of UVB radiation was used to induce oxidative damage in HFF-1. Based on this, we performed measurements of cell proliferation, reactive oxygen species (ROS) levels, antioxidant enzyme activity, inflammation-related mediators, and NF-κB nuclear localization with or without the addition of MA. MA significantly promoted cell proliferation viability at 10 and 20 μM. The addition of MA 24 h before UVB irradiation was more effective at enhancing cell proliferation and also produced lower ROS levels compared to co-cultured fibroblasts and MA for 24 h after irradiation. However, there was no statistically significant difference between groups at concentrations of 10 and 20 μM. The pretreatment group with MA had elevated superoxide dismutase and catalase activities, decreased IL-6 generation, and lowered mRNA levels of IL-6, TNF-α and MMP3 in comparison with the UVB-irradiated group without additional MA. Meanwhile, the nuclear translocation of NF-κB and the degradation of IκB were inhibited by MA pretreatment. Taken together, these findings suggest that MA may alleviate UVB-induced oxidative damage in HFF-1 by inhibiting the nuclear translocation of NF-κB.

Surviving Sepsis Campaign.

Surviving Sepsis Campaign.

Optimizing ozone dose and contact time for removal of antibiotic-resistant P. aeruginosa, A. baumannii, E. coli, and associated resistant genes in effluent of an activated sludge process in a municipal WWTP.

This study aimed to investigate the impact of ozonation on inactivation of antibiotic-resistant bacteria (ARB) including E. coli, P. aeruginosa, and A. baumannii, as well as on removal of 16S-rRNA gene and their associated antibiotic-resistant genes (ARGs) indigenously present in effluent of municipal wastewater treatment plant. The Chick-Watson model was used to describe bacterial inactivation rates at specific ozone doses. Maximum reduction of total cultivable A. baumannii, E. coli, and P. aeruginosa were found to be 7.6, 7.1, and 4.7 log, respectively, with the highest ozone dose of 0.48 gO3/gCOD at 12min contact time. According to the study results, complete inactivation of ARB and bacterial regrowth was not observed after 72h incubation. The culture methods overestimated the performance of disinfection processes and propidium monoazide combined with qPCR, and showed the presence of viable but non-culturable bacteria after ozonation. ARGs were more persistent to ozone than ARB. The results of this study highlighted the significance of specific ozone dose and contact time in ozonation process considering the bacterial species and associated ARGs as well as the wastewater physicochemical characteristics, in order to help diminish the entrance of the biological microcontaminants into the environment.

Mosquito Adult Bioassays.

Topical application and bottle bioassays measure the responses of adult mosquitoes to specific doses of an insecticide (dose-response). Topical application bioassays are generally used to measure the dose-response of adult mosquitoes to insecticides in which the amount (dose) of insecticides the mosquitoes receive is known in the laboratory. Here, a 0.5-µL drop of the insecticide dissolved in a relatively nontoxic solvent, such as acetone, is applied to the thorax of insects, and the insects' susceptibility to the insecticide is determined in terms of either the median lethal dose (LD50) or 90% of the mortality lethal dose (LD90). Bottle bioassays measure the dose-responses in which the exact amount of insecticide in a bottle is known while the exact amount of insecticide that mosquitoes (field-collected or laboratory-susceptible) receive is not known. Bottle bioassays can be either single dose tests or multiple dose applications. The bottle bioassay described in this protocol is a modified form of the World Health Organization (WHO) and U.S. Centers for Disease Control (CDC) bottle bioassays. For the single bottle assay, a detailed protocol with the amount (dose/bottle) of each insecticide and threshold times is provided by the CDC; here we provide protocols for topical and bottle bioassay applications with multiple doses.

Assessment of Soil Fertility through Response of Rice (Oryza sativa L.) to Nutrient Omission in Alfisols of Kondagaon District of Chhattisgarh in India

The investigation was carried out with the aim to identify the specific yield limiting nutrients through response of rice to nutrient omission in pot culture under completely randomized design with 3 replications and 11 treatments during kharif season 2017 and to demonstrate the optimum use of identified limiting nutrients in wheat crop at field level in Kondagaon district during rabi season 2017-18. The treatments were formulated by keeping one treatment with application of all nutrients in optimum level and others by sequentially omitting each nutrient. The soil had a clay loam texture, neutral reaction (pH 6.6), normal electrical conductivity, medium organic C, available P and K, low available N and S, high available Ca, Mg, Fe, Mn and Cu and marginal available Zn and B. Omission of N and P nutrients significantly reduced the growth, yield and nutrients uptake by rice in comparison to all nutrients. The maximum grain yield of 73.0 g pot-1 was recorded, in all nutrients pot and 50.1 % reduction in grain yield of rice, from the maximum yield, was recorded in N omitted pots, followed by 18.8 % reduction in P omitted pots and omission of other nutrients didn’t reduce the grain yield significantly indicating that only N and P were yield limiting nutrients. In field verification during rabi season, 19.0 % increase in wheat grain yield and 23.0 % increase in net return was recorded, due to optimum dose of identified yield limiting nutrients over farmer's practice dose. The results clearly indicate that the site specific nutrient management dose based on yield limiting nutrient identified through nutrient omission study was found economically profitable to the farmers.

Sintilimab Plus Apatinib and Chemotherapy as Second‑/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial

BackgroundThe prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients.MethodsIn this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator’s choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety.ResultsFrom May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9–72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4–11.5) and 12.5 months (95% CI, 3.7–21.3), respectively. Grade 3–4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3–4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred.ConclusionSintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer.Trial registrationClinicalTrials.gov: NCT05025033, 27/08/2021.

Efficiency of post-preparation treatment by gamma radiation to guarantee quality properties of plum molasses

Purpose This study aimed to assess specific gamma irradiation doses to be applied as a post-preparation process to assure the chemical, physical and sensory properties of plum molasses (PM). Materials and methods Samples of PM were treated with 0, 3, 6 and 9 kGy in a 60Co gamma irradiation plant. Proximate composition, chemical, the physical and sensory determination was accomplished immediately after treatment. Results Our results showed that, the moisture content of PM were significantly (p < .05) rise by treating with 3 kGy. Whereas, ash and reducing sugar quantity of PM was significantly (p < .05) decreased by treatment at the same dose (3 kGy). Irradiation treatment induced small and not significant alterations (p > .05) in crude protein, crud fat, and total sugar of PM. The chemical and physical parameters including; total acidity (TA), pH, volatile basic nitrogen (VBN), total soluble solids (TSS) (%, Brix), viscosity and color, which were elected as the indicators of quality, were all well within the recommended values for PM treated with 0, 3, 6 and 9 kGy. Sensory determination indicated no significant (p > .05) alterations between irradiated samples and non-irradiated samples of PM. Conclusion Irradiation treatment at 3 kGy was considered as acceptable to be used for the preservation purpose of PM without modifying their quality properties.

A Scoping Review of the Impact of COVID-19 on Kidney Transplant Patients in the United States.

SARS-CoV-2, responsible for the COVID-19pandemic, is a highly infectious virus that quickly became and continues to be a public health emergency, given the severe international implications. Immunocompromised patients, such as those undergoing kidney transplantation, are at an increased risk for severe illness from COVID-19 and require hospitalization for more aggressive treatment to ensure survival. COVID-19 has been infecting kidney transplant recipients (KTRs), affecting their treatment protocols, and threatening their survival. The objective of this scoping review was to summarize the published literature regarding the impact of COVID-19 on KTRs in the United States in terms of prevention, various treatment protocols, COVID-19 vaccination, and risk factors. The databases such as PubMed, MEDLINE/Ebsco, and Embase were used to search for peer-reviewed literature. The search was restricted to articles that were published on KTRs in the United States from January 1, 2019, toMarch 2022. The initial search yielded 1,023 articles after removing duplicates, leading to a final selection of 16 articles after screening with inclusion and exclusion criteria. Four domains emerged from the review: (1) impacts of COVID-19 on performing kidney transplants, (2) impacts of COVID-19 vaccinations on KTRs, (3) outcomes of treatment regiments for KTRs with COVID-19, and (4) risk factors associated with an increased mortality rate of COVID-19 in KTRs. Waitlisted patients for kidney transplants had a higher risk of mortality compared to nontransplant patients. COVID-19 vaccinations in KTRs are found to be safe, and the immune response can be improved by placing patients on a low dose of mycophenolate before vaccination. Withdrawal of immunosuppressants showed a mortality rate of 20% without increasing the rate of acute kidney injury (AKI). There is evidence to support that kidney transplantation with the accompanying immunosuppressant regimen can provide KTRs with better COVID-19 infection outcomes compared to waitlisted patients. Hospitalization, graft dysfunction, AKI, and respiratory failure were the most common risk factors that increased the risk of mortality in COVID-19-positive KTRs. Withdrawing KTRs from immunosuppressive drugs increased the mortality rate. Further studies are needed to investigate the effects of specific drugs and dosages on the severity and mortality rate of COVID-19 in KTRs.

In vitro dissolution test of ketoprofene: development and evaluation of release from soft and hard gelatine capsules

Ketoprofen belongs to a group of widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is found in several doses and various forms of medications. Therapeutic efficacy is related to the rate of release of the active substances, which depends on the formulation, the quality of the constituent substances and solubility. In order to determine the efficacy of drug products containing ketoprofen available on the pharmaceutical market in Poland, studies comparing the release profiles of the active substance contained in specific formulation and doses, Ketokaps MAX, 50 mg, soft capsules, Ketonal Active, 50 mg, hard capsules, Ketokaps MED, 100 mg, soft capsules, Refastin, 100 mg, film-coated tablets and Ketonal Forte, 100 mg, film-coated tablets have been conducted. Drug release has been tested using FaSSGF and FaSSIF bioequivalent media in a type IV flow apparatus. The results indicate that the product Ketokaps MAX, 50 mg has a shorter release time of ketoprofen and a faster reached maximum concentration of the released active substance than the market product Ketonal Active, 50 mg. The same outcomes will be achieved by the product Ketokaps MED, 100 mg compared to the market products Refastin, 100 mg and Ketonal Forte, 100 mg. In vitro studies confirm that the tested products differ noticeably in the kinetics of release of the active substance. Ketokaps MAX, 50 mg and Ketokaps MED, 100 mg achieve c max in a shorter time.

A Case of Oligospermic Male Infertility Successfully Treated with Personalised Homoeopathic Medicine Phosphoricum acidum

AbstractA 25-year-old Indian, male being married for two years presented with complaints of low sperm count for one year at Homoeopathic Seva Niketan, Durga Park, New Delhi, India. The patient came to the clinic with complaints of oligospermia or oligozoospermia, headache, weak memory, and constipation. The couple had undergone various medical tests and sought the help from various infertility specialists and were told that the wife had no medical condition preventing them from having a child. The patient was treated on the wholistic concept of homoeopathy with specific doses of Phosphoricum acidum resulting in fruitful conception within three years. These were evident from the time to time semen analysis reports of the patient and presence of a live foetus in his wife's diagnostic reports.

Abstract P432: Statin Initiation for Primary Prevention and Dose Intensity According to Age in the Women’s Health Initiative

Introduction: Over 50% of US adults older than 75 live free of atherosclerotic cardiovascular disease (ASCVD) and diabetes (DM), yet data on incident statin use among this population are lacking. Our objective was to assess statin initiation by age among the Women’s Health Initiative cohort free of ASCVD and DM at baseline (1993). Hypothesis: Statin initiation is higher at older ages and differs by race/ethnicity. Methods: Exclusions were statin use at baseline, known ASCVD, DM, and no follow-up after baseline. Self-reported medication use was assessed in 1996 and 2008. Specific statin and dose prescribed at the time of initiation were identified using National Drug Codes and determined statin intensity, defined by the ACC/AHA guidelines. We estimated the adjusted association between age group (&lt;65, 65-74, and ≥75) and statin initiation and assessed for heterogeneity by race/ethnicity. We also assessed statin dose at the time of initiation. Results: Over 12 years of follow-up, 27% of 99,631 women free of ASCVD and DM at baseline initiated a statin; initiation was lower with older age (Table). This association remained after adjustment for ASCVD risk factors and did not differ by race/ethnicity (p for interaction &gt;0.5). Moderate intensity dose was most common at statin initiation overall, and moderate and high intensity dose were both lower with older age. Conclusion: Of women free of ASCVD and DM, women older than 75 were least likely to start a statin and most likely to start low intensity statin therapy at initiation than younger women. We identified a potential clinical gap for investigation: whether lower overall use of statins and lower intensity statin therapy among older women are associated with preventable ASCVD.

Electrical impedance decreases in annulus fibrosus cartilage exposed to microsecond pulsed electric fields ex vivo

Electropermeabilization of biomembranes often is measured by microscopic imaging of a membrane-impermeable fluorophore that penetrates the cells following pulsed electric field (PEF) exposure. PEF exposure subsequently changes physiological properties of tissue. One way to probe these changes in tissue is measuring electrical properties by way of electrochemical impedance spectroscopy (EIS). In this study, we analyse impedance and conductivity of bovine annulus fibrosus (AF) cartilage before and after exposures to PEF of 100 μs duration. Two PEF parameters–electric field amplitude and number of pulses–are varied, and total specific dose of PEF is calculated. AF tissue conductivity increases with both amplitude and number of pulses, indicating electropermeabilization of the AF cells. A Live/Dead cell imaging assay validates the EIS measurements, indicating intratissue cell permeabilization by μsPEF exposure. These results support the extension of EIS to monitor extent of electropermeabilization of cells within cartilage tissue.

Enhancing the Neuroprotection Potential of Edaravone in Transient Global Ischemia Treatment with Glutathione- (GSH-) Conjugated Poly(methacrylic acid) Nanogel as a Promising Carrier for Targeted Brain Drug Delivery.

Ischemic stroke is the most common among various stroke types and the second leading cause of death, worldwide. Edaravone (EDV) is one of the cardinal antioxidants that is capable of scavenging reactive oxygen species, especially hydroxyl molecules, and has been already used for ischemic stroke treatment. However, poor water solubility, low stability, and bioavailability in aqueous media are major EDV drawbacks. Thus, to overcome the aforementioned drawbacks, nanogel was exploited as a drug carrier of EDV. Furthermore, decorating the nanogel surface with glutathione as targeting ligands would potentiate the therapeutic efficacy. Nanovehicle characterization was assessed with various analytical techniques. Size (199 nm, hydrodynamic diameter) and zeta potential (-25 mV) of optimum formulation were assessed. The outcome demonstrated a diameter of around 100 nm, sphere shape, and homogenous morphology. Encapsulation efficiency and drug loading were determined to be 99.9% and 37.5%, respectively. In vitro drug release profile depicted a sustained release process. EDV and glutathione presence in one vehicle simultaneously made the possibility of antioxidant effects on the brain in specific doses, which resulted in elevated spatial memory and learning along with cognitive function in Wistar rats. In addition, significantly lower MDA and PCO and higher levels of neural GSH and antioxidant levels were observed, while histopathological improvement was approved. The developed nanogel can be a suited vehicle for drug delivery of EDV to the brain and improve ischemia-induced oxidative stress cell damage.

Conifer-killing bark beetles locate fungal symbionts by detecting volatile fungal metabolites of host tree resin monoterpenes.

Outbreaks of the Eurasian spruce bark beetle (Ips typographus) have decimated millions of hectares of conifer forests in Europe in recent years. The ability of these 4.0 to 5.5 mm long insects to kill mature trees over a short period has been sometimes ascribed to two main factors: (1) mass attacks on the host tree to overcome tree defenses and (2) the presence of fungal symbionts that support successful beetle development in the tree. While the role of pheromones in coordinating mass attacks has been well studied, the role of chemical communication in maintaining the fungal symbiosis is poorly understood. Previous evidence indicates that I. typographus can distinguish fungal symbionts of the genera Grosmannia, Endoconidiophora, and Ophiostoma by their de novo synthesized volatile compounds. Here, we hypothesize that the fungal symbionts of this bark beetle species metabolize spruce resin monoterpenes of the beetle's host tree, Norway spruce (Picea abies), and that the volatile products are used as cues by beetles for locating breeding sites with beneficial symbionts. We show that Grosmannia penicillata and other fungal symbionts alter the profile of spruce bark volatiles by converting the major monoterpenes into an attractive blend of oxygenated derivatives. Bornyl acetate was metabolized to camphor, and α- and β-pinene to trans-4-thujanol and other oxygenated products. Electrophysiological measurements showed that I. typographus possesses dedicated olfactory sensory neurons for oxygenated metabolites. Both camphor and trans-4-thujanol attracted beetles at specific doses in walking olfactometer experiments, and the presence of symbiotic fungi enhanced attraction of females to pheromones. Another co-occurring nonbeneficial fungus (Trichoderma sp.) also produced oxygenated monoterpenes, but these were not attractive to I. typographus. Finally, we show that colonization of fungal symbionts on spruce bark diet stimulated beetles to make tunnels into the diet. Collectively, our study suggests that the blends of oxygenated metabolites of conifer monoterpenes produced by fungal symbionts are used by walking bark beetles as attractive or repellent cues to locate breeding or feeding sites containing beneficial microbial symbionts. The oxygenated metabolites may aid beetles in assessing the presence of the fungus, the defense status of the host tree and the density of conspecifics at potential feeding and breeding sites.