Search Results (21)

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food–drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food–drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions. Full article

Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article

Germinated brown rice (GBR), rich in high starch content and bioactive compounds, has excellent gel-forming properties, rendering it highly promising for applications in food 3D printing, a cutting-edge personalized manufacturing technology. This study systematically investigates the effects of different concentrations of konjac glucomannan (KGM) and curdlan (CD) blends on the 3D printing performance and physicochemical properties of GBR gel. The results indicated that the appropriate addition of KGM/CD blends significantly enhances the printing accuracy and shape retention of GBR gel. Specifically, under the KGM to CD ratio of 3:1 (KC3) formulation obtained by combining 2.25% KGM and 0.75% CD, the printing accuracy was highest with a minimized error of 4.97 ± 0.45%, and optimal structural stability was maintained within 5 h post-printing. Rheological measurements revealed that the flow behavior index (n) of the KC3 system was 0.049 ± 0.014, indicating superior flowability and significantly improved overall rheological stability. Additionally, the blend system not only increased the hardness and gel elasticity of the GBR gel but also significantly enhanced its cohesiveness and adhesiveness, reaching the highest values of 0.323 ± 0.02 and −217.488 ± 22.499, respectively, in the KC3 formulation. Further thermal analysis, low-field nuclear magnetic resonance analysis, along with Fourier-transform infrared spectroscopy and scanning electron microscopy observations, collectively demonstrated that the KGM/CD blend effectively reinforced the stability of the GBR gel network structure. These findings provide theoretical support for optimizing GBR applications in food 3D printing. Full article

The global energy transition represents a pivotal aspect of the pursuit of sustainable development and the reduction of greenhouse gas emissions. The objective of this study was to examine the dynamic relationships between global primary energy consumption and the consumption of individual energy sources (nuclear, oil, coal, natural gas, renewables) from 2011 to 2023. To examine both long-run and short-run relationships between variables, advanced econometric methods were employed, including the Johansen cointegration test and the Vector Error Correction Model (VECM). Furthermore, an Index of Sustainable Energy Transformation (ISTE) was devised to quantify the advancement of the transition to low-carbon energy sources. The analysis confirms the existence of long-term equilibrium relationships between global primary energy consumption and the consumption of individual energy sources. The analysis revealed that renewable energy consumption exerts a considerable influence on primary energy consumption, both in the short and long term. The ISTE index demonstrated a notable increase over the period of 2011 to 2023, indicative of advancement in the global energy transition. The results confirm the existence of a stable long-term equilibrium between global primary energy consumption and the consumption of individual energy sources. The observed increase in the ISTE index indicates progress towards low-carbon energy sources, which has important implications for energy policy and sustainable development. The results can support policymakers in monitoring the progress of the energy transition and shaping policies to accelerate the development of renewable energy sources. Full article

Stem cell therapy in cat patients needs a high quantity of mesenchymal stromal/stem cells (MSCs) requiring in vitro propagation under culture conditions which may potentially impact cellular characteristics and genetic stability. This study aimed to assess the in vitro characteristics and cytogenetic stability of cat adipose tissue-derived MSCs (cAT-MSCs). For this purpose, morphological features, clonogenic potential, and proliferative capacity of cAT-MSCs were assessed at passages 2 (P₂), P₄, and P₆. Multipotency and immunophenotype were evaluated. Cytogenetic analyses were conducted up to P₆. The cAT-MSCs exhibited a spindle-shaped morphology in early passages. The doubling time increased from 2.5 days at P₂ to 9.4 at P₄ and 10.5 at P₆, accompanied by the observation of nuclear abnormalities such as cluster formation, karyorrhexis, karyolysis, and a decline in the mitotic index at P₄. Cells demonstrated multipotency capacity and were CD45−, CD90+, and CD44+. Metaphase analysis at P₂ and P₄ revealed some indications of structural instability such as gaps, breaks, deletions, duplications, and early chromatid segregation, but these alterations did not show an increase across passages. In conclusion, cAT-MSCs decreased their proliferative capacity after P₄, accompanied by morphological alterations and signs of structural instability. Full article

Indigo carmine has a variety of uses in foods, textiles, medicine, pharmaceuticals, and cosmetics. There are studies reporting the toxic potential of indigo carmine on human health and the environment. In this study, we investigated the cytogenotoxic effects of indigo carmine using apical root cells of Allium cepa. Allium cepa bulbs were subjected to four treatments with indigo carmine (0.0032, 0.0064, 0.0125, and 0.2 mg/mL) and to ultrapure water as a control. After 5 days, root growth, root length, mitotic index, mitotic inhibition, chromosomal anomalies, and cell morphology were analyzed. According to our results, a decrease in root length and mitotic index was observed at all concentrations of indigo carmine. Additionally, several types of chromosomal abnormalities were observed, such as disturbed metaphase, sticky chain metaphase, anaphase bridge, and laggard chromosomes. Moreover, histological observation indicated that indigo carmine induces alterations in various components of root tip tissue, such as deformation and alteration of the cell wall, progressive condensation of chromatin, shrinkage of the nuclei, and an increase in the number of irregularly shaped nuclei and nuclear fragments. Our results indicate that the tested concentrations of indigo carmine may have toxic effects and raise concerns about its intensive use in many fields. Full article

There is a great need for novel approaches to treating bacterial infections, due to the vast dissemination of resistance among pathogenic bacteria. Staphylococcus aureus are ubiquitous Gram-positive pathogenic bacteria and are rapidly acquiring antibiotic resistance. Here, celecoxib was encapsulated into cubosomal nanoparticles, and the particle morphology, size distribution, zeta potential, entrapment efficiency, and celecoxib release were evaluated in vitro. Also, a systemic infection model in mice elucidated the in vivo antibacterial action of the celecoxib cubosomes. Cubosomes are a nanotechnology-based delivery system which can adhere to the external peptidoglycan layers of Gram-positive bacteria and penetrate them. The size distribution investigation revealed that the prepared celecoxib-loaded cubosomes had a mean particle size of 128.15 ± 3.04 nm with a low polydispersity index of 0.235 ± 0.023. The zeta potential measurement showed that the prepared cubosomes had a negative surface charge of −17.50 ± 0.45, indicating a highly stable nanodispersion formation with little susceptibility to particle aggregation. The cubosomal dispersion exhibited an entrapment efficiency of 88.57 ± 2.36%. The transmission electron micrograph for the prepared celecoxib-loaded cubosomes showed a narrow size distribution for the cubosomal nanoparticles, which had a spherical shape and were non-aggregated. The tested cubosomes diminished the inflammation in the treated mice’s liver and spleen tissues, as revealed by hematoxylin and eosin stain and Masson’s trichrome stain. The immunostained tissues with nuclear factor kappa B and caspase-3 monoclonal antibodies revealed a marked decrease in these markers in the celecoxib-treated group, as it resulted in negative or weak immunostaining in liver and spleen that ranged from 4.54% to 17.43%. This indicates their inhibitory effect on the inflammatory pathway and apoptosis, respectively. Furthermore, they reduced the bacterial burden in the studied tissues. This is alongside a decrease in the inflammatory markers (interleukin-1 beta, interleukin-6, cyclooxygenase-2, and tumor necrosis factor-alpha) determined by ELISA and qRT-PCR. The IL-1β levels were 16.66 ± 0.5 pg/mg and 17 ± 0.9 pg/mg in liver and spleen, respectively. Also, IL-6 levels were 85 ± 3.2 pg/mg and 84 ± 2.4 pg/mg in liver and spleen, respectively. In conclusion, the current study introduced cubosomes as an approach for the formulation of celecoxib to enhance its in vivo antibacterial action by improving its oral bioavailability. Full article

The genus Nepeta belongs to the largest Lamiaceae family, with 300 species, which are distributed throughout the various regions of Africa, Asia, India, and America. Along with other plant families distinguished by their medicinal and therapeutic values, the Nepeta genus of Lameaceae remains relatively valuable. Hence, the phytochemicals of N. paulsenii Briq. were extracted using different plant parts, i.e., leaves, stem, roots, flowers, and the whole plant by using various solvents (ethanol, water, and ethyl acetate), obtaining 15 fractions. Each extract of dried plant material was analyzed by FT-IR and GC-MS to identify the chemical constituents. The cytotoxicity of each fraction was analyzed by MTT assay and mitochondrial membrane potential and nuclear condensation assays against lung cancer cells. Among the ethyl acetate and ethanolic extracts, the flowers showed the best results, with IC₅₀ values of 51.57 μg/mL and 50.58 μg/mL, respectively. In contrast, among the water extracts of the various plant segments, the stem showed the best results, with an IC₅₀ value of 123.80 μg/mL. 5-flourouracil was used as the standard drug, providing an IC₅₀ value of 83.62 μg/mL. The Hoechst 33342 stain results indicated apoptotic features, i.e., chromatin dissolution and broken down, fragmented, and crescent-shaped nuclei. The ethanolic extracts of the flowers showed more pronounced apoptotic effects on the cells. The mitochondrial membrane potential indicated that rhodamine 123 fluorescence signals suppressed mitochondrial potential due to the treatment with the extracts. Again, the apoptotic index of the ethanolic extract of the flowers remained the highest. Hence it can be concluded that the flower part of N. paulsenii Briq. was found to be the most active against the A459 human lung cancer cell line. Full article

This paper investigates the impact of the amount of training data and the shape variability on the segmentation provided by the deep learning architecture U-Net. Further, the correctness of ground truth (GT) was also evaluated. The input data consisted of a three-dimensional set of images of HeLa cells observed with an electron microscope with dimensions $8192\times 8192\times 517$. From there, a smaller region of interest (ROI) of $2000\times 2000\times 300$ was cropped and manually delineated to obtain the ground truth necessary for a quantitative evaluation. A qualitative evaluation was performed on the $8192\times 8192$ slices due to the lack of ground truth. Pairs of patches of data and labels for the classes nucleus, nuclear envelope, cell and background were generated to train U-Net architectures from scratch. Several training strategies were followed, and the results were compared against a traditional image processing algorithm. The correctness of GT, that is, the inclusion of one or more nuclei within the region of interest was also evaluated. The impact of the extent of training data was evaluated by comparing results from 36,000 pairs of data and label patches extracted from the odd slices in the central region, to 135,000 patches obtained from every other slice in the set. Then, 135,000 patches from several cells from the $8192\times 8192$ slices were generated automatically using the image processing algorithm. Finally, the two sets of 135,000 pairs were combined to train once more with 270,000 pairs. As would be expected, the accuracy and Jaccard similarity index improved as the number of pairs increased for the ROI. This was also observed qualitatively for the $8192\times 8192$ slices. When the $8192\times 8192$ slices were segmented with U-Nets trained with 135,000 pairs, the architecture trained with automatically generated pairs provided better results than the architecture trained with the pairs from the manually segmented ground truths. This suggests that the pairs that were extracted automatically from many cells provided a better representation of the four classes of the various cells in the $8192\times 8192$ slice than those pairs that were manually segmented from a single cell. Finally, the two sets of 135,000 pairs were combined, and the U-Net trained with these provided the best results. Full article

Physical activity is associated with a host of positive health outcomes and is shaped by both genetic and environmental factors. We aim to: (1) estimate sibling resemblance in two physical activity phenotypes [total number of steps∙day⁻¹ and minutes for moderate steps per day (min∙day⁻¹)]; and (2) investigate the joint associations of individual characteristics and shared natural environment with intra-pair sibling similarities in each phenotype. We sampled 247 biological siblings from 110 nuclear families, aged 6–17 years, from three Peruvian regions. Physical activity was measured using pedometers and body mass index was calculated. In general, non-significant variations in the intraclass correlation coefficients were found after adjustment for individual characteristics and geographical area for both phenotypes. Further, no significant differences were found between the three sib-ship types. Sister-sister pairs tended to take fewer steps than brother-brother (β = −2908.75 ± 954.31). Older siblings tended to walk fewer steps (β = −81.26 ± 19.83), whereas body mass index was not associated with physical activity. Siblings living at high-altitude and in the Amazon region had higher steps/day (β = 2508.92 ± 737.94; β = 2213.11 ± 776.63, respectively) compared with their peers living at sea-level. In general, we found no influence of sib-types, body mass index, and/or environment on the two physical activity phenotypes. Full article

The common bean (Phaseolus vulgaris L.), whose annual production is 26 million tons worldwide, is one of the main sources of protein and is known as one of the most important food sources. In this study, the karyotype variations and the genome size of four common bean genotypes in Turkey were investigated to determine whether the geographic variables in these regions affected the genome size and the karyotype parameters. In addition, it is known that as that the cytological and chromosomal parameters change under the influence of the climatic conditions of each region, appropriate and stable cytological methods for each plant facilitate and enable the determination of the chromosomal structure and the identification of specific chromosomes in the genotypes of the relevant region. Correct and valuable information such as this enables breeders and researchers to determine the correct shape and actual size of chromosomes. The genome size of the genotypes was measured with a flow cytometer, and chromosome analyses were performed with the squash method. For each genotype, the karyotype parameters, such as the number of somatic chromosomes, the Mean Total Chromosome Length (MTCL), the Mean Centromere Index (MCI), and the Mean Arm Ratio (MAR), were measured. The results showed that the highest and the lowest amounts of DNA per nucleus (3.28 pg and 1.49 pg) were observed in the Bitlis and Elaziğ genotypes. In addition, all genotype chromosome numbers were counted to be 2n = 2x = 22. The Mean Total Chromosome Length varied from 15.65 µm in Elaziğ to 34.24 µm in the Bitlis genotype. The Mean Chromosome Length ranged between 1.42 µm and 3.11 µm in the Elaziğ and Bitlis genotypes. The Hakkari and Van genotypes consist of eleven metacentric chromosomes, while the Bitlis and Elaziğ genotypes consist of ten metacentric chromosomes and one sub-metacentric chromosome. However, the Mean Centromere Index and Arm Ratio differed considerably among the genotypes. The highest (46.88) and the lowest (43.18) values of the Mean Centromere Index were observed in the Hakkari and Elaziğ genotypes, respectively. On the other hand, the lowest (1.15) and the highest (1.36) values of the Mean Arm Ratio were obtained in the Bitlis and Elaziğ genotypes, respectively. Eventually, intraspecies variations in genome size and chromosomal parameters were observed, and it was determined that the changes in nuclear DNA content and different chromosomal parameters among the four Phaseolus genotypes from four different regions of Turkey indicate the effect of climate change in the regions on these parameters. Such information in these areas can be used as useful information for the improvement of this plant and breeding programs. Full article

Nuclear power plant emergency robots are robots used to respond to significant public safety incidents, such as uncontrolled radioactive sources and nuclear catastrophe leaks. However, there are no standardized evaluation criteria for the optimal design of the robots. We offer a quantitative analytic algorithm for optimizing nuclear power plant emergency robots to address this issue. The method optimizes the structural parameters of the robot in accordance with the workspace by analyzing, comparing, and evaluating the workspace. The approach comprises constructing a kinematic model of the mechanical arm and proposing an optimization algorithm based on the alpha shape to accurately describe the manipulator workspace; employing the proposed convex hull algorithm to quantitatively analyze and evaluate the workspace generated by different solutions in terms of area, volume, task demand, Structural Length Index and Global Conditioning Index; and determining the robotic arm joint parameters by selecting the optimum workspace design solution. Using the suggested algorithm, we optimize the design of the master and slave robotic arms of the nuclear power plant emergency robots. Theoretical calculations and simulation results demonstrate that the method is an effective and practical evaluation technique that not only accurately describes the workspace but also optimizes the design of the nuclear power plant emergency robots. Full article

A series of compounds with Schiff base and ester linking units attached to the electron-withdrawing side arm (Cl, NO₂, and OH) have been successfully synthesized through four schemes of the chemical route. These compounds were characterized using Fourier Transform Infrared spectroscopy (FTIR), Nuclear Magnetic Resonance spectroscopy (NMR), and Carbon, Hydrogen and Nitrogen (CHN) elemental analysis. The epoxy resin was used as a matrix of molding to observe the refinement of fire-retardant properties of the modified cyclotriphosphazene compounds. The fire-retardant testing was done using Limiting Oxygen Index (LOI). The LOI value of pure epoxy resin was increased from 22.75% to 24.71% when incorporated with 1 wt.% of hexasubstituted cyclotriphosphazene (HCCP). Interestingly, all the final compounds gave a positive increment in the LOI value and the highest LOI value was obtained from the compound containing a nitro side arm with LOI value of 26.90%. In order to understand the thermal stability of these compounds, Thermogravimetric Analysis (TGA) was carried out. The compound with the nitro group at the terminal end has the highest char residue which is 34.2% at 700 °C. This indicated that the presence of the nitro withdrawing group was able to enhance the fire retardancy of the materials. Based on SEM observation, the shape of the final compound’s char residue demonstrated the formation of a porous protective layer with a dense surface. The dielectric property was conducted according to ASTM D149 AC breakdown voltage to determine its dielectric strength. The results showed that the highest dielectric strength value belonged to the compound containing a nitro group side arm with 24.41 kV/mm⁻¹ due to the π electron delocalization. Full article

Based on their morphological and genetic similarity, several studies have proposed that Lutjanus campechanus and Lutjanus purpureus are the same species, but there is no confirmed consensus yet. A population-based study concerning otolith shape and genetic analyses was used to evaluate if L. campechanus and L. purpureus are the same species. Samples were collected from populations in the southwestern Gulf of Mexico and the Venezuelan Caribbean. Otolith shape was evaluated by traditional and outline-based geometric morphometrics. Genetic characterization was performed by sequencing the mtDNA control region and intron 8 of the nuclear gene FASD2. The otolith shape analysis did not indicate differences between species. A nested PERMANOVA identified differences in otolith shape for the nested population factor (fishing area) in morphometrics and shape indexes (p = 0.001) and otolith contour (WLT4 anterior zone, p = 0.005 and WLT4 posterodorsal zone, p = 0.002). An AMOVA found the genetic variation between geographic regions to be 10%, while intrapopulation variation was 90%. Network analysis identified an important connection between haplotypes from different regions. A phylogenetic analysis identified a monophyletic group formed by L. campechanus and L. purpureus, suggesting insufficient evolutionary distances between them. Both otolith shape and molecular analyses identified differences, not between the L. campechanus and L. purpureus species, but among their populations, suggesting that western Atlantic red snappers are experiencing a speciation process. Full article

Docetaxel (DTX) is classified as a class IV drug that exhibits poor aqueous solubility (6–7 µg/mL in water) and permeability (P-glycoprotein substrate). The main objective of this study was to construct, characterize, and evaluate docetaxel loaded nanomicellar formulation in vitro for oral delivery to enhance the absorption and bioavailability of DTX, as well as to circumvent P-gp efflux inhibition. Formulations were prepared with two polymeric surfactants, hydrogenated castor oil-40 (HCO-40) and D-α-Tocopherol polyethylene glycol 1000 succinate (VIT E TPGS) with solvent evaporation technique, and the resulting DTX nanomicellar formulations were characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), Fourier Transform Infrared Spectroscopy (FT–IR), X-ray powder diffraction (XRD), and transmission electron microscopy (TEM). Proton NMR, FT–IR, and XRD data indicated that DTX was completely encapsulated within the hydrophobic core of the nanomicelles in its amorphous state. TEM data revealed a smooth spherical shape of the nanomicellar formulation. The optimized formulation (F-2) possessed a mean diameter of 13.42 nm, a zeta potential of −0.19 mV, with a 99.3% entrapment efficiency. Dilution stability study indicated that nanomicelles were stable up to 100-fold dilution with minimal change in size, poly dispersity index (PDI), and zeta potential. In vitro cytotoxicity study revealed higher anticancer activity of DTX nanomicelles at 5 µM compared to the native drug against breast cancer cell line (MCF-7) cells. The LC–MS data confirmed the chemical stability of DTX within the nanomicelles. In vitro drug release study demonstrated faster dissolution of DTX from the nanomicelles compared to the naked drug. Our experimental results exhibit that nanomicelles could be a drug delivery system of choice to encapsulate drugs with low aqueous solubility and permeability that can preserve the stability of the active constituents to provide anticancer activity. Full article