Chronic stress intensify PTZ-induced seizures by triggering neuroinflammation and oxidative stress.

BACKGROUND: Epilepsy is a paroxysmal abnormal hypersynchronous electrical discharge characterized by recurrent seizures. It affects more than 50 million people worldwide. Stress is the leading cause of neurodegeneration and can produce seizures that may lead to or aggravate epilepsy. Inflammation plays a vital role in epilepsy by modulating oxidative stress, and levels of neuroinflammatory cytokines including NF-κB, TNF-α, and IL-1ß. METHODS: Stress-induced changes in behavior were evaluated in mice by employing behavioral assessment tests such as an elevated plus maze, light-dark box, open field test, tail suspension test, Y-maze, novel object recognition test, and Morris water maze in pentylenetetrazole (PTZ) kindled mice. Behavioral changes in all these paradigms including seizure score, latency, and frequency showed an increase in symptoms in PTZ (35 mg/kg) induced seizures in stressed mice (RS-PTZ) as compared to PTZ, Stress, and normal animals. RESULTS: The Enzyme-linked immunosorbent assay (ELISA) results confirmed increased in serum cortisol levels. Histological examinations showed neurodegenerative changes in the hippocampus and cortex regions. The spectrophotometric evaluation showed an increase in oxidative stress by decreasing antioxidant production i.e. reduced glutathione, glutathione -s- transferase, and catalase (CAT), and increasing oxidant levels such as maloaldehyde and nitric oxide. Immunohistochemistry results showed increased expression of NF-κB, TNF-α, and IL-1ß in the cortex and hippocampus of mice brains. CONCLUSIONS: Results from the study conclude that stress increases the likelihood of eliciting an epileptic attack by increasing the level of reactive oxygen species and neuroinflammation.

AI-driven drug discovery: Exploring Abaucin as a promising treatment against multidrug-resistant Acinetobacter baumannii.

Background and Aims: This study presents a comprehensive overview of a well-recognized critical pathogen Acinetobacter baumannii and demonstrates the potential of artificial intelligence (AI) in discovering new antibiotics. It is well-known for causing serious infections, especially in patients admitted to intensive care units, which is further compromised by bacterium's resistance to even last-resort antibiotics like carbapenems, posing critical challenges in its treatment and eradication. This article discusses Abaucin, a revolutionary antibiotic created from artificial intelligence, as a creative and potential treatment for A. baumannii. Methods: A comprehensive literature search was conducted using various databases including PubMed, Google Scholar, Cochrane, Science Direct, MEDLINE. Only articles written in English were considered. This correspondence was written after a thorough evaluation of all the articles that discussed Abaucin's discovery, potency against A. baumannii, and the potential of AI in discovering new antibiotics. In addition, references from the selected articles were also examined to ensure a comprehensive review of the literature. Results: This article highlights the discovery of a novel AI-derived antibiotic, Abaucin that offers a promising solution for A. baumannii infections. Abaucin has a narrow range of action that minimizes the risk of inter-pathogen spread of resistance, making the drug more appealing and effective. Its potential to suppress wound infections caused by multidrug-resistant A. baumannii paves a hope for the eradication of superbugs. Further investigation and trials are needed to determine its effectiveness in human subjects and its integrity in the clinical workflow. machine learning (ML) and precision approach could revolutionize treatment strategies. Conclusion: The discovery of Abaucin as an antibiotic to combat drug-resistant A. baumannii bacteria showcases AI and ML's potential to uncover novel antibiotics, thereby offering alternative treatment options. This novel inception of the AI-derived antibiotic, Abaucin marks the first step in introducing an innovative treatment option and represents a substantial leap in the treatment of drug-resistant illnesses and the use of AI in medical advancements.

Microplastic accumulation in groundwater: Data-scaled insights and future research.

Given that microplastics (MPs) in groundwater have been concerned for risks to humans and ecosystems with increased publications, a Contrasting Analysis of Scales (CAS) approach is developed by this study to synthesize all existing data into a hierarchical understanding of MP accumulation in groundwater. Within the full data of 386 compiled samples, the median abundance of MPs in Open Groundwater (OG) and Closed Groundwater (CG) were 4.4 and 2.5 items/L respectively, with OG exhibiting a greater diversity of MP colors and larger particle sizes. The different pathways of MP entry (i.e., surface runoff and rock interstices) into OG and CG led to this difference. At the regional scale, median MP abundance in nature reserves and landfills were 17.5 and 13.4 items/L, respectively, all the sampling points showed high pollution load risk. MPs in agricultural areas exhibited a high coefficient of variation (716.7%), and a median abundance of 1.0 items/L. Anthropogenic activities at the regional scale are the drivers behind the differentiation in the morphological characteristics of MPs, where groundwater in residential areas with highly toxic polymers (e.g., polyvinylchloride) deserves prolonged attention. At the local scale, the transport of MPs is controlled by groundwater flow paths, with a higher abundance of MP particles downstream than upstream, and MPs with regular surfaces and lower resistance (e.g., pellets) are more likely to be transported over long distances. From the data-scaled insight this study provides on the accumulation of MPs, future research should be directed towards network-based observation for groundwater-rich regions covered with landfills, residences, and agricultural land.

Comparative pharmacokinetic evaluation of glimepiride orodispersable and conventional tablets in rabbits.

OBJECTIVES: Glimepiride Orodispersable Tablets (ODT) were prepared with the goal to have rapid onset of action and higher bioavailability with ease administration to individuals with swallowing difficulty to ameliorate patient compliance. SIGNIFICANCE: Glimepiride is a contemporary hypoglycemic medication that belongs to the family of sulfonylurea derivatives. It is used in type 2 diabetes mellitus. Compliance adherence remains one of the limitations with the conventional drug delivery system especially in pediatric, geriatric, psychiatric, and traveling patients, for such population ODT provides a good alternate dosage form compared with Commercial Tablets. METHOD: The Comparative in vivo pharmacokinetic parameters of the prepared ODT and conventional tablets (CT) were evaluated using an animal model. The plasma concentration of Glimepiride after oral administration of a single dose was determined at predetermined time intervals with HPLC. The pharmacokinetic parameters were calculated using PK Solutions 2.0 from Summit PK® software. RESULTS: The Cmax obtained with ODT (22.08 µg/ml) was significantly (p = 0.006) high, a lower tmax of 3.0 hr was achieved with the orodispersable formulation of the drug. The ODT showed 104.34% relative bioavailability as compared to CT and left shift of tmax as well. CONCLUSION: As per findings of the in vivo investigation, the Glimepiride ODT would be beneficial in terms of patient compliance, quick onset of action, and increased bioavailability.

Tamoxifen-Loaded Eudragit Nanoparticles: Quality by Design Approach for Optimization of Nanoparticles as Delivery System.

Nanoparticles have numerous applications as drug carriers in drug delivery. The aim of the study was to produce tamoxifen nanoparticles with a defined size and higher encapsulation for efficient tissue uptake with controlled drug release. The quality by design approach was utilized to produce tamoxifen-loaded Eudragit nanoparticles by identifying the significant process variables using the nanoprecipitation method. The process variables (amount of drug, polymer, and surfactant) were altered to analyze the influence on particle size (PS), % encapsulation efficiency (EE). The results showed that the drug and polymer individually as well as collectively have an impact on PS, while the surfactant has no impact on the PS. The %EE was influenced by the surfactant individually and in interaction with the drug. The linear regression model was endorsed to fit the data showing high R2 values (PS, 0.9146, %EE, 0.9070) and low p values (PS, 0.0004, EE, 0.0005). The PS and EE were confirmed to be 178 nm and 90%, respectively. The nanoparticles were of spherical shape, as confirmed by SEM and TEM. The FTIR confirmed the absence of any incompatibility among the ingredients. The TGA confirmed that the NPs were thermally stable. The in vitro release predicted that the drug release followed Higuchi model.

Transdermal Delivery of Glimepiride: A Novel Approach Using Nanomicelle-Embedded Microneedles.

Glimepiride (GM) is a hydrophobic drug that dissolves slowly and yields inconsistent clinical responses after oral administration. Transdermal drug delivery (TDD) is an appropriate alternative to oral administration. Microneedles (MNs) offer a promising delivery system that penetrates the skin, while polymeric micelles can enhance the solubility; hence, the combination of both results in high drug bioavailability. This study aims to improve glimepiride's solubility, dissolution rate, and bioavailability by incorporating nanomicelles into MNs for TDD. The nanomicelles formulated with 10% Soluplus® (SP) and 40% GM had a mean particle size of 82.6 ± 0.54, PDI of 0.1 ± 0.01, -16.2 ± 0.18 zeta potential, and achieved a 250-fold increase in solubility. The fabricated pyramid shaped GM-dissolving MNs were thermally stable and had no formulation incompatibility, as confirmed by thermal and FTIR analysis. The in vitro dissolution profile revealed that the GM release from nanomicelles and nanomicelle-loaded DMN was concentration-independent following non-Fickian transport mechanism. Improved pharmacokinetic parameters were obtained with dose of 240 µg as compared to 1 mg of GM oral tablet, in healthy human volunteers. The observed Cmax, Tmax and MRT were 1.56 µg/mL ± 0.06, 4 h, and 40.04 h ± 3.37, respectively. The safety profile assessment indicated that microneedles are safe with no adverse effects on skin or health. This study provides an alternative delivery system for the administration of glimepiride, resulting in improved bioavailability, enhanced patient compliance, and reduced dosing frequency.

Vaccine Adjuvants: Selection Criteria, Mechanism of Action Associated with Immune Responses and Future Directions.

The most effective method to minimize the prevalence of infectious diseases is vaccination. Vaccines enhance immunity and provide protection against different kinds of infections. Subunit vaccines are safe and less toxic, but due to their lower immunogenicity, they need adjuvants to boost the immune system. Adjuvants are small particles/molecules integrated into a vaccine to enhance the immunogenic feedback of antigens. They play a significant role to enhance the potency and efficiency of vaccines. There are several types of adjuvants with different mechanisms of action; therefore, improved knowledge of their immunogenicity will help develop a new generation of adjuvants. Many trials have been designed using different kinds of vaccine adjuvants to examine their safety and efficacy, but in practice, only a few have entered in animal and human clinical trials. However, for the development of safe and effective vaccines, it is important to have adequate knowledge of the side effects and toxicity of different adjuvants. The current review discussed the adjuvants which are available for producing modern vaccines as well as some new classes of adjuvants in clinical trials.

First insight into the occurrence, spatial distribution, sources, and risks assessment of antibiotics in groundwater from major urban-rural settings of Pakistan.

Antibiotics contamination in the water environment is a high priority global concern. Growing levels of antibiotics in freshwater resources, especially groundwater, due to anthropogenic sources such as pharmaceutical and veterinary applications, are alarming. The present study aims to investigate the occurrence, spatial distribution, source apportionment, ecological, and human health risks of antibiotics (n = 23) in groundwater samples (n = 144) of highly populated cities of Pakistan. The elevated level of antibiotics was detected in Faisalabad with the mean concentrations of 13.8 ng/L, followed by Gujrat (7.8 ng/L), Lahore (4.04 ng/L), Quetta 3.9 ng/L, Rawalpindi/Islamabad (2.29 ng/L), and Peshawar (2.03 ng/L), respectively. Out of 23 investigated antibiotics, tigecycline and ciprofloxacin were predominantly present in groundwater with average concentrations of 21.3 ng/L and 18.2 ng/L, respectively. The spatial distribution analyses revealed that among the targeted cities, Faisalabad, an industrial hub of the country, had the most polluted groundwater with dominant classes of antibiotics including quinolones (except flumequine), ß-Lactams, tetracyclines, sulfonamides, and amphenicols, implying an elevated consumption of human and veterinary drugs in the city. The occurrence of targeted antibiotics varied greatly among cities (p < 0.05). PCA-MLR analysis confirmed domestic discharge (31%), animal husbandry (19%), and pharmaceutical/hospital discharge (48%) as the chief contributors to antibiotics contamination in groundwater of Faisalabad. The risk quotient (RQ) values of targeted antibiotics were reported as 1.16E-07 to 1.03E-02, and demonstrated that antibiotics pose no risks to human health, while hazard quotient (HQ) values were observed as 09.5E-05 to 6.6E-01, and only ciprofloxacin, flumequine, oxytetracycline, and sulfamethoxazole revealed moderate to low ecological risks to water species (0.1 < HQ < 1). Since, no detailed study has been conducted to evaluate the antibiotics' contamination in groundwater of Pakistan, this robust investigation provides a way forward to further explore the environmental and human health implications of antibiotics in major urban-rural settings in the region.

Antibiotics and antibiotic resistant genes (ARGs) in groundwater: A global review on dissemination, sources, interactions, environmental and human health risks.

The discovery and evolution of antibiotics for humans and animals are among the most significant milestones of the 20th century. However, antibiotics play a significant role in the induction and dissemination of antibiotic resistance genes (ARGs) in groundwater that has recently become the primary environmental concern. They are administrated to humans and animals on a large scale and are persistent in the environment. Long term impacts of antibiotics in the ecological environment are not still clearly understood, and their occurrence and consequences have become an important research topic worldwide. The hotspot reservoirs of antibiotics and ARGs include medical facilities, livestock farming, aquaculture, landfills, on-site sanitation systems, sewage, and wastewater treatment plants. Our meta-analysis demonstrated that antibiotics, including ciprofloxacin, sulfamethoxazole, erythromycin, and tetracycline were found at high concentrations while sulfonamide and tetracycline ARGs were more prevalent in groundwater. Moreover, the highest reported concentrations of targeted antibiotics were used to calculate hazard quotient (HQ) and risk quotient (RQ) in global groundwater bodies to estimate environmental and human health risks, respectively. Due to limited available ecotoxicity data, RQ and HQ can only be calculated for a few antibiotics in groundwater. The risk assessment of antibiotics demonstrated that antibiotics with their current groundwater levels pose no human health risks, whereas only ciprofloxacin, erythromycin, flumequine, and sulfamethoxazole revealed moderate to low risks to aquatic species. The occurrence of ARGs and antibiotic resistant bacteria (ARBs) in groundwater is also not likely to pose human health risk but consumption of groundwater contaminated with ARGs and ARBs might contribute to the development of antibiotic resistance in humans. The present review also sheds light on the relationship between ARGs, antibiotics, microbial communities, and environmental factors in groundwater, and reported a significant correlation between them. It also addresses prospects for future outlooks into further areas of relevant research.

BioFed: federated query processing over life sciences linked open data.

BACKGROUND: Biomedical data, e.g. from knowledge bases and ontologies, is increasingly made available following open linked data principles, at best as RDF triple data. This is a necessary step towards unified access to biological data sets, but this still requires solutions to query multiple endpoints for their heterogeneous data to eventually retrieve all the meaningful information. Suggested solutions are based on query federation approaches, which require the submission of SPARQL queries to endpoints. Due to the size and complexity of available data, these solutions have to be optimised for efficient retrieval times and for users in life sciences research. Last but not least, over time, the reliability of data resources in terms of access and quality have to be monitored. Our solution (BioFed) federates data over 130 SPARQL endpoints in life sciences and tailors query submission according to the provenance information. BioFed has been evaluated against the state of the art solution FedX and forms an important benchmark for the life science domain. METHODS: The efficient cataloguing approach of the federated query processing system 'BioFed', the triple pattern wise source selection and the semantic source normalisation forms the core to our solution. It gathers and integrates data from newly identified public endpoints for federated access. Basic provenance information is linked to the retrieved data. Last but not least, BioFed makes use of the latest SPARQL standard (i.e., 1.1) to leverage the full benefits for query federation. The evaluation is based on 10 simple and 10 complex queries, which address data in 10 major and very popular data sources (e.g., Dugbank, Sider). RESULTS: BioFed is a solution for a single-point-of-access for a large number of SPARQL endpoints providing life science data. It facilitates efficient query generation for data access and provides basic provenance information in combination with the retrieved data. BioFed fully supports SPARQL 1.1 and gives access to the endpoint's availability based on the EndpointData graph. Our evaluation of BioFed against FedX is based on 20 heterogeneous federated SPARQL queries and shows competitive execution performance in comparison to FedX, which can be attributed to the provision of provenance information for the source selection. CONCLUSION: Developing and testing federated query engines for life sciences data is still a challenging task. According to our findings, it is advantageous to optimise the source selection. The cataloguing of SPARQL endpoints, including type and property indexing, leads to efficient querying of data resources over the Web of Data. This could even be further improved through the use of ontologies, e.g., for abstract normalisation of query terms.