Dr Mohammed Mahmoud Youssif

Progressive familial intrahepatic cholestasis (PFIC) syndromes are rare autosomal recessive disorders. We present the first detailed phenotype-genotype of PFIC children with normal gamma-glutamyltransferase (GGT) [normal GGT/PFIC] in an African population. Thirty-one pediatric patients belonging to 28 unrelated Egyptian families with normal GGT/PFIC were reported. Clinical, biochemical, histopathological, and genetic data were systematically analyzed. Patients were 15 males/16 females (55 ± 52 months at diagnosis). Apart from cholestasis, clinical features included severe pruritus (visual analogue scale 7.5 ± 3.4), hepatomegaly (80.6%), sleep deprivation (41.9%), and splenomegaly (19.4%). 13/28 families had ABCB11 variants (PFIC2), 6/28 families had ATP8B1 (PFIC1) and TJP2 (PFIC4) variants each, 2/28 had MYO5B variants (PFIC10), and one family had USP53 variants (PFIC7). Twenty-five disease-causing variants were reported, including 16 novel variants. PFIC1 patients were more severely affected compared to other PFIC syndromes, as the incidence of growth retardation, sibling deaths, skin changes, and progression to biliary diversion were all significantly higher (p value 0.006, 0.012, 0.037, and 0.012, respectively). In contrast, none of the 13 PFIC2 children progressed to biliary diversion, and all four PFIC10 children had normal liver transaminases. Our study expands the global phenotypic and genotypic knowledge of normal GGT/PFIC and will facilitate better care for the syndrome in Egypt.

Determination of postmortem interval (PMI) is a fundamental aspect of forensic medicine, aiding in the reconstruction of the time of death in medico-legal investigations. The present study aims to compare gender-based postmortem changes and investigates the role of collagen fibers as a potential indicator of PMI in albino rats. Eighteen male and nine female adult albino rats were examined. Three prostates, three uterine horns, and the quadriceps muscle of the hind limb of each animal were collected at six time points (0, 6, 24, 36, 48, and 144 h postmortem) after scarifying rats by neck dislocation. Morphological analysis revealed progressive softening of the organs with darker discoloration with increasing PMI. Histological examination using hematoxylin and eosin staining showed cellular degradation up to 48 h PM. Masson's trichrome staining highlighted the persistence of collagen fibers up to 144 h. Notably, male prostates exhibited greater resistance to postmortem degradation compared to female uteri, suggesting that potential sex identification by gonads is possible up to 48 h PM.

Neurobrucellosis is a severe and rare complication of human brucellosis, particularly in the pediatric population. It manifests with diverse clinical presentations, with meningoencephalitis being the most common. Limited cases have been reported in Saudi Arabia. Here, we present the case of an 11-year-old boy diagnosed with neurobrucellosis who developed diplopia, inward deviation of the left eye, and ophthalmoplegia. Cerebrospinal fluid analysis revealed pleocytosis, elevated protein levels, and high opening pressure. Brain magnetic resonance imaging demonstrated microabscesses with nodular enhancement, dural thickening in the quadrigeminal cistern, and swelling with edema of the left optic nerve. To the best of our knowledge, this is the first reported case of a patient with brain microabscesses secondary to infection in Saudi Arabia. This case highlights the need for heightened awareness of neurobrucellosis as a differential diagnosis in children presenting with unusual neurological symptoms in endemic regions.

Sandestig-Stefanova syndrome (SANDSTEF) (OMIM: 618804) is a recently identified autosomal recessive disorder characterized by a complex phenotype affecting multiple organ systems. To date, only 10 cases have been reported in the literature. Here, we present a newly identified patient exhibiting a distinct clinical presentation, along with a novel homozygous splice variant in NUP188. The proband has multiple system involvement, including ophthalmology, central nervous system, skin, distinct facial features, congenital heart disease, and respiratory system; eventually, he passed away with respiratory failure. A novel splice variant was identified using ES (NM_015354.2c.1962-2A>C p.(?)). The variant was confirmed by Sanger sequencing and was found to segregate from the parents. RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status. The identification of a novel pathogenic variant contributes to a deeper understanding of the molecular mechanisms underlying the disorder and expands its phenotypic spectrum.

The bidirectional communication between liver and skeletal muscle represents a critical yet underexplored axis in human physiology. Dysfunction in either organ can accelerate pathology in the other, amplifying disease progression. Understanding this interconnected system is essential for developing targeted and effective therapeutic strategies. This comprehensive review elucidates the complex pathophysiological mechanisms underlying liver-muscle crosstalk and identifies novel therapeutic targets for simultaneous intervention in both organs. We analyzed peer-reviewed literature focusing on molecular pathways, biomarkers, and therapeutic interventions targeting the liver-muscle axis, including cardiac muscle interactions. Key parameters examined included inflammatory mediators (TNF-α, IL-6), metabolic regulators (mTOR, AMPK), hepatokines, myokines, cardiokines, and emerging biomarkers such as zonulin. The liver-muscle axis operates through multiple interconnected pathways: (1) inflammatory cascades where TNF-α inhibits muscle mTOR signaling while promoting hepatic stellate cell activation; (2) metabolic disruption through insulin resistance and AMPK pathway dysfunction affecting both organs simultaneously; (3) gut-liver-muscle crosstalk mediated by microbiome-derived metabolites and intestinal permeability markers like zonulin; (4) hepatokine-myokine signaling networks that coordinate metabolic homeostasis; and (5) liver-heart crosstalk involving cardiomyocyte-hepatocyte interactions through FGF21, IL-6/STAT3 signaling, and inflammatory pathways that distinguish cardiac muscle from skeletal muscle responses. Studying the liver-muscle axis helps in understanding metabolic diseases, transforming them from isolated organ pathologies to interconnected systemic disorders. This framework opens new avenues for precision medicine approaches, biomarker development, and therapeutic innovation that simultaneously optimize liver, skeletal muscle, and cardiac health.

This study introduces and statistically optimizes novel Tetra-Synergistic Bilosomes (TSB), an advanced nano-platform for topical delivery of voriconazole (VOR) in otomycosis therapy. The term "Tetra-Synergistic" reflects the incorporation of four complementary components: Cremophor® EL, sodium deoxycholate, Brij® 58, and Brij® S2, working in synergy to enhance therapeutic efficacy. TSB was fabricated using the thin-film hydration method and optimized through a 2 D-optimal design. Three formulation factors were investigated: Cremophor® EL: VOR ratio, sodium deoxycholate: cholesterol ratio, and Brij® 58: Brij® S2 ratio, with the optimization goal of maximizing EE%, minimizing vesicular size, and maintaining ZP within the acceptable stability range. The model demonstrated excellent predictability, achieving a desirability value of 0.888. The optimized TSB exhibited high EE% (91.6%), a suitably small VS (217.9nm), and stable ZP (- 24.1mV). FTIR confirmed VOR entrapment, while TEM revealed nano-sized spherical vesicles. Moreover, TSB displayed a biphasic In-vitro release profile and remained stable for three months under refrigeration. Importantly, microbiological evaluation confirmed the superior antifungal performance of TSB. Compared with VOR suspension, TSB showed a larger inhibition zone, a lower minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), and a faster fungicidal effect, eradicating fungal growth in 33% less time. Ex-vivo permeation studies revealed a 2.18-fold enhancement ratio, supported by confocal laser scanning microscopy confirming deeper tissue penetration. Histopathological analysis further validated the safety of topical application without any tissue damage. Collectively, these results establish TSB as a pioneering, microbiologically potent, and clinically promising nano-vesicular system for the effective management of otomycosis.

Alzheimer disease (AD) is a neurodegenerative condition that progressively develops structural changes in the brain, resulting in different stages of severity, which makes accurate multiclass classification from magnetic resonance imaging (MRI) challenging. Despite promising outcomes of deep learning models, a great number of current methods disregard disease progression, suffer from evaluation leakage, or lack interpretability. This paper introduces DeepAttentionADNet, a lightweight hybrid CNN-Transformer framework designed for multiclass staging of Alzheimer's disease using MRI images. The proposed model integrates convolutional feature extraction with transformer-based global context modeling. To capture the ordered nature of disease severity, a progression-aware ordinal learning objective is proposed. Moreover, consistency regularization is utilized to enhance robustness by imposing consistent prediction with spatial perturbation. A leakage-free k-fold cross-validation protocol is adopted, in which data splitting is performed prior to augmentation. Also, to promote interpretability, token-level importance maps based on transformer embeddings are utilized to visualize spatial regions that were used to make classification decisions. The experimental findings on a multiclass MRI dataset of Alzheimer disease demonstrate consistent and high performance across cross-validation folds (mean F1-score (0.991 ± 0.003) and AUROC (0.9998 ± 0.0002)), without losing transparency and progress awareness. The proposed framework provided a robust and interpretable method of Alzheimer disease severity classification using MRI.

β-thalassemia is an inherited blood disorder with long-term associated complications. The purpose of this study was to evaluate the clinical significance of the lncRNA-HBBP1 and lncRNA-XIST expression profiles in the diagnosis of β-thalassemia patients. One hundred children patients with β-thalassemia participated in this case-control study: 50 patients diagnosed as Beta Thalassemia Major (β-TM) and 50 patients diagnosed as Beta Thalassemia Intermedia (β-TI) groups. Furthermore, there were 50 children as healthy control group. Assessment of both genes' expression was performed by RT-qPCR. The findings displayed that both lncRNA-HBBP1 and lncRNA-XIST were highly expressed within the β-TM group than in the β-TI and the control groups (P < 0.001 for both). The lncRNA-HBBP1 and lncRNA-XIST expression were significantly higher in β-thalassemia patients presented with jaundice, thalassemia facies, or organomegaly (p < 0.001 for all). In addition, lncRNA-XIST expression was significantly higher in β-thalassemia patients with splenectomy (p = 0.002). Spearman correlation revealed that the expression of both genes was significantly correlated with HbF % in β-TM and β-TI groups (p < 0.001 for both). Based on the ROC curve analysis, the sensitivity of lncRNA-HBBP1 and lncRNA-XIST for discriminating the β-TM group from the β-TI group was 82% and 80%, respectively. Collectively, the examined lncRNAs could offer novel biomarkers for β-thalassemia disorder once confirmed in extensive upcoming investigations.

AIMS: Pulmonary fibrosis (PF) is a destructive, inflammatory intersectional lung disease that has lethal consequences. Autophagy, a cellular homeostasis sustaining system, has shown a vital function in PF progression. Nitazoxanide (NTZ) is a broad-spectrum antiprotozoal agent that exhibits anti-inflammatory, antiviral, and anti-fibrotic properties. This study explores the potential therapeutic effect of NTZ on bleomycin (BLM)-induced PF in rats and studies its impact on autophagy pathways.

MATERIALS AND METHODS: Four groups of adult male Wistar rats: the control group, BLM group (intratracheal single dose of 5 mg/kg), BLM + NTZ (200 mg/kg/day, p.o., for 28 days) group, and BLM + wortmannin (WM) (15 μg/kg/day, i.v., for 28 days) group, where WM was used to validate the role of PI3K/Akt/mTOR signaling pathway in PF.

KEY FINDINGS: BLM administration promoted extensive degenerative changes and distortion of lung architecture that were reversed by NTZ. BLM upregulated the miR-350, PI3K/Akt/mTOR pathway, transforming growth factor-β1 (TGF-β1), and Smad3 while reducing autophagy-related proteins; beclin1 and LC3B, and the anti-inflammatory interleukin-37 (IL-37) relative to the control group. BLM induced tissue inflammation and apoptosis, and increased TNF-α, IL-6, and caspase-3 relative to the control group. NTZ significantly alleviated BLM-induced collagen fiber deposition and PF, suppressed miR-350/Akt/mTOR signaling, TGF-β1, IL-6, TNF-α, caspase-3 expressions, upregulated IL-37, and elevated autophagy-related proteins relative to the BLM group.

SIGNIFICANCE: This study demonstrates, for the first time, the potential role of miR-350 in PF, and reveals a potential therapeutic role for NTZ in ameliorating BLM-induced PF, presumably by modifying the miR-350/Akt/mTOR/beclin1 signaling.

This work describes the design, synthesis, and anticancer evaluation of a new acridine hybrid (ACNP). ACNP showed cytotoxic effect with IC values of 4.3 and 10 μg/mL against MCF-7 and MDA-MB 231; respectively, versus CC value of 439.72 μg/mL of normal lung fibroblast cells (WI-38 cells) with high selectivity index (SI) of 102.2 and 43.9 for MCF-7 and MDA-MB 231 of cancer cells respectively. ACNP showed a cytotoxic synergetic effect when combined with paclitaxel in MDA-MB 231 and MCF-7 cell lines. A significant down regulation of PI3K, mTOR and AKT was demonstrated in cells treated with paclitaxel or ACNP as single therapy with minimal expression in cells treated with combination of both. ACNP treated cells recorded an increase in protein expression level of Caspase-3, Caspase-9 while Ki67 showed a declined expression in MDA-MB 231 and MCF-7 cell lines. Molecular docking investigation was performed on PI3K and Caspase-3 to predict the possible binding modes of the acridine tricyclic skeleton with the molecular targets. The ADME study revealed that ACNP has high GI absorption and blood brain barrier although oral bioavailability was poor. These results suggested that ACNP maybe a promising candidate for further preclinical development.

This study aimed to examine therapeutic impact of exosomes derived from adipose tissue- mesenchymal stem cells (AD-MSCs-Exos) on a rat model of hepatorenal toxicity. 32 Wistar male rats were grouped into 4 groups: Control group, rats received intraperitoneally (i.p.) phosphate buffered saline (PBS). Cyclophosphamide (CTX) group, rats injected i.p. with a single dose of CTX (50 mg/kg) followed by rotating doses of 8 mg/kg of CTX daily for 2 weeks. CTX + AD-MSCs group, rats infused with (1 × 10 AD-MSCs cells/rat) dissolved in PBS intravenously (i.v.) day after day for 1 week starting from second day of CTX last dose. CTX + AD-MSCs-Exos group, rats injected with 100 μg of Exos derived from AD-MSCs in 1 ml PBS by i.v. injection for 1 week starting from second day of CTX last dose. 5 weeks following initial CTX dose, blood, liver, and kidneys extracted. Serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine and urea levels; hepatic malate dehydrogenase (MDH) and glutamate dehydrogenase (GLDH); renal kidney injury molecule-1 (KIM-1) and clusterin measured. Tumor necrosis factor alpha (TNF-α) and malonialdehyde (MDA) were estimated in hepatic and renal tissues. Furthermore, nuclear factor kappa B/toll like receptor-4 (NF-κB/TLR-4), nuclear factor erythroid 2- related factor 2/heme oxygenase-1 (Nrf-2/HO-1) and BCL-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) signaling pathways were analyzed by qRT-PCR. Immunohistochemical staining for cyclooxygenase-2 "COX-2" and inducible nitric oxide synthase "iNOS" performed in hepatic and renal tissues. Finally, histopathological investigation of both liver and kidney tissue carried out. Treatment with MSCs and their derived exosomes markedly improved antioxidant and anti-inflammatory markers while reducing apoptotic gene expression compared to CTX group. Specifically, in liver tissues; Bax expression decreased 2.6-fold and 3.3-fold, while Bcl-2 increased 3.1-fold and 1.8-fold in AD-MSCs- and AD-MSCs-Exos groups, respectively. Similarly, NF-κB was reduced 1.5-fold and 2.8-fold; Nrf2 and HO-1 were upregulated by approximately 7.4- and 5.2-fold (AD-MSCs) and 7.4- and 6.2-fold (AD-MSCs Exos), respectively compared to CTX group. In kidney tissues, Compared to CTX group, Bax expression decreased by approximately 1.5-fold and 3.6-fold, whereas Bcl-2 increased 3.0-fold and 4.4-fold in AD-MSCs- and AD-MSCs Exos groups, respectively. NF-κB and TLR-4 both were downregulated by ~2.6 (AD-MSCs) and 7.9, 2.1-fold (AD-MSCs Exos), while Nrf2 and HO-1 were upregulated by 12.1 and 2.2- fold (AD-MSCs); 12.8- and 3.0-fold (AD-MSCs Exos), respectively. These findings confirm that both treatments mitigate CTX induced hepatorenal injury through modulation of apoptosis, inflammation, and oxidative stress pathways, with exosomes exhibiting slightly superior therapeutics efficacy. Also, immunological and histopathological investigation verified curative effect of MSCs-Exos against CTX-induced hepatorenal toxicity. These findings highlight that both AD-MSCs and their exosomes confer significant therapeutic effect against CTX-induced hepatorenal toxicity through modulation of apoptosis, inflammation, and oxidative stress pathways. Importantly, AD-MSCs-Exos demonstrated superior therapeutic efficacy compared to AD-MSCs in restoring antioxidant defenses and attenuating inflammatory and apoptotic responses in both liver and kidney tissues.

Astaxanthin, a xanthophyll carotenoid derived primarily from Hematococcus lacustris, has been proposed as a potent bioactive compound demonstrating wide therapeutic applicability. In addition to its distinct molecular structure, astaxanthin has exceptional antioxidant property, surpassing that of other carotenoids and conventional antioxidants, while also exerting robust anti-inflammatory effects. The present review focuses on the current evidence of the complex multifaceted therapeutic actions of astaxanthin, including cardiovascular protection, neuroprotection, hepatoprotection, renal support, dermatological health, immune modulation, and emerging roles in metabolic disorders, reproductive health, and cancer prevention. Mechanistic insights highlight its potential to control key molecular mechanisms, including the NF-κB, Nrf2, MAPK, and TGF-β/Smad pathways, alongside the enhancement of endogenous antioxidant defenses. Preclinical and clinical findings have demonstrated benefits in conditions such as atherosclerosis, myocardial ischemia, nonalcoholic fatty liver disease, hypertension, Alzheimer's disease, Parkinson's disease, and inflammatory skin diseases. By integrating evidence drawn from molecular, experimental, and clinical studies, this review underscores astaxanthin's potential as a complementary therapeutic agent and functional nutraceutical. The breadth of its bioactivity positions astaxanthin as a promising natural compound for targeted disease prevention and health promotion.

Skeletal muscle (SkM) accounts for 30%-40% of body mass. SkM is required for body movement, energy metabolism, and material metabolism, all of which directly impact human quality of life. This review traces the key medicinal plants used for alleviating skeletal muscle disorders (SkMDs), with a focus on lifestyle modifications and exercise. A comprehensive literature search was conducted using databases such as Google Scholar, Elsevier, Springer Nature, Wiley, PubMed, and EKB. SkMDs are a broad category of conditions that affect the muscles, bones, joints, and connective tissues, resulting in major impairments in movement, function, and quality of life. SkMDs affect more than 1.3 billion people worldwide and are a major cause of disability and economic hardship. Conventional therapy approaches, such as pharmaceutical interventions and surgical procedures, are typically limited by undesirable side effects, extended recovery times, and patient dissatisfaction, especially when focusing only on symptom relief. In response, complementary and alternative medicine, particularly medicinal herbs, has grown in popularity to improve SkMD management. Medicinal plants have a diverse range of pharmacologically active compounds with anti-inflammatory, analgesic, and antioxidant effects, making them promising additions to traditional treatments. Berberine, curcumin, resveratrol, quercetin, (-)-epicatechin, and ginsenosides have been reported to have potential in SkMDs. These compounds exert their effects through multiple mechanisms, such as enhancing muscle protein synthesis, reducing inflammation, and modulating hormones that influence muscle mass. Overall, the study emphasizes the ability of natural supplementation approaches to improve clinical outcomes, improve patient well-being, and provide a more sustainable model for treating SkMDs.

Skin aging is a complex and irreversible natural process impacted by genetics, lifestyle, and environmental variables, leading to wrinkles, loss of elasticity, and uneven skin tone. There is a growing demand for natural skincare products, which are perceived as safer, more sustainable, and effective in combating the signs of aging. Clerodendrum infortunatum (C. infortunatum) Linn. (Family Lamiaceae) has traditional medicinal uses, including hepatoprotection, antimicrobial, and vermifuge activity, as well as benefits in alleviating inflammation, arthritis, and diabetes. This study aims to investigate the metabolites present in different solvent-extracted fractions of the aerial parts of C. infortunatum through liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiling, and to evaluate their anti-aging potential using in vitro anti-collagenase and anti-elastase assays. The correlation between the identified metabolites and bioactivity was investigated using a partial least squares (PLS) chemometric approach. To confirm these findings, molecular docking studies were performed to assess the inhibitory potential of the metabolites most strongly correlated with bioactivity against elastase and collagenase target enzymes. This study is the first to correlate the secondary metabolites of C. infortunatum solvent-extracted fractions with their newly discovered anti-aging properties, representing a significant contribution to the field. Additionally, it presents the first molecular docking analysis of salsaside A, jionoside C, and 6'-caffeoyl-12-glucosyloxy-jasmonic acid against collagenase and elastase enzymes, revealing significant binding affinities and promising inhibitory potential. These findings underscore the potential of these metabolites as novel anti-aging compounds through their strong interactions with key target enzymes.

Modafinil is a well-established wake-promoting agent with emerging applications as a cognitive enhancer; however, its clinical potential is constrained by poor aqueous solubility and suboptimal systemic absorption, limiting effective brain delivery. This study presents transethosomes as a hitherto unexplored nanocarrier for modafinil and combines design-driven formulation with nuclear imaging-based biodistribution. Transethosomal vesicles were prepared using the ethanol injection method and systematically optimized through a 2 factorial design employing Design-Expert software. Key formulation variables were investigated for their impact on EE%, PS, PDI, and ZP. Additionally, an in-vivo biodistribution and pharmacokinetic studies were conducted after labeling MOD with Technetium-99 m using sodium dithionite as a reducing agent. The optimized formulation achieved a high desirability value (0.919), superior EE% (85.87%), nanoscale PS (180.30 nm), and a negative ZP (- 42.60 mV), indicative of excellent vesicular stability. Morphological and FTIR analyses confirmed spherical vesicles, drug-excipient compatibility, and preservation of Modafinil's structure. In-vitro studies demonstrated a controlled biphasic release, supporting sustained drug availability, while stability assessments revealed no significant changes in vesicular characteristics over time. Ex-vivo studies highlighted markedly enhanced permeability, due to improved membrane fluidity and vesicle deformability from ethanol and the edge activator. The radiolabeling efficiency was high (92.18%), and it was stable for two hours. Biodistribution and pharmacokinetic studies confirmed significantly higher brain drug accumulation, elevated brain C (5.4%ID/g) and AUC, reduced T (10 min) and high relative bioavailability (424.3 ± 4.5%). Importantly, histopathological examination of nasal mucosa revealed normal architecture. Collectively, these findings establish transethosomes as a promising and safe nano-platform for advanced brain targeting. HIGHLIGHTS: Modafinil-loaded transethosomes were designed as nanovesicles for brain targeting. The optimized formulation showed spherical morphology, uniform size distribution, and strong drug-carrier compatibility. Stability studies confirmed preserved physicochemical properties throughout storage. Ex-vivo permeation revealed significantly enhanced mucosal drug transport versus plain modafinil dispersion. In-vivo radio-distribution unambiguously confirmed superior uptake into the brain and improved targeting efficiency when contrasted with the reference preparation.

Venous thromboembolism (VTE) and pulmonary embolism (PE), remains a major global health burden, necessitating prolonged and reliable anticoagulant therapy. Although Apixaban (APX) is a cornerstone oral anticoagulant for VTE management, its therapeutic performance is limited by poor aqueous solubility and low oral bioavailability. To overcome these challenges, this study introduces a hybrid niosomal delivery system designed to enhance the absorption and systemic persistence of APX. The system was engineered by integrating hybrid of surfactants together with cholesterol to form a stable, vesicular matrix. Formulations were prepared via the ethanol injection method and systematically optimized using a 2 factorial design, assessing the influence of Span 60 concentration (Factor-A), cholesterol: drug ratio (Factor-B), and Tween 80 amount (Factor-C). The optimized formulation achieved a desirability score of 0.738, demonstrating high entrapment efficiency (72.82%), nanoscale particle size (160.05 nm) and a distinctly stable potential (-47.15 mV). TEM imaging confirmed spherical vesicles, and in-vitro release studies revealed a biphasic pattern characterized by an initial burst followed by sustained diffusion. Pharmacodynamics evaluations showed that the optimized formula produced a 1.55-fold increase in cuticle bleeding time (CBT) and a 1.65-fold prolongation in prothrombin time (PT) relative to the APX suspension. Pharmacokinetics assessments further demonstrated enhanced oral bioavailability, evidenced by increased AUC and C, along with reduced terminal elimination rate constant (λz) and extended systemic retention. Overall, the developed hybrid niosomes present a promising oral platform for APX delivery, offering improved absorption, and sustained therapeutic action.

The timely detection of impending seizures can offer physicians a critical window of opportunity to implement interventions and enable epileptic patients to take preventive and coping measures promptly. Traditional seizure prediction research has primarily focused on segment-based classification of EEG signals rather than event-based prediction, resulting in a lack of temporal continuity in prediction outcomes and limiting their practical usefulness. To address this limitation, this study introduces an innovative two-step approach for seizure prediction. First, the PSO-DAM-2DCNN model, which combines a particle swarm optimization (PSO) algorithm with a two-dimensional convolutional neural network (2DCNN) that features a dual attention mechanism (DAM) integrating spatial and channel attention modules, is utilized to conduct segment-based prediction. Subsequently, a two-layer 'k-of-n' logic filter is employed to detect seizure events effectively. The proposed method demonstrates promising performance on both the CHB-MIT and the Huashan Hospital private datasets, excelling in both segment-based performance metrics and event-based metrics such as FPR/h, FNR, and TPR.

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of coronavirus disease 2019 (COVID-19), characterized by persistent fever, systemic inflammation, and organ failure. Its clinical features may overlap with hemophagocytic syndrome, Kawasaki disease, macrophage activation syndrome, and toxic shock syndrome.

The purpose of this study was to evaluate how universal adhesives affected the proliferation of gingival fibroblasts and human dental pulp stem cells by measuring cell viability at different time points: 1 min, 1 h, and 6 h. The measurement of TNF-α levels after 6 h was performed to assess any inflammatory reactions or cytokine release triggered by the materials. The antimicrobial properties against Lactobacilli and Streptococcus mutans, using the agar diffusion assay after 24 h were assessed. The single-bottle adhesives tested were: Huge Bond (Huge Dental, USA), Single Bond Universal (3 M, USA), and G-Premio BOND (GC, Japan). Huge Bond and Single Bond showed a marked decrease in cell viability after 6 h, with Single Bond exhibiting the most significant reduction (p < 0.0001). Huge Bond exhibited the highest TNF-α expression, followed by Single Bond and G-Premio. Huge Bond stands out for its superior performance against both bacterial strains (p = 0.0001). Methacrylate monomers are mostly associated with cytotoxicity if not fully polymerized because they have the ability to leach and harm dental pulp cells and gingival fibroblasts. All three materials have initial antimicrobial activity associated with the acidic monomer that was prominent with Huge Bond and G-Premio.

The outcome of acute myeloid leukemia (AML) is heterogeneous, with both patient-related and disease-related factors contributing to an individual patient’s likelihood of achieving a therapeutic response and survival. The Calcitonin Receptor-Like (CALCRL) gene, which encodes the calcitonin receptor-like receptor, has emerged as a point of interest in studying AML. Its expression levels may hold clinical relevance and contribute to the prognostic assessment of AML patients. In the current study, we evaluated CALCRL gene expression levels to verify their possible association with the clinical and laboratory characteristics of AML and to clarify its potential role as a molecular prognostic marker in a cohort of Egyptian AML patients. Methods: CALCRL gene expression was estimated in 80 newly diagnosed adult Egyptian AML patients by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Results: CALCRL gene expression in AML cases ranged from 0.11 to 104.11, with a median value of 2.1. It was higher in AML cases compared to controls; however, the difference was not statistically significant. AML cases were stratified into high and low CALCRL expression groups. Overall survival (OS) was higher in CALCRL-low compared to CALCRL-high expressers, yet the difference was not statistically significant. There was no statistical difference between CALCRL-high and CALCRL-low expressers regarding their complete remission rate (CR) and relapse-free survival (RFS). However, the incidence of relapse was higher in CALCRL-low expressers. In our study, the median age of the AML cases was 43 years. OS was significantly longer in CALCRL-low expressers, while RFS was significantly longer in CALCRL-high expressers younger than 43 years old. Conclusion: Studying CALCRL gene expression in larger cohorts and over longer follow-up periods is highly recommended to gain deeper insight into its functional role in oncogenesis and chemoresistance, as well as its potential as a molecular prognostic marker and future therapeutic target.

BackgroundLeukocyte platelet-rich fibrin (PRF), a second-generation blood-derived concentrate, has been thoroughly studied. Decreasing the relative centrifugation force during PRF production is said to enhance the contents of cellular and growth factors, which subsequently improves their therapeutic impact.

Aim

To evaluate the low-speed centrifugation concept used in the preparation of PRF and compare it to high-speed centrifugation.

Patients and methods

Eighty healthy volunteers participated in our study, and they were divided into two equal groups (group I and group II). Three noncoagulated blood samples were withdrawn from each volunteer. Two protocols were selected for the preparation of the PRF clot: a high-speed protocol at 2400 rpm for 10 min (group I) and a low-speed protocol at 1200 rpm for 10 min (group II).

Results

The three PRF clots were examined: the first for macroscopic and histological analysis, the second for scanning electron microscopy, and the third for cellular counts using an automated hematology analyzer, as well as for measuring the concentrations of vascular endothelial growth factor and transforming growth factor β1 in the fluid exudate produced from its compression. The PRF prepared using the low-speed protocol had higher concentrations of cellular components, vascular endothelial growth factor, and transforming growth factor β1 than those prepared with the high-speed protocol. PRF prepared using a low-speed protocol is sufficient and offers better quality than that prepared using a high-speed protocol.

The holobiont" refers to the plant and its associated microbiota that are pivotal to the plant's health, fitness, and survival. By in vitro culturing and functionally characterizing members of the plant microbiota, their specific roles in influencing plant responses to environmental changes can be determined and manipulated to foster sustainable agriculture and ecosystem management.

Phytohormones play an important role in plant adaptation to the environment by regulating stress responses via a dynamic system. Conventional techniques used in assessing the concentrations of phytohormones can only give a static picture at a certain moment, hence, the dynamic physiological processes that influence stress resistance cannot be analyzed. There is a need to change the paradigm of analysis from a static approach to a dynamic multi-scale imaging and monitoring approach. In this paper, we review the recent developments in bioelectronics and optoelectronics that enable the observation of phytohormone at different biological levels. Finally, we look at the application of Artificial Intelligence (AI) in the data analysis of multiple sensors and present the concept of the "Dynamic Plant Digital Twin."

Phytohormones play an important role in plant adaptation to the environment by regulating stress responses via a dynamic system. Conventional techniques used in assessing the concentrations of phytohormones can only give a static picture at a certain moment, hence, the dynamic physiological processes that influence stress resistance cannot be analyzed. There is a need to change the paradigm of analysis from a static approach to a dynamic multi-scale imaging and monitoring approach. In this paper, we review the recent developments in bioelectronics and optoelectronics that enable the observation of phytohormone at different biological levels. Finally, we look at the application of Artificial Intelligence (AI) in the data analysis of multiple sensors and present the concept of the "Dynamic Plant Digital Twin."

INTRODUCTION: The development of novel anticancer agents targeting DNA replication and repair mechanisms remains a priority in leukemia therapy. In this study, newly synthesized derivatives incorporating bis-indole and pyrazolo[3,4-]pyridine scaffolds were evaluated for their antiproliferative potential against leukemia cell lines.

METHODS: The antiproliferative activity of the synthesized compounds was assessed in four cancer cell lines, including acute myeloid leukemia (MV4-11) and chronic myeloid leukemia (K562). Growth inhibition (GI) values were determined. DNA relaxation assays were performed to evaluate inhibition of topoisomerase I and IIα activities. Cell cycle distribution, apoptosis induction, and DNA damage response markers were analyzed using cellular and molecular assays. Combination studies were conducted using CHK1, ATR, and PARP-1 inhibitors.

RESULTS: Compounds , , and demonstrated the most potent antiproliferative activity, with GI values below 2.5 μM in leukemic cell lines. Compound exhibited notable cytotoxicity, with GI values of 1.1 μM (MV4-11) and 2.7 μM (K562). Compounds and significantly inhibited topoisomerase I activity and effectively suppressed topoisomerase IIα-mediated DNA relaxation. Cellular studies revealed S-phase cell cycle arrest, activation of apoptotic pathways (caspase cleavage and PARP-1 degradation), and induction of DNA damage response markers (γH2AX, p-CHK1, p53). In MV4-11 cells, combination treatment with CHK1 or ATR inhibitors resulted in pronounced synergistic cytotoxicity, whereas co-treatment with a PARP-1 inhibitor produced minimal synergy.

DISCUSSION: These findings identify bis-indole and pyrazolo[3,4-]pyridine derivatives, particularly compound , as potent dual topoisomerase inhibitors with significant antileukemic activity. Their ability to induce DNA damage and enhance cytotoxicity in combination with DNA damage response inhibitors highlights their potential therapeutic value, especially in combination strategies targeting replication stress pathways in leukemia.

Elderberry (Sambucus nigra L.) has been traditionally implemented in diverse preparations such as herbal teas, syrups or juices as remedies for respiratory, febrile and other health conditions. Phytochemical and chromatographic analyses of different organs mapped their metabolite profiles and allowed identification, and sometimes isolation, of their main bioactive compounds.

Introduction: Oral mucositis is a debilitating complication in patients receiving head and neck radiotherapy. Benzydamine hydrochloride has been broadly used for the management of radiation induced oral mucositis .Aloe vera has anti-inflammatory and wound-healing properties therefore the aim of the present study to evaluate the efficacy of aloe vera gel in radiation induced oral mucositis Materials and Methods: Thirty-six head and neck cancer patients undergoing radiotherapy were randomly allocated to receive either 10% Aloe vera gel (Arm A) or benzydamine hydrochloride gel (Arm B), applied three times daily for six weeks. Oral mucositis severity (RTOG scale) and Numerical Rating Scale were assessed at baseline and at weeks 2, 4, 6, and 10. Results: No statistically significant differences were observed between groups in mucositis grade or pain scores at any assessment time point (p > 0.05). Both groups demonstrated a similar sequential pattern, with mucositis and pain reaching their peak around week 6 while getting better by week 10. Intragroup analysis showed significant changes over time in both arms (p < 0.0001). Conclusions: Aloe vera gel demonstrated comparable efficacy to benzydamine hydrochloride in the prevention and management of radiation induced oral mucositis therefore aloe vera may represent a feasible substitute Trial registration: The current study was registered in clinicaltrials.gov ID NCT06879366

Ammonia-hydrogen co-combustion offers a promising pathway for carbon–neutral internal combustion engines (ICEs), yet the synergistic effects of ammonia energy ratio (AER) and valve overlap angle (VOA) on combustion dynamics and emissions lack comprehensive analysis in dual-fuel engines. This study experimentally investigates the interplay between AER, VOA, and operating conditions (load, speed) in a turbocharged dual-fuel engine. Results reveal that increasing AER from 0% to 86% at 2000 rpm and 5 bar BMEP reduces peak combustion temperature by ∼ 26% (2700 K to 2000 K), heat transfer losses by 25% (43% to 32%), and NOx emissions by 64%, albeit with a 100% increase in unburned NH3 emissions and doubled combustion duration. Higher loads (BMEP > 5 bar) enable AER exceeding 95%, while elevated engine speeds prolong ignition delay and limit maximum AER. Negative VOA reduces pumping losses and internal exhaust gas recirculation (EGR), enhancing combustion stability and AER tolerance. Conversely, positive VOA increases EGR, destabilizing combustion and restricting AER to 25% at 50 °CA overlap. Optimizing valve-closed injection timing improves mixture homogeneity and combustion efficiency. This work establishes a foundational framework for balancing stability, efficiency, and emissions in ammonia-hydrogen engines, emphasizing the necessity of synergistic parameter optimization under dynamic operating conditions.

Ammonia-hydrogen co-combustion offers a promising pathway for carbon–neutral internal combustion engines (ICEs), yet the synergistic effects of ammonia energy ratio (AER) and valve overlap angle (VOA) on combustion dynamics and emissions lack comprehensive analysis in dual-fuel engines. This study experimentally investigates the interplay between AER, VOA, and operating conditions (load, speed) in a turbocharged dual-fuel engine. Results reveal that increasing AER from 0% to 86% at 2000 rpm and 5 bar BMEP reduces peak combustion temperature by ∼ 26% (2700 K to 2000 K), heat transfer losses by 25% (43% to 32%), and NOx emissions by 64%, albeit with a 100% increase in unburned NH3 emissions and doubled combustion duration. Higher loads (BMEP > 5 bar) enable AER exceeding 95%, while elevated engine speeds prolong ignition delay and limit maximum AER. Negative VOA reduces pumping losses and internal exhaust gas recirculation (EGR), enhancing combustion stability and AER tolerance. Conversely, positive VOA increases EGR, destabilizing combustion and restricting AER to 25% at 50 °CA overlap. Optimizing valve-closed injection timing improves mixture homogeneity and combustion efficiency. This work establishes a foundational framework for balancing stability, efficiency, and emissions in ammonia-hydrogen engines, emphasizing the necessity of synergistic parameter optimization under dynamic operating conditions.