Thymol as a Component of Chitosan Systems-Several New Applications in Medicine: A Comprehensive Review.

Thymol, a plant-derived monoterpene phenol known for its broad biological activity, has often been incorporated into chitosan-based biomaterials to enhance therapeutic efficacy. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we conducted a systematic literature review from 2018 to 2023, focusing on the biomedical implications of thymol-loaded chitosan systems. A review of databases, including PubMed, Scopus, and Web of Science was conducted using specific keywords and search criteria. Of the 90 articles, 12 were selected for the review. Thymol-loaded chitosan-based nanogels (TLCBS) showed improved antimicrobial properties, especially against multidrug-resistant bacterial antagonists. Innovations such as bipolymer nanocarriers and thymol impregnated with photosensitive chitosan micelles offer advanced bactericidal strategies and show potential for bone tissue regeneration and wound healing. The incorporation of thymol also improved drug delivery efficiency and biomechanical strength, especially when combined with poly(dimethylsiloxane) in chitosan-gelatin films. Thymol-chitosan combinations have also shown promising applications in oral delivery and periodontal treatment. This review highlights the synergy between thymol and chitosan in these products, which greatly enhances their therapeutic efficacy and highlights the novel use of essential oil components. It also highlights the novelty of the studies conducted, as well as their limitations and possible directions for the development of integrated substances of plant and animal origin in modern and advanced medical applications.

Monitoring stability indicating impurities and aldehyde content in lipid nanoparticle raw material and formulated drugs.

Lipid nanoparticles (LNPs) are designed to protect and transport sensitive payloads or active pharmaceutical ingredients as part of new therapeutic modalities. As a multi-component particle, a high degree of quality control is necessary to ensure raw materials are free of critical impurities that could adversely impact the drug product. In this study, we demonstrate a reversed phase liquid chromatography method hyphenated with a single quadrupole mass spectrometer (RPLC-MS) as an alternative platform to methods that incorporate evaporative light scattering or charged aerosol detectors in the detection and quantitation of critical impurities associated with LNPs. The proposed RPLC-MS method offers an increase of up to 2 orders of magnitude in dynamic range and 3 orders of magnitude in sensitivity in the analysis of impurities associated with LNPs compared to conventional detectors. Access to complementary mass data enabled the detection and identification of stability indicating impurities as part of stress studies carried out on an ionizable lipid. In addition to confirmation of peak identity, complementary mass data was also used to assess residual aldehydes in raw material and formulated LNPs in accordance with regulatory guidance. Following derivatization using 2,4-dinitrophenylhydrazine, aldehyde content in the ionizable lipid raw material was determined to exceed the reporting threshold of 0.05% in 30% of the test cases. The experimental findings observed in this study demonstrate the utility of the proposed RPLC-MS method in the identification and monitoring of stability-indicating attributes associated with LNPs as part of current Good Manufacturing Practices for improved consumer safety in drug products.

Image-guided high-dose-rate brachytherapy as the method of choice in medically inoperable early-stage endometrial cancer patients.

PURPOSE: About 3-9% of patients with endometrial cancer are unable to undergo surgery due to medical comorbidities, including morbid obesity, or age-related frailty syndrome. An alternative curative option is irradiation. The aim of this prospective study was to evaluate clinical outcomes of high-dose-rate intracavitary brachytherapy (HDR-ICBT) treatment in such patients. MATERIALS AND METHODS: Seventy-eight patients with FIGO stage I-II endometrial cancer disqualified from surgery were treated with HDR-ICBT with 45-52,5 Gy prescribed to high-risk clinical target volume (HR-CTV) in 5-9 fractions given once a week. All fractions were planned using computed tomography (CT) scans. RESULTS: The median follow-up time was 67 months. Median age was 79 years (range: 42-93 years). Median body mass index (BMI) was 39,1 kg/m2 (range: 24,2-68 kg/m2). We observed no statistically significant impact of BMI ≥ 40 on overall survival (OS) or prgression free survival (PFS). The 3- and 5-year OS for the whole population were 69% and 55%, respectively. The impact of high risk features (FIGO II, grade 3 or type 2 cancer) on OS was significant (p = 0,049). The 5-year cumulative incidence of local failure, distant metastases and non-cancer death were 12,9% [95% CI: 5,4%-20,5%], 6,4% [95% CI: 0,9%-11,9%], 33,1% [95% CI: 22,3%-43,9%], respectively. The 5-year risk of cancer and non-cancer death were 9% (95% CI: 3%-16%) and 36% (95% CI: 25%-47%), respectively. We observed G1 vaginal apex stenosis only. CONCLUSIONS: CT-guided HDR-ICBT is a feasible and safe management of FIGO stage I endometrial cancer in obese and elderly patients. The survival outcome of the treated group is influenced more by associated comorbidities than by the progression of endometrial cancer.

Comparison of double-phase hologram and binary amplitude encoding: holographic projection and vortex beam generation.

Utilizing computer-generated holograms is a promising technique because these holograms can theoretically generate arbitrary waves with high light efficiency. In phase-only spatial light modulators, encoding complex amplitudes into phase-only holograms is a significant issue, and double-phase holograms have been a popular encoding technique. However, they reduce the light efficiency. In this study, our complex amplitude encoding, called binary amplitude encoding (BAE), and conventional methods including double-phase hologram, iterative algorithm, and error diffusion methods were compared in terms of the fidelity of reproduced light waves and light efficiency, considering the applications of lensless zoomable holographic projection and vortex beam generation. This study also proposes a noise reduction method for BAE holograms that is effective when the holograms have different aspect ratios. BAE is a non-iterative method, which allows holograms to be obtained more than 2 orders of magnitude faster than iterative holograms; BAE has about 3 times higher light efficiency with comparable image quality compared to double-phase holograms.

In Vitro Antiglycation and Methylglyoxal Trapping Effect of Peppermint Leaf (Mentha × piperita L.) and Its Polyphenols.

The most significant reactive α-dicarbonyl RCS involved in the pathomechanism of glycation and related diseases is methylglyoxal (MGO). Hyperglycemia promotes the generation of MGO and leads to the formation of advanced glycation end products (AGEs). Therefore, MGO trapping and glycation inhibition appear to be important therapeutic targets in prediabetes, diabetes, and in the early prevention of hyperglycemic complications. Peppermint leaf is commonly used as herbal tea, rich in polyphenols. Eriocitrin, its predominant component, in a double-blind, randomized controlled study reversed the prediabetic condition in patients. However, the antiglycation activity of this plant material and its polyphenols has not been characterized to date. Therefore, the aim of this study was to evaluate the ability of a peppermint leaf dry extract and its polyphenols to inhibit non-enzymatic protein glycation in a model with bovine serum albumin (BSA) and MGO as a glycation agent. Peppermint polyphenols were also evaluated for their potential to trap MGO in vitro, and the resulting adducts were analyzed by UHPLC-ESI-MS. To relate chemical composition to glycation inhibitory activity, the obtained peppermint extract was subjected to qualitative and quantitative analysis. The capability of peppermint leaf polyphenols to inhibit glycation (27.3-77.2%) and form adducts with MGO was confirmed. In the case of flavone aglycones, mono- and di-adducts with MGO were observed, while eriodictyol and eriocitrin effectively produced only mono-adducts. Rosmarinic acid and luteolin-7-O-glycosides did not reveal this action. IC50 of the peppermint leaf dry extract was calculated at 2 mg/mL, equivalent to a concentration of 1.8 µM/mL of polyphenols, including ~1.4 µM/mL of flavonoids and ~0.4 µM/mL of phenolic acids. The contribution of the four major components to the anti-AGE activity of the extract was estimated at 86%, including eriocitrin 35.4%, rosmarinic acid 25.6%, luteolin-7-O-rutinoside 16.9%, luteolin-7-O-ß-glucuronoside 8.1%, and others 14%. The effect of peppermint dry extract and polyphenols in inhibiting MGO-induced glycation in vitro was comparable to that of metformin used as a positive control.

Headspace Solid-Phase Micro-Extraction Versus Hydrodistillation of Volatile Compounds from Leaves of Cultivated Mentha Taxa: Markers of Safe Chemotypes.

Various mint taxa are widely cultivated and are used not only for medicinal purposes but also in cosmetic and industrial applications. The development of new varieties or cultivars of mint generates difficulties in their correct identification and safe use. Volatile organic compounds (VOCs) from the leaves of seven different taxa of the genus Mentha obtained by hydrodistillation (HD) and headspace solid-phase microextraction (HS-SPME) were analyzed using gas chromatography-mass spectrometry (GC-MS). Principal component analysis (PCA) was also performed. Comparative GC-MS analysis of the obtained extracts showed similarity in the major compounds. PCA data allowed the separation of two groups of chemotypes among the analyzed mints, characterized by the abundance of piperitenone oxide and carvone. Two out of seven analyzed taxa were not previously examined for VOC profile, one was examined only for patent application purposes, and six out of seven were investigated for the first time using the HS-SPME technique. The presented analysis provides new data on the abundance and qualitative characterization of VOCs in the studied mint plants and on the safety of their use, related to the possibility of the presence of potentially toxic components. HS-SPME is a valuable method to extend the characterization of the VOC profile obtained by hydrodistillation.

Stability of Rosmarinic Acid and Flavonoid Glycosides in Liquid Forms of Herbal Medicinal Products-A Preliminary Study.

Peppermint leaf, sage leaf, thyme herb, and their preparations are common components of herbal medicinal products (HMPs). According to the European Pharmacopoeia guidelines, the above-mentioned plant substances are standardized for the content of essential oils, omitting polyphenols, which also have a significant impact on their activities. The aim of this study was to evaluate the stability of the predominant polyphenols-rosmarinic acid, luteolin-7-O-ß-glucuronide, and eriocitrin-in selected commercial liquid HMPs containing thyme, sage, and peppermint under long-term, intermediate, and accelerated testing conditions. Qualitative and quantitative analyses of these polyphenols were performed by the previously optimized and validated HPLC-DAD method. Rosmarinic acid stability was better in hydroethanolic than in an aqueous solution. The effect of the solvent on the stability of luteolin-7-O-ß-glucuronide and eriocitrin could not be determined and requires further investigation. The present study is the first to analyze the stability of these compounds in commercial herbal medicinal products. The expiration dates proposed by the manufacturers of the tested HMPs did not guarantee stable levels of all analyzed polyphenols throughout the stated period. However, this study is preliminary and requires continuation on a larger number of medicinal products.

Suppression of spurious image duplicates in Fourier holograms by pixel apodization of a spatial light modulator.

Holographic projectors and near-eye displays are a promising technology with truly three-dimensional, natural viewing and excellent energetic efficiency. Spatial light modulators with periodic pixel matrices cause image duplicates, which distract the viewer and waste energy of the playback beam. We present the engineering of the far field intensity envelope, which suppresses higher-order image duplicates in the simplest possible optical setup by physically changing the shape of modulator pixels with attached apodizing masks. Numerical and experimental results show the limited number of perceived duplicates and better uniformity in off-axis projections for the price of compromised energetic efficiency due to amplitude masks.

LC-ESI/LTQ-Orbitrap-MS Based Metabolomics in Evaluation of Bitter Taste of Arbutus unedo Honey.

Strawberry tree honey is a high-value honey from the Mediterranean area and it is characterised by a typical bitter taste. To possibly identify the secondary metabolites responsible for the bitter taste, the honey was fractionated on a C18 column and the individual fractions were subjected to sensory analysis and then analysed by liquid chromatography coupled with high-resolution tandem mass spectrometry in negative ion mode, using a mass spectrometer with an electrospray source coupled to a hybrid high resolution mass analyser (LC-ESI/LTQ-Orbitrap-MS). A chemometric model obtained by preliminary principal component analysis (PCA) of LC-ESI/LTQ-Orbitrap-MS data allowed the identification of the fractions that caused the perception of bitterness. Subsequently, a partial least squares (PLS) regression model was built. The studies carried out with multivariate analysis showed that unedone (2-(1,2-dihydroxypropyl)-4,4,8-trimethyl-1-oxaspiro [2.5] oct-7-en-6-one) can be considered responsible for the bitter taste of strawberry tree honey. Confirmation of the bitter taste of unedone was obtained by sensory evaluation of a pure standard, allowing it to be added to the list of natural compounds responsible for giving the sensation of bitterness to humans.

Thymol and Thyme Essential Oil-New Insights into Selected Therapeutic Applications.

Thymol (2-isopropyl-5-methylphenol) belongs to the phenolic monoterpenes and mostly occurs in thyme species. It is one of the main compounds of thyme essential oil. Both thymol and thyme essential oil have long been used in traditional medicine as expectorant, anti-inflammatory, antiviral, antibacterial, and antiseptic agents, mainly in the treatment of the upper respiratory system. The current search for new directions of biological or therapeutic activities of natural plant substances with known structures includes thyme essential oil and thymol. Novel studies have demonstrated their antibiofilm, antifungal, antileishmanial, antiviral, and anticancer properties. Also, their new therapeutic formulations, such as nanocapsules containing these constituents, can be beneficial in medicinal practice and create opportunities for their extensive use. Extensive application of thymol and thyme essential oil in the healthcare sector is very promising but requires further research and analysis.

Improved HLA-based prediction of coeliac disease identifies two novel genetic interactions.

Human Leucocyte Antigen (HLA) testing is useful in the clinical work-up of coeliac disease (CD) with high negative but low positive predictive value. We construct a genomic risk score (GRS) using HLA risk genotypes to improve CD prediction and guide exclusion criteria. Imputed HLA genotypes for five European CD case-control GWAS (n > 15,000) were used to construct and validate an interpretable HLA-based risk model (HDQ15), which shows statistically significant improvements in predictive performance upon all previous HLA-based risk models. Conditioning on this model, we find two novel associations, HLA-DQ6.2 and HLA-DQ7.3, that interact significantly with HLA-DQ2.5 (p = 2.51 × 10-9, 1.99 × 10-7, respectively). Integrating these novel alleles into a new risk model (HDQ17) leads to predictive performance equivalent or better than the strongest reported GRS (GRS228) using 228 single nucleotide polymorphisms (SNPs). We also demonstrate that our proposed HLA-based models can be implemented using only six HLA tagging SNPs with statistically equivalent predictive performance. Using insights from our model to guide exclusionary criteria, we find the positive predictive value of CD testing in high-risk populations can be increased by 55%, from 17.5 to 27.1%, while maintaining a negative predictive value above 99%. Our results suggest that HLA typing is currently undervalued in CD assessment.

Dosimetric evaluation of vaginal cuff brachytherapy planning in cervical and endometrial cancer patients.

PURPOSE: The aim of the study was to perform a prospective analysis of dosimetric consequences of rectal enema administration before vaginal cuff brachytherapy (VCB), the dose distribution in organs at risk (OARs), and the presence of air gaps (AGs) in patients with cervical or endometrial cancer. MATERIAL AND METHODS: In total, 75 patients treated in 2019 were randomly divided into two groups including 38 patients with and 37 without an enema before VCB. All patients received post-operative high-dose-rate (HDR). Single-channel vaginal cylinders with active length of 2.75 cm were used. Prescription dose was 7 Gy at 5 mm depth from the applicator surface in all directions. Treatment plans were based on computed tomography (CT). RESULTS: Enema performed before cylinder insertion had no effect on rectosigmoid Dmax or D2cm3. Rectosigmoid median V100 was 0.5 cm3 (range, 0-2.7 cm3). V100 ≥ 1 cm3 in 22 and ≥ 2 cm3 in 6 patients, with Dmax up to 19.7 Gy (282%) were observed. No effect of bladder volume in the range of 27-256 cm3 on Dmax or D2cm3 was found. The median bladder V100 was 0.1 cm3 (range, 0-1.4 cm3). There were 62 (83%) patients with AGs, with 24% at the top of the vagina and 75% on the remaining length of the vagina. Most of the AGs were small (≤ 3 mm), but in 5 (8%) cases, they were bigger than 5 mm. CONCLUSIONS: VCB planning with the use of CT is essential. CT can facilitate the selection of optimal cylinder size to reduce the occurrence of large AGs. A few percent of plans require correction of dose distribution because of hot spots in OARs and the presence of AGs. Enema before cylinder insertion does not influence rectosigmoid Dmax and D2cm3. The analysis revealed no bladder volume effect on bladder doses Dmax and D2cm3.

Evaluation of bioactive compounds and antioxidant capacity of edible feijoa (Acca sellowiana (O. Berg) Burret) flower extracts.

ABSTRACT: The research aimed to evaluate the polyphenolic composition and the antioxidant capacity of edible extracts of feijoa (Acca sellowiana (O. Berg) Burret) flowers. Phenolic compounds of whole feijoa flower (FM), feijoa petals (PM) and feijoa petals juice (PJ) were identified by high-performance liquid chromatography coupled with electrospray mass spectrometry and quantified by liquid chromatography coupled with ultraviolet/visible detection. Moreover, the total polyphenol (TP) content was measured spectrophotometrically and the antioxidant capacities of the extracts were evaluated by FRAP, CUPRAC, DPPH·, and ABTS·+ assays. The FM showed TP content (395.14 ± 7.91 mg GAE/L) higher than PM and PJ, and exhibited better antioxidant capacities. FM extracts were characterized by the high content of anthocyanins (115.3 ± 3.6 mg/L), flavonols (42.9 ± 3.3 mg/L) and the presence of ellagic acid (7.9 ± 0.2 mg/L) and other galloyltannins. In addition, cyanidin-3-O-glucoside and apigenin were detected in all the three extracts. The present study provided an overview on particular bioactive compounds that characterise different parts of edible feijoa flowers. Among the latter, FM proved to be the most suitable for exploitation in the food and health manufactory.

Analysis of Polyphenolic Composition of a Herbal Medicinal Product-Peppermint Tincture.

The pharmacological activity of peppermint leaf (Menthae piperitae folium) for medical use is mainly attributed to the presence of essential oil, which, according to the European Pharmacopoeia (Ph. Eur.), should constitute not less than 12 mL/kg of raw material. The content of polyphenols in peppermint-based preparations, except peppermint leaf dry extract, has not yet been considered as an essential parameter in the pharmacopeial assessment of peppermint quality. This study concerns the evaluation of the presence of representatives of polyphenolic compounds in 23 commercial peppermint tinctures (ethanolic extracts) purchased in pharmacies in Poland. The non-volatile polyphenolic fraction was investigated, and the presence of flavonoids and phenolic acids was quantified. High performance liquid chromatography coupled with a diode-array detector (HPLC-DAD) and an electrospray ionization mass spectrometer (U(H)PLC-ESI-MS) were used in the experiment. The study showed that eriocitrin, luteolin-7-O-rutinoside, and rosmarinic acid were the main polyphenolic components of the peppermint tinctures, as previously reported for peppermint leaf. Despite this, the research shows the extremely diverse content of the mentioned compounds in analyzed commercial medicinal products. In light of these results, it seems that the pharmacopeial assessment for the peppermint leaf (Ph. Eur.) and peppermint tincture (Polish Pharmacopoeia (FP)) requires correction and supplementation.

Exploring effective approaches for haplotype block phasing.

BACKGROUND: Knowledge of phase, the specific allele sequence on each copy of homologous chromosomes, is increasingly recognized as critical for detecting certain classes of disease-associated mutations. One approach for detecting such mutations is through phased haplotype association analysis. While the accuracy of methods for phasing genotype data has been widely explored, there has been little attention given to phasing accuracy at haplotype block scale. Understanding the combined impact of the accuracy of phasing tool and the method used to determine haplotype blocks on the error rate within the determined blocks is essential to conduct accurate haplotype analyses. RESULTS: We present a systematic study exploring the relationship between seven widely used phasing methods and two common methods for determining haplotype blocks. The evaluation focuses on the number of haplotype blocks that are incorrectly phased. Insights from these results are used to develop a haplotype estimator based on a consensus of three tools. The consensus estimator achieved the most accurate phasing in all applied tests. Individually, EAGLE2, BEAGLE and SHAPEIT2 alternate in being the best performing tool in different scenarios. Determining haplotype blocks based on linkage disequilibrium leads to more correctly phased blocks compared to a sliding window approach. We find that there is little difference between phasing sections of a genome (e.g. a gene) compared to phasing entire chromosomes. Finally, we show that the location of phasing error varies when the tools are applied to the same data several times, a finding that could be important for downstream analyses. CONCLUSIONS: The choice of phasing and block determination algorithms and their interaction impacts the accuracy of phased haplotype blocks. This work provides guidance and evidence for the different design choices needed for analyses using haplotype blocks. The study highlights a number of issues that may have limited the replicability of previous haplotype analysis.

Image-guided high-dose-rate brachytherapy for prostate cancer patients with previous rectal resection and pelvic irradiation: feasibility study.

PURPOSE: The aim of this study was to describe treatment procedure and early clinical outcomes of high-dose-rate (HDR) interstitial brachytherapy (BT) in clinically localized prostate cancer patients previously treated for rectal cancer with abdominoperineal rectal resection and external beam radiation therapy (EBRT). MATERIAL AND METHODS: Between February and July 2015, two patients with clinically localized prostate cancer without rectal access were treated in our brachytherapy department. HDR interstitial brachytherapy was conducted with the guidance of fluoroscopy and computed tomography (CT) imaging. Brachytherapy was combined with hormonal therapy. RESULTS: Follow-up lasted for 34 and 39 months for patient 1 and 2, respectively. Both patients remained free from biochemical recurrence according to the Phoenix definition. No severe G3/G4 late toxicity was observed, and neither patient experienced any gastrointestinal morbidity. Acute and late urinary toxicities were at an acceptance level, and were scored G1 and G2 for patient 1, and G3 and G1 for patient 2, respectively. CONCLUSIONS: Fluoroscopy and 3D CT image-guided interstitial brachytherapy is feasible and appears to be a suitable treatment technique for patients with clinically localized prostate cancer after previous rectal resection and external beam radiation therapy.

Miniature holographic projector with cloud computing capability.

A fully functional miniaturized projection head below 5 cm3 is presented, using computer-generated holograms dynamically displayed on a liquid-crystal spatial light modulator. Spatial division of the modulator is used for color projection without color breakup, and specially designed, anti-reflection coated prisms ensure simple light paths with small losses. Real-time calculations are performed on a remote server with on-the-fly compression of holographic fringes. Cloud computing allows 1 W of local electrical power usage and apparent image brightness equivalent to 15-500 lm/W efficiency, depending on the displayed content. The properties of the projector allow future applications in handheld displays.

Analysis of the long-term stability of the output of electron beams generated by the Novac11™ IORT accelerator.

AIM: The aim of the study was to analyze the long-term stability of electron beams generated by the Novac11™ IORT accelerator. BACKGROUND: Novac11™ (NRT®) is a mobile electron accelerator designed to irradiate small areas of tissue, up to 10 cm in diameter, with electron beams during surgical procedures. It is characterized by a great mobility guaranteed by a number of degrees of freedom enabling irradiation in the conditions of an operating theatre. MATERIALS AND METHODS: Over the period of January 2013 and September 2016, the measurement sessions of the output of clinically used beam qualities (6, 8 and 10 MeV) were carried out 41 times. Because of the unsatisfactory long-term stability, an extra procedure of tuning of the magnetron, suggested by the manufacturer, was introduced in October 2015, 15 measurements were performed since then. The output of the Novac11™ accelerator was measured in the reference conditions recommended by the IAEA Report 398, the measurements of the charge in the ionization chamber at the reference depth were carried out with a Dose1™ electrometer and a plane-parallel chamber PPC05™ from IBA®. RESULTS: The introduction of the tuning of the magnetron procedure resulted in satisfactory long-term stability of the measured outputs below 2%. CONCLUSIONS: After the introduction of the STV parameter tuning procedure, the long-term stability of the Novac11™ output increased considerably and is within the values declared by the manufacturer.

Collective matrix of spatial light modulators for increased resolution in holographic image projection.

We present a method to increase the resolution of holographically projected images by the use of a collective matrix of two phase-only spatial light modulators. As a result of fine alignment and common coherent illumination of the modulators, a synthetic aperture is formed with a doubled number of active pixels. In this paper we present theoretical analysis and numerical simulations which stand in good agreement for different distances between the apertures of modulators. We have achieved experimentally controlled field interference from both modulators on the projection screen, exhibiting increased resolution in one spatial direction and residual effects of the dead space between modulators. Then we have proved numerically possibility to extend our approach on bigger synthetic apertures consisted of more than two modulators.