Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-cateni...Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-catenin(WβC)signaling pathway,a crucial player in neurogenesis,neuronal survival,and synaptic plasticity,is involved in several cellular mechanisms related to NDs.Dysregulation of this pathway is a hallmark in the development of various NDs.This study explores multiple polyphenolic compounds,such as flavonoids,stilbenes,lignans,and phenolic acids,and their potential to protect the nervous system.It provides a comprehensive analysis of their effects on the WβC pathway,elucidating their modes of action.The study highlights the dual function of polyphenols in regulating and protecting the nervous system,providing reassurance about the research benefits.This review provides a comprehensive analysis of the results obtained from both in vitro studies and in vivo research,shedding light on how these substances influence the various components of the pathway.The focus is mainly on the molecular mechanisms that allow polyphenols to reduce oxidative stress,inflammation,and apoptotic processes,ultimately improving the function and survival of neurons.This study aims to offer a thorough understanding of the potential of polyphenols in targeting the WβC signaling pathway,which could lead to the development of innovative therapeutic options for NDs.展开更多
Background:Locally advanced laryngeal squamous cell carcinoma(LA-LSCC)presents clinical challenges due to the lack of reliable non-invasive biomarkers.This study aimed to evaluate miR-449a as a diagnostic and prognost...Background:Locally advanced laryngeal squamous cell carcinoma(LA-LSCC)presents clinical challenges due to the lack of reliable non-invasive biomarkers.This study aimed to evaluate miR-449a as a diagnostic and prognostic biomarker in LA-LSCC.Methods:miR-449a expression was analyzed in tumor tissues,adjacent normal tissues,and serum from 81 LA-LSCC patients and 50 controls using quantitative real-time reverse transcription polymerase chain reaction(qRT-PCR).We assessed the diagnostic accuracy by Receiver Operating Characteristic curve(ROC curves),clinicopathological associations,survival outcomes(Kaplan-Meier),and treatment response dynamics.Results:miR-449a was significantly downregulated in LA-LSCC tissues(p<0.0001)and serum(p<0.0001),with a strong tissue-serum correlation(R^(2)=0.988).Tissue miR-449a demonstrated a diagnostic accuracy(Area Under the Curve,AUC=0.857),while serum showed moderate accuracy(AUC=0.734).High miR-449a expression correlated with favorable clinicopathological features and improved survival(median overall survival:67.82 vs.23.74 months;p=0.0012).Multivariate analysis confirmed miR-449a as an independent prognostic factor(p<0.001).miR-449a levels increased post-treatment,particularly in responders to chemotherapy/radiation(p<0.0001).Conclusion:miR-449a serves as a non-invasive biomarker for LA-LSCC diagnosis,prognosis,and treatment monitoring.Its dynamic expression highlights potential for risk stratification and therapy response prediction,warranting further validation in larger cohorts.展开更多
Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinso...Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease,this plasticity is disrupted,leading to cognitive and motor deficits.This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease.Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function,while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control.Enhancing neuronal plasticity offers therapeutic potential for these diseases.A systematic literature review was conducted using databases such as PubMed,Scopus,and Google Scholar,focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease.Data synthesis identified key themes such as synaptic mechanisms,neurogenesis,and therapeutic strategies,linking molecular insights to clinical applications.Results highlight that targeting synaptic plasticity mechanisms,such as long-term potentiation and long-term depression,shows promise.Neurotrophic factors,advanced imaging techniques,and molecular tools(e.g.,clustered regularly interspaced short palindromic repeats and optogenetics)are crucial in understanding and enhancing plasticity.Current therapies,including dopamine replacement,deep brain stimulation,and lifestyle interventions,demonstrate the potential to alleviate symptoms and improve outcomes.In conclusion,enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases.Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.展开更多
Male breast cancer(MBC)is rare,representing 0.5%–1%of all breast cancers,but its incidence is increasing due to improved diagnostics and awareness.MBC typically presents in older men,is human epidermal growth factor ...Male breast cancer(MBC)is rare,representing 0.5%–1%of all breast cancers,but its incidence is increasing due to improved diagnostics and awareness.MBC typically presents in older men,is human epidermal growth factor receptor 2(HER2)-negative and estrogen receptor(ER)-positive,and lacks routine screening,leading to delayed diagnosis and advanced disease.Major risk factors include hormonal imbalance,radiation exposure,obesity,alcohol use,and Breast Cancer Gene 1 and 2(BRCA1/2)mutations.Clinically,it may resemble gynecomastia but usually appears as a unilateral,painless mass or nipple discharge.Advances in imaging and liquid biopsy have enhanced early detection.Molecular mechanisms involve hormonal signaling,HER2/epidermal growth factor receptor(EGFR)pathways,tumor suppressor gene alterations,and epigenetic changes.While standard treatments mirror those for female breast cancer,emerging options such as cyclin-dependent kinase 4 and 6(CDK4/6),and poly(ADP-ribose)polymerase(PARP)inhibitors,immunotherapy,and precision medicine are reshaping management.Incorporating artificial intelligence,molecular profiling,and male-specific clinical trials is essential to improve outcomes and bridge current diagnostic and therapeutic gaps.展开更多
The cloud-fog computing paradigm has emerged as a novel hybrid computing model that integrates computational resources at both fog nodes and cloud servers to address the challenges posed by dynamic and heterogeneous c...The cloud-fog computing paradigm has emerged as a novel hybrid computing model that integrates computational resources at both fog nodes and cloud servers to address the challenges posed by dynamic and heterogeneous computing networks.Finding an optimal computational resource for task offloading and then executing efficiently is a critical issue to achieve a trade-off between energy consumption and transmission delay.In this network,the task processed at fog nodes reduces transmission delay.Still,it increases energy consumption,while routing tasks to the cloud server saves energy at the cost of higher communication delay.Moreover,the order in which offloaded tasks are executed affects the system’s efficiency.For instance,executing lower-priority tasks before higher-priority jobs can disturb the reliability and stability of the system.Therefore,an efficient strategy of optimal computation offloading and task scheduling is required for operational efficacy.In this paper,we introduced a multi-objective and enhanced version of Cheeta Optimizer(CO),namely(MoECO),to jointly optimize the computation offloading and task scheduling in cloud-fog networks to minimize two competing objectives,i.e.,energy consumption and communication delay.MoECO first assigns tasks to the optimal computational nodes and then the allocated tasks are scheduled for processing based on the task priority.The mathematical modelling of CO needs improvement in computation time and convergence speed.Therefore,MoECO is proposed to increase the search capability of agents by controlling the search strategy based on a leader’s location.The adaptive step length operator is adjusted to diversify the solution and thus improves the exploration phase,i.e.,global search strategy.Consequently,this prevents the algorithm from getting trapped in the local optimal solution.Moreover,the interaction factor during the exploitation phase is also adjusted based on the location of the prey instead of the adjacent Cheetah.This increases the exploitation capability of agents,i.e.,local search capability.Furthermore,MoECO employs a multi-objective Pareto-optimal front to simultaneously minimize designated objectives.Comprehensive simulations in MATLAB demonstrate that the proposed algorithm obtains multiple solutions via a Pareto-optimal front and achieves an efficient trade-off between optimization objectives compared to baseline methods.展开更多
Micro/nanorobots represent a groundbreaking advancement in nanotechnology,with applications spanning medicine,envi-ronmental remediation,and industrial processes.A major challenge in their development is achieving eff...Micro/nanorobots represent a groundbreaking advancement in nanotechnology,with applications spanning medicine,envi-ronmental remediation,and industrial processes.A major challenge in their development is achieving efficient and bio-compatible propulsion.Enzyme-driven propulsion,particularly using catalase,offers a promising solution due to its ability to decompose hydrogen peroxide(H2O2)into water and oxygen,generating thrust for autonomous movement.Compared to metal-based catalysts,catalase-powered systems exhibit superior biocompatibility and lower toxicity,making them ideal for biomedical applications.This review explores the role of catalase in micro/nanorobot propulsion,highlighting self-propulsion mechanisms,different nanorobot types,and their applications in drug delivery,infection treatment,cancer therapy,and biosensing.Additionally,recent advancements in biodegradable enzyme-powered nanorobots and their poten-tial in overcoming biological barriers are discussed.With further research,catalase-driven nanorobots could revolutionize targeted therapy and diagnostic techniques,paving the way for innovative solutions in nanomedicine.展开更多
Objective:To determine the genetic diversity,natural selection and mutations in Plasmodium(P.)knowlesi drug resistant molecular markers Kelch 13 and dhps gene in clinical samples of Malaysia.Methods:P.knowlesi full-le...Objective:To determine the genetic diversity,natural selection and mutations in Plasmodium(P.)knowlesi drug resistant molecular markers Kelch 13 and dhps gene in clinical samples of Malaysia.Methods:P.knowlesi full-length gene sequences Kelch 13 gene(PkK13)from 40 samples and dhps gene from 30 samples originating from Malaysian Borneo were retrieved from public databases.Genetic diversity,natural selection,and phylogenetic analysis of gene sequences were analysed using DNAsp v5.10 and MEGA v5.2.Results:Seventy-two single nucleotide polymorphic sites(SNPs)across the full-length PkK13 gene(63 synonymous substitutions and 9 non-synonymous substitutions)with nucleotide diversity ofπ~0.005 was observed.Analysis of the full-length Pkdhps gene revealed 73 SNPs andπ~0.006(44 synonymous substitutions and 29 non-synonymous substitutions).A high number of haplotypes(PkK13;H=37 and Pkdhps;H=29)with haplotype diversity of Hd~0.99 were found in both genes,indicating population expansion.Nine mutant alleles were identified in PkK13 amino acid alignment of which,7(Asp3Glu,Lys50Gln,Lys53Glu,Ser123Thr,Ser127Pro,Ser149Thr and Ala169Thr)were within the Plasmodium specific domain,2(Val372Ile and Lys424Asn)were in the BTB/POZ domain and no mutation was observed within the kelch propeller domain.The 29 non-synonymous mutations in the Pkdhps gene were novel and only presented in exon 1 and 2.Conclusions:Monitoring the mutations from clinical samples collected from all states of Malaysia along with clinical efficacy studies will be necessary to determine the drug resistance in P.knowlesi.展开更多
Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address t...Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.展开更多
Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options...Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.展开更多
Artemisia dracunculus L.,or tarragon,is a perennial herb from the Asteraceae family that is extensively cultivated for its aromatic leaves,which are valued for its preventative and therapeutic properties in both cooke...Artemisia dracunculus L.,or tarragon,is a perennial herb from the Asteraceae family that is extensively cultivated for its aromatic leaves,which are valued for its preventative and therapeutic properties in both cookery and traditional medicine.This study aims to investigate the antibacterial,antioxidant,and anti-inflammatory properties of A.dracunculus(tarragon)essential oil(ADEO),with estragole(57.23%)identified as the major compound through gas chromatography-mass spectrometry(GC-MS)analysis.ADEO exhibited varying degrees of antibacterial activity,with Escherichia coli showing higher resistance inhibition zone(IZ)=14.7±0.58 mm,minimum (inhibitory concentration(MIC)=2%and minimum bactericidal concentration(MBC)=4%),while Bacillus subtilis(IZ=24.05±2.11 mm and MIC=MBC=0.125%)and Staphylococcus aureus(IZ=18.69±1.45 mm,MIC=0.0612%and MBC=0.125%)were more sensitive to its actions.Antioxidant ability was assessed using 1,1-diphenyl-2-picrylhydrazil(DPPH),2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS),xanthine oxidase inhibition,and beta-carotene bleaching assays.ADEO showed remarkable antiradical effect on DPPH(IC_(50)=127.05±3.47μg/mL)and ABTS radical(IC_(50)=89.60±8.73μg/mL)as well as significant inhibition of xanthine oxidase(IC_(50)=47.9±2.04μg/mL)and lipid peroxidation(IC_(50)=231.63±5.21μg/mL).ADEO also showed significant anti-inflammatory activity by inhibiting the enzymesCOX-1(IC_(50)=59.2±2.43μg/mL),Cyclo-oxygenase-2(COX-2)(IC_(50)=74.68±1.34μg/mL)and 5-lipooxygense(5-LOX)(IC_(50)=93.18±1.87μg/mL),which are involved in the inflammatory pathway.These findings suggest that ADEO,with its high estragole content,holds promising potential as a natural antibacterial,antioxidant,and anti-inflammatory agent for preventive and therapeutic applications.Further research is needed to explore its safety and efficacy in clinical settings.展开更多
Background:The JAK2^(V617F)mutation plays a crucial part in the pathogenesis of myeloproliferative neoplasms(MPN),which includes polycythemia vera(PV),essential thrombocythemia(ET),and primary myelofibrosis(PMF)leadin...Background:The JAK2^(V617F)mutation plays a crucial part in the pathogenesis of myeloproliferative neoplasms(MPN),which includes polycythemia vera(PV),essential thrombocythemia(ET),and primary myelofibrosis(PMF)leading to aberrant proliferation and survival of hematopoietic cells.Alongside the challenges of drug resistance and side effects,identifying novel compounds that selectively target JAK2^(V617F)could provide more effective and safer therapeutic options for patients with MPNs.Materials and Methods:We employed computational approaches like high-throughput virtual screening,molecular dynamics simulations(MDS),and binding free energy calculations to identify inhibitors targeting wild and mutant JAK2 kinases.JAK2^(V617F)positive HEL,wild type JAK2 positive TF-1,and non-cancerous Vero cells were used for in vitro validations.Results:SBLJ23 emerged as a top candidate inhibitor with specificity for JAK2^(V617F).Protein-ligand interaction studies and MDS revealed stable interactions and binding of SBLJ23 over the simulation period,with Root Mean Square Deviation(RMSD)indicating consistent binding after 1t15ns.SBLJ23 displayed a half maximal inhibitory concentration(IC_(50))value of 522.4 nM against the JAK2 enzyme.The compound exhibited inhibition of cell proliferation in HEL and TF-1 cells,with half maximal cell growth inhibitory concentration(GI 50)values of 2.51 and 15.87μM,respectively.Moreover,SBLJ23 induced G 2/M cell cycle arrest in HEL cells to facilitate apoptosis in these cell lines.The compound significantly reduced the percentage of phospho JAK2 and phospho STAT3 in HEL cells.Conclusion:High binding affinity,stable interaction profile,favorable binding free energy,and in vitro validations claim SBLJ23 as a potential lead compound against JAK2^(V617F)and suggest further development and optimization towards clinical application in managing myeloproliferative neoplasms.展开更多
Objectives:Targeting epigenetic modifications in anticancer therapy is a promising approach to overcoming cancer cell chemoresistance.The histone deacetylase/DNA methyltransferase inhibitor,parthenolide(PTL),has antit...Objectives:Targeting epigenetic modifications in anticancer therapy is a promising approach to overcoming cancer cell chemoresistance.The histone deacetylase/DNA methyltransferase inhibitor,parthenolide(PTL),has antitumor activity,but contrasting findings exist on its effect in normal cells.This study aims to examine the nongenomic toxic mechanisms of PTL in human erythrocytes.Methods:Cell death as stimulated by 20–200μMof PTL for 24 h at 37℃ was assessed using fluorescence-assorted cell sorting and spectrophotometric assays.Canonical markers of cell death,including membrane scrambling,oxidative stress,and Ca^(2+)mobilization,were captured by annexin V-fluorescein isothiocyanate,2′,7′-dichlorodihydrofluorescein diacetate,and Fluo4/AM labeling,respectively.Rescue experiments usingawide arrayof inhibitorswere also conducted.Results:PTL stimulated significantmembrane scrambling and blebbing,and showed potent hemolytic activity coupled with significant elevations in dichlorofluorescein and Fluo4 fluorescence.While hemolysis was ameliorated by glutathione,caffeine,acetylsalicylic acid,staurosporin,necrosulfonamide,guanosine,and Ca^(2+)deprivation,it was rather exacerbated by necrostatin-2,tumor necrosis factor α(TNFα)or Fas ligand(FasL)neutralization,and concurrent Ca^(2+)deprivation and membrane depolarization.In contrast,eryptosis was attenuated by N-acetyl-cysteine,TNFα,or FasL blockade,and simultaneous Ca^(2+)elimination and KCl enrichment;and augmented by necrostatin-2,necrosulfonamide,and adenosine triphosphate.Interestingly,loss of volume was only prevented by melatonin,acetylsalicylic acid,and N(gamma)-nitro-L-arginine methyl ester.Conclusion:PTL stimulates oxidative hemolysis and eryptosis through Ca^(2+)mobilization and death ligand signaling involving the cyclooxygenase/protein kinase C/mixed lineage kinase domain-like pseudokinase axis.This research highlights the non-genomic toxic mechanisms of PTL and presents potential pharmacological targets for mitigating its adverse off-target effects.展开更多
Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networ...Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networks(CNNs)excel in local feature extraction,their ability to capture global contextual relationships in complex cellular morphologies is limited.This study introduces a hybrid CNN-Transformer framework to enhance normal blood cell classification,laying the groundwork for future leukemia diagnostics.Methods:The proposed architecture integrates pre-trained CNNs(ResNet50,EfficientNetB3,InceptionV3,CustomCNN)with Vision Transformer(ViT)layers to combine local and global feature modeling.Four hybrid models were evaluated on the publicly available Blood Cell Images dataset from Kaggle,comprising 17,092 annotated normal blood cell images across eight classes.The models were trained using transfer learning,fine-tuning,and computational optimizations,including cross-model parameter sharing to reduce redundancy by reusing weights across CNN backbones and attention-guided layer pruning to eliminate low-contribution layers based on attention scores,improving efficiency without sacrificing accuracy.Results:The InceptionV3-ViT model achieved a weighted accuracy of 97.66%(accounting for class imbalance by weighting each class’s contribution),a macro F1-score of 0.98,and a ROC-AUC of 0.998.The framework excelled in distinguishing morphologically similar cell types demonstrating robustness and reliable calibration(ECE of 0.019).The framework addresses generalization challenges,including class imbalance and morphological similarities,ensuring robust performance across diverse cell types.Conclusion:The hybrid CNN-Transformer framework significantly improves normal blood cell classification by capturing multi-scale features and long-range dependencies.Its high accuracy,efficiency,and generalization position it as a strong baseline for automated hematological analysis,with potential for extension to leukemia subtype classification through future validation on pathological samples.展开更多
The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative ba...The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative bacterial infections,serves as a crucial final recourse against carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Nevertheless,the clinical usage of PMB is impeded by its pronounced nephrotoxicity and poor infection site targeting.This investigation is geared to construct a nanoparticle formulation(named HA-PMB@H)comprising hyaluronic acid(HA)and PMB via a simple Schiff base reaction and further coating HA by electrostatic action.HA-PMB@H shows an average size of(153.8±24.3)nm,and a mean zeta potential of(−25.6±5.2)mV.Additionally,PMB can be released from HA-PMB@H more thoroughly and efficiently at pH 5.5 compared to pH 7.4,which demonstrates the Schiff base modification of PMB paves the way for its release at focus of infection.The uptake ratio of HA-PMB@H by alveolar epithelial cells(RLE-6TN)surpassed that of free PMB devoid of HA,which facilitates to the intracellular sterilization of PMB.Furthermore,the employment of HA-PMB@H ameliorated the toxicity of PMB towards human embryonic kidney cells(HEK 293)and pulmonary microvascular endothelial cells(HULEC-5a).What is more,HA-PMB@H effectively managed severe pneumonia induced by CRKP samples from clinical patients diagnosed with CRKP infection in vivo,substantially enhancing the survival rate of mice.Consequently,this nano-delivery system holds promising clinical significance in the combat against drug-resistant bacterial infections.展开更多
AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a co...AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.展开更多
AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
Background:Diabetes mellitus(DM)is a prevalent chronic metabolic condition characterized by high blood sugar levels,resulting from insufficient insulin production or ineffective insulin use,posing substantial global h...Background:Diabetes mellitus(DM)is a prevalent chronic metabolic condition characterized by high blood sugar levels,resulting from insufficient insulin production or ineffective insulin use,posing substantial global health issues.Research on the relationship between glycemic status and the ratio of neutrophils to lymphocytes(NLR)and monocytes to lymphocytes(MLR)is limited.This study aimed to fill these knowledge gaps by examining the connection between DM and inflammatory markers within the Asir region.Methods:Data from 3545 participants were retrospectively analyzed.The dataset,gathered between 2021 and 2023,comprises 38 laboratory tests obtained from the Future Lab Pioneer database.The study's inclusion criteria focused on diabetes profile tests(glycated hemoglobin[HbA1c]and fasting blood glucose[FBG])and manually computed inflammatory markers(NLR and MLR),which were stratified by age and sex.Results:This study demonstrated significant differences in NLR levels compared with FBG levels across all adult age groups and adult female participants(p<0.0001),as well as among all elderly age groups(p=0.0006)and elderly women(p=0.01).MLR levels were significant in all adult age groups(p=0.04)and in adult women(p=0.02).When NLR and MLR were compared to HbA1c levels,a significant difference in the mean NLR was found in adult women(p=0.005).Additionally,the mean MLR levels were significant in all adult age groups(p=0.04)and adult women(p=0.02).Conclusion:Although a larger sample size is necessary for this research,the results indicate that NLR and MLR could serve as valuable indicators for evaluating inflammation in people with disrupted glucose metabolism,particularly in adult and female populations.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of ...BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of adenomas in the colon during the second decade of life.If prophylactic colectomy is not performed,most patients eventually develop colorectal cancer(CRC).CASE SUMMARY We present the mutational profile of a case of FAP that progressed to CRC.A 45-year-old Saudi man presented with intestinal obstruction and underwent a total colectomy.The colon showed hundreds of polyps and two infiltrative ulcerative lesions,which proved to be adenocarcinoma according to histopathology.We performed next-generation sequencing and found mutations in the TP53,NRAS,EGFR PDGFR,MET,KIT,ERBB2,and GUSP genes.CONCLUSION To the best of our knowledge,this case report is the first to sheds the light on the mutation profile of FAP that progressed to CRC in Saudi Arabia.展开更多
The interest in using the Datura stramonium plant is due to its natural products,which are used in many pharmaceutical industries.The objective of the current study was to assess the therapeutic and cytotoxic effects ...The interest in using the Datura stramonium plant is due to its natural products,which are used in many pharmaceutical industries.The objective of the current study was to assess the therapeutic and cytotoxic effects of the D.stramonium plant on two types of human cancer cell models(MCF7 and HT29)in vitro.A soxhlet apparatus was used to obtain methanolic extract from dried plant leaves.The recovered crude,after the solvent had evaporated,was then dispersed at varied concentrations of extract 100,50,20,and 0.0µg/mL and tested to see how the cells responded.Also,the cancer-testis antigen(CTA)gene transcription in the two cell types exposed to the plant extract was examined using a semi-quantitative real-time polymerase chain reaction.Gas chromatography–mass spectrometry(GC-MS)results produced the significant main metabolites Nonanoic acid,Tropine N-Oxide,3,6-Ditigloyloxy-7-hydroxytropane,Hexadecanoic acid,2-Pentadecanone,6,10,14-trimethyl-,Carvenone,methyl ester,Phytol,Aposcopolamine,Hyoscyamine,4,8,12,16-Tetramethylheptadecan-4-olide,Scopolamine,Alpha.-Tocospiro A,1,2-Cycloheptanedione,3,3,7,7-tetramethyl-,dihydrazone,Campesterol,Stigmasterol,Gamma-Sitosterol and dl-.alpha.-Tocopherol.The results showed that the two types of cell lines impacted by D.stramonium extract,through untreated type 1 cells(MCF7)gave a highly significant transcription according to all applicable genes.All implemented analyses cleared the strong genetic impacts of Datura extract on cancer cells’genomes.TGIF2LY and C2orf63 transcript accumulation were also significantly elevated when exposed to plant extract at a level of 50µg/mL in cell line type 2(HT29),but TGIF2LY and P53 had the lowest relative expression at a level of 100µg/mL when treated the same cell line type.展开更多
The increasing incidence of neurodegenerative diseases(NDs)and the constraints of existing treatment methods have spurred a keen interest in investigating alternative therapies.Medicinal plants,renowned for their long...The increasing incidence of neurodegenerative diseases(NDs)and the constraints of existing treatment methods have spurred a keen interest in investigating alternative therapies.Medicinal plants,renowned for their long-standing use in traditional medicine,offer a hopeful avenue for discovering new neuroprotective agents.This study emphasizes the potential neuroprotective characteristics of edible fruit plants in Bangladesh,specifically focusing on their traditional folk medicine uses for neurological disorders.This study provides an in-depth overview of the different types of edible fruit trees in Bangladesh and their phytochemicals,including flavonoids,terpenoids,and phenolic acids.This work examines the scientific data supporting the neuroprotective properties of bioactive chemicals from plants.It further explores the mechanisms by which these compounds work to counteract oxidative stress,decrease inflammation,and stimulate neurogenesis.Moreover,the study investigates toxicological characteristics and bioactive components of some fruits,emphasizing the importance of further investigation to measure their safety profile comprehensively.This thorough study highlights the potential benefits of Bangladesh's edible fruit trees as a rich source of neuroprotective chemicals.It also shows that additional research might lead to novel approaches for improving brain functioning and preventing NDs.展开更多
基金financially supporting this work through the Large Research Group Project under Grant no.R.G.P.2/509/45
文摘Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-catenin(WβC)signaling pathway,a crucial player in neurogenesis,neuronal survival,and synaptic plasticity,is involved in several cellular mechanisms related to NDs.Dysregulation of this pathway is a hallmark in the development of various NDs.This study explores multiple polyphenolic compounds,such as flavonoids,stilbenes,lignans,and phenolic acids,and their potential to protect the nervous system.It provides a comprehensive analysis of their effects on the WβC pathway,elucidating their modes of action.The study highlights the dual function of polyphenols in regulating and protecting the nervous system,providing reassurance about the research benefits.This review provides a comprehensive analysis of the results obtained from both in vitro studies and in vivo research,shedding light on how these substances influence the various components of the pathway.The focus is mainly on the molecular mechanisms that allow polyphenols to reduce oxidative stress,inflammation,and apoptotic processes,ultimately improving the function and survival of neurons.This study aims to offer a thorough understanding of the potential of polyphenols in targeting the WβC signaling pathway,which could lead to the development of innovative therapeutic options for NDs.
基金The authors extend their appreciation to Taif University,Saudi Arabia,for supporting this work through project No.(TU-DSPP-2024-54).
文摘Background:Locally advanced laryngeal squamous cell carcinoma(LA-LSCC)presents clinical challenges due to the lack of reliable non-invasive biomarkers.This study aimed to evaluate miR-449a as a diagnostic and prognostic biomarker in LA-LSCC.Methods:miR-449a expression was analyzed in tumor tissues,adjacent normal tissues,and serum from 81 LA-LSCC patients and 50 controls using quantitative real-time reverse transcription polymerase chain reaction(qRT-PCR).We assessed the diagnostic accuracy by Receiver Operating Characteristic curve(ROC curves),clinicopathological associations,survival outcomes(Kaplan-Meier),and treatment response dynamics.Results:miR-449a was significantly downregulated in LA-LSCC tissues(p<0.0001)and serum(p<0.0001),with a strong tissue-serum correlation(R^(2)=0.988).Tissue miR-449a demonstrated a diagnostic accuracy(Area Under the Curve,AUC=0.857),while serum showed moderate accuracy(AUC=0.734).High miR-449a expression correlated with favorable clinicopathological features and improved survival(median overall survival:67.82 vs.23.74 months;p=0.0012).Multivariate analysis confirmed miR-449a as an independent prognostic factor(p<0.001).miR-449a levels increased post-treatment,particularly in responders to chemotherapy/radiation(p<0.0001).Conclusion:miR-449a serves as a non-invasive biomarker for LA-LSCC diagnosis,prognosis,and treatment monitoring.Its dynamic expression highlights potential for risk stratification and therapy response prediction,warranting further validation in larger cohorts.
基金financially supported by King Abdulaziz University,Deanship of Scientific Research(DSR)。
文摘Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease,this plasticity is disrupted,leading to cognitive and motor deficits.This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease.Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function,while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control.Enhancing neuronal plasticity offers therapeutic potential for these diseases.A systematic literature review was conducted using databases such as PubMed,Scopus,and Google Scholar,focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease.Data synthesis identified key themes such as synaptic mechanisms,neurogenesis,and therapeutic strategies,linking molecular insights to clinical applications.Results highlight that targeting synaptic plasticity mechanisms,such as long-term potentiation and long-term depression,shows promise.Neurotrophic factors,advanced imaging techniques,and molecular tools(e.g.,clustered regularly interspaced short palindromic repeats and optogenetics)are crucial in understanding and enhancing plasticity.Current therapies,including dopamine replacement,deep brain stimulation,and lifestyle interventions,demonstrate the potential to alleviate symptoms and improve outcomes.In conclusion,enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases.Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.
文摘Male breast cancer(MBC)is rare,representing 0.5%–1%of all breast cancers,but its incidence is increasing due to improved diagnostics and awareness.MBC typically presents in older men,is human epidermal growth factor receptor 2(HER2)-negative and estrogen receptor(ER)-positive,and lacks routine screening,leading to delayed diagnosis and advanced disease.Major risk factors include hormonal imbalance,radiation exposure,obesity,alcohol use,and Breast Cancer Gene 1 and 2(BRCA1/2)mutations.Clinically,it may resemble gynecomastia but usually appears as a unilateral,painless mass or nipple discharge.Advances in imaging and liquid biopsy have enhanced early detection.Molecular mechanisms involve hormonal signaling,HER2/epidermal growth factor receptor(EGFR)pathways,tumor suppressor gene alterations,and epigenetic changes.While standard treatments mirror those for female breast cancer,emerging options such as cyclin-dependent kinase 4 and 6(CDK4/6),and poly(ADP-ribose)polymerase(PARP)inhibitors,immunotherapy,and precision medicine are reshaping management.Incorporating artificial intelligence,molecular profiling,and male-specific clinical trials is essential to improve outcomes and bridge current diagnostic and therapeutic gaps.
基金appreciation to the Princess Nourah bint Abdulrahman University Researchers Supporting Project number(PNURSP2025R384)Princess Nourah bint Abdulrahman University,Riyadh,Saudi Arabia.
文摘The cloud-fog computing paradigm has emerged as a novel hybrid computing model that integrates computational resources at both fog nodes and cloud servers to address the challenges posed by dynamic and heterogeneous computing networks.Finding an optimal computational resource for task offloading and then executing efficiently is a critical issue to achieve a trade-off between energy consumption and transmission delay.In this network,the task processed at fog nodes reduces transmission delay.Still,it increases energy consumption,while routing tasks to the cloud server saves energy at the cost of higher communication delay.Moreover,the order in which offloaded tasks are executed affects the system’s efficiency.For instance,executing lower-priority tasks before higher-priority jobs can disturb the reliability and stability of the system.Therefore,an efficient strategy of optimal computation offloading and task scheduling is required for operational efficacy.In this paper,we introduced a multi-objective and enhanced version of Cheeta Optimizer(CO),namely(MoECO),to jointly optimize the computation offloading and task scheduling in cloud-fog networks to minimize two competing objectives,i.e.,energy consumption and communication delay.MoECO first assigns tasks to the optimal computational nodes and then the allocated tasks are scheduled for processing based on the task priority.The mathematical modelling of CO needs improvement in computation time and convergence speed.Therefore,MoECO is proposed to increase the search capability of agents by controlling the search strategy based on a leader’s location.The adaptive step length operator is adjusted to diversify the solution and thus improves the exploration phase,i.e.,global search strategy.Consequently,this prevents the algorithm from getting trapped in the local optimal solution.Moreover,the interaction factor during the exploitation phase is also adjusted based on the location of the prey instead of the adjacent Cheetah.This increases the exploitation capability of agents,i.e.,local search capability.Furthermore,MoECO employs a multi-objective Pareto-optimal front to simultaneously minimize designated objectives.Comprehensive simulations in MATLAB demonstrate that the proposed algorithm obtains multiple solutions via a Pareto-optimal front and achieves an efficient trade-off between optimization objectives compared to baseline methods.
基金The Large Research Group Project under grant number RGP.02/516/45.
文摘Micro/nanorobots represent a groundbreaking advancement in nanotechnology,with applications spanning medicine,envi-ronmental remediation,and industrial processes.A major challenge in their development is achieving efficient and bio-compatible propulsion.Enzyme-driven propulsion,particularly using catalase,offers a promising solution due to its ability to decompose hydrogen peroxide(H2O2)into water and oxygen,generating thrust for autonomous movement.Compared to metal-based catalysts,catalase-powered systems exhibit superior biocompatibility and lower toxicity,making them ideal for biomedical applications.This review explores the role of catalase in micro/nanorobot propulsion,highlighting self-propulsion mechanisms,different nanorobot types,and their applications in drug delivery,infection treatment,cancer therapy,and biosensing.Additionally,recent advancements in biodegradable enzyme-powered nanorobots and their poten-tial in overcoming biological barriers are discussed.With further research,catalase-driven nanorobots could revolutionize targeted therapy and diagnostic techniques,paving the way for innovative solutions in nanomedicine.
基金supported by the institutional funding committee of Najran University,Najran,Saudi Arabia(Project code:NU/IFC/ENT/01/007).
文摘Objective:To determine the genetic diversity,natural selection and mutations in Plasmodium(P.)knowlesi drug resistant molecular markers Kelch 13 and dhps gene in clinical samples of Malaysia.Methods:P.knowlesi full-length gene sequences Kelch 13 gene(PkK13)from 40 samples and dhps gene from 30 samples originating from Malaysian Borneo were retrieved from public databases.Genetic diversity,natural selection,and phylogenetic analysis of gene sequences were analysed using DNAsp v5.10 and MEGA v5.2.Results:Seventy-two single nucleotide polymorphic sites(SNPs)across the full-length PkK13 gene(63 synonymous substitutions and 9 non-synonymous substitutions)with nucleotide diversity ofπ~0.005 was observed.Analysis of the full-length Pkdhps gene revealed 73 SNPs andπ~0.006(44 synonymous substitutions and 29 non-synonymous substitutions).A high number of haplotypes(PkK13;H=37 and Pkdhps;H=29)with haplotype diversity of Hd~0.99 were found in both genes,indicating population expansion.Nine mutant alleles were identified in PkK13 amino acid alignment of which,7(Asp3Glu,Lys50Gln,Lys53Glu,Ser123Thr,Ser127Pro,Ser149Thr and Ala169Thr)were within the Plasmodium specific domain,2(Val372Ile and Lys424Asn)were in the BTB/POZ domain and no mutation was observed within the kelch propeller domain.The 29 non-synonymous mutations in the Pkdhps gene were novel and only presented in exon 1 and 2.Conclusions:Monitoring the mutations from clinical samples collected from all states of Malaysia along with clinical efficacy studies will be necessary to determine the drug resistance in P.knowlesi.
文摘Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.
基金financially supporting this work through the Large Research Group Project under grant number R.G.P.2/510/45。
文摘Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.
文摘Artemisia dracunculus L.,or tarragon,is a perennial herb from the Asteraceae family that is extensively cultivated for its aromatic leaves,which are valued for its preventative and therapeutic properties in both cookery and traditional medicine.This study aims to investigate the antibacterial,antioxidant,and anti-inflammatory properties of A.dracunculus(tarragon)essential oil(ADEO),with estragole(57.23%)identified as the major compound through gas chromatography-mass spectrometry(GC-MS)analysis.ADEO exhibited varying degrees of antibacterial activity,with Escherichia coli showing higher resistance inhibition zone(IZ)=14.7±0.58 mm,minimum (inhibitory concentration(MIC)=2%and minimum bactericidal concentration(MBC)=4%),while Bacillus subtilis(IZ=24.05±2.11 mm and MIC=MBC=0.125%)and Staphylococcus aureus(IZ=18.69±1.45 mm,MIC=0.0612%and MBC=0.125%)were more sensitive to its actions.Antioxidant ability was assessed using 1,1-diphenyl-2-picrylhydrazil(DPPH),2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS),xanthine oxidase inhibition,and beta-carotene bleaching assays.ADEO showed remarkable antiradical effect on DPPH(IC_(50)=127.05±3.47μg/mL)and ABTS radical(IC_(50)=89.60±8.73μg/mL)as well as significant inhibition of xanthine oxidase(IC_(50)=47.9±2.04μg/mL)and lipid peroxidation(IC_(50)=231.63±5.21μg/mL).ADEO also showed significant anti-inflammatory activity by inhibiting the enzymesCOX-1(IC_(50)=59.2±2.43μg/mL),Cyclo-oxygenase-2(COX-2)(IC_(50)=74.68±1.34μg/mL)and 5-lipooxygense(5-LOX)(IC_(50)=93.18±1.87μg/mL),which are involved in the inflammatory pathway.These findings suggest that ADEO,with its high estragole content,holds promising potential as a natural antibacterial,antioxidant,and anti-inflammatory agent for preventive and therapeutic applications.Further research is needed to explore its safety and efficacy in clinical settings.
文摘Background:The JAK2^(V617F)mutation plays a crucial part in the pathogenesis of myeloproliferative neoplasms(MPN),which includes polycythemia vera(PV),essential thrombocythemia(ET),and primary myelofibrosis(PMF)leading to aberrant proliferation and survival of hematopoietic cells.Alongside the challenges of drug resistance and side effects,identifying novel compounds that selectively target JAK2^(V617F)could provide more effective and safer therapeutic options for patients with MPNs.Materials and Methods:We employed computational approaches like high-throughput virtual screening,molecular dynamics simulations(MDS),and binding free energy calculations to identify inhibitors targeting wild and mutant JAK2 kinases.JAK2^(V617F)positive HEL,wild type JAK2 positive TF-1,and non-cancerous Vero cells were used for in vitro validations.Results:SBLJ23 emerged as a top candidate inhibitor with specificity for JAK2^(V617F).Protein-ligand interaction studies and MDS revealed stable interactions and binding of SBLJ23 over the simulation period,with Root Mean Square Deviation(RMSD)indicating consistent binding after 1t15ns.SBLJ23 displayed a half maximal inhibitory concentration(IC_(50))value of 522.4 nM against the JAK2 enzyme.The compound exhibited inhibition of cell proliferation in HEL and TF-1 cells,with half maximal cell growth inhibitory concentration(GI 50)values of 2.51 and 15.87μM,respectively.Moreover,SBLJ23 induced G 2/M cell cycle arrest in HEL cells to facilitate apoptosis in these cell lines.The compound significantly reduced the percentage of phospho JAK2 and phospho STAT3 in HEL cells.Conclusion:High binding affinity,stable interaction profile,favorable binding free energy,and in vitro validations claim SBLJ23 as a potential lead compound against JAK2^(V617F)and suggest further development and optimization towards clinical application in managing myeloproliferative neoplasms.
基金funded by the Ongoing Research Funding Program at King Saud University,Riyadh,Saudi Arabia through grant number ORF-2025-554.
文摘Objectives:Targeting epigenetic modifications in anticancer therapy is a promising approach to overcoming cancer cell chemoresistance.The histone deacetylase/DNA methyltransferase inhibitor,parthenolide(PTL),has antitumor activity,but contrasting findings exist on its effect in normal cells.This study aims to examine the nongenomic toxic mechanisms of PTL in human erythrocytes.Methods:Cell death as stimulated by 20–200μMof PTL for 24 h at 37℃ was assessed using fluorescence-assorted cell sorting and spectrophotometric assays.Canonical markers of cell death,including membrane scrambling,oxidative stress,and Ca^(2+)mobilization,were captured by annexin V-fluorescein isothiocyanate,2′,7′-dichlorodihydrofluorescein diacetate,and Fluo4/AM labeling,respectively.Rescue experiments usingawide arrayof inhibitorswere also conducted.Results:PTL stimulated significantmembrane scrambling and blebbing,and showed potent hemolytic activity coupled with significant elevations in dichlorofluorescein and Fluo4 fluorescence.While hemolysis was ameliorated by glutathione,caffeine,acetylsalicylic acid,staurosporin,necrosulfonamide,guanosine,and Ca^(2+)deprivation,it was rather exacerbated by necrostatin-2,tumor necrosis factor α(TNFα)or Fas ligand(FasL)neutralization,and concurrent Ca^(2+)deprivation and membrane depolarization.In contrast,eryptosis was attenuated by N-acetyl-cysteine,TNFα,or FasL blockade,and simultaneous Ca^(2+)elimination and KCl enrichment;and augmented by necrostatin-2,necrosulfonamide,and adenosine triphosphate.Interestingly,loss of volume was only prevented by melatonin,acetylsalicylic acid,and N(gamma)-nitro-L-arginine methyl ester.Conclusion:PTL stimulates oxidative hemolysis and eryptosis through Ca^(2+)mobilization and death ligand signaling involving the cyclooxygenase/protein kinase C/mixed lineage kinase domain-like pseudokinase axis.This research highlights the non-genomic toxic mechanisms of PTL and presents potential pharmacological targets for mitigating its adverse off-target effects.
基金the Deanship of Graduate Studies and Scientific Research at Najran University,Saudi Arabia,for their financial support through the Easy Track Research program,grant code(NU/EFP/MRC/13).
文摘Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networks(CNNs)excel in local feature extraction,their ability to capture global contextual relationships in complex cellular morphologies is limited.This study introduces a hybrid CNN-Transformer framework to enhance normal blood cell classification,laying the groundwork for future leukemia diagnostics.Methods:The proposed architecture integrates pre-trained CNNs(ResNet50,EfficientNetB3,InceptionV3,CustomCNN)with Vision Transformer(ViT)layers to combine local and global feature modeling.Four hybrid models were evaluated on the publicly available Blood Cell Images dataset from Kaggle,comprising 17,092 annotated normal blood cell images across eight classes.The models were trained using transfer learning,fine-tuning,and computational optimizations,including cross-model parameter sharing to reduce redundancy by reusing weights across CNN backbones and attention-guided layer pruning to eliminate low-contribution layers based on attention scores,improving efficiency without sacrificing accuracy.Results:The InceptionV3-ViT model achieved a weighted accuracy of 97.66%(accounting for class imbalance by weighting each class’s contribution),a macro F1-score of 0.98,and a ROC-AUC of 0.998.The framework excelled in distinguishing morphologically similar cell types demonstrating robustness and reliable calibration(ECE of 0.019).The framework addresses generalization challenges,including class imbalance and morphological similarities,ensuring robust performance across diverse cell types.Conclusion:The hybrid CNN-Transformer framework significantly improves normal blood cell classification by capturing multi-scale features and long-range dependencies.Its high accuracy,efficiency,and generalization position it as a strong baseline for automated hematological analysis,with potential for extension to leukemia subtype classification through future validation on pathological samples.
基金supported by the National Natural Science Foundation of China(Nos.81860543,32360237)Guizhou Provincial Science and Technology Projects(Nos.ZK[2024]235,ZK[2023]Key Project 041).
文摘The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative bacterial infections,serves as a crucial final recourse against carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Nevertheless,the clinical usage of PMB is impeded by its pronounced nephrotoxicity and poor infection site targeting.This investigation is geared to construct a nanoparticle formulation(named HA-PMB@H)comprising hyaluronic acid(HA)and PMB via a simple Schiff base reaction and further coating HA by electrostatic action.HA-PMB@H shows an average size of(153.8±24.3)nm,and a mean zeta potential of(−25.6±5.2)mV.Additionally,PMB can be released from HA-PMB@H more thoroughly and efficiently at pH 5.5 compared to pH 7.4,which demonstrates the Schiff base modification of PMB paves the way for its release at focus of infection.The uptake ratio of HA-PMB@H by alveolar epithelial cells(RLE-6TN)surpassed that of free PMB devoid of HA,which facilitates to the intracellular sterilization of PMB.Furthermore,the employment of HA-PMB@H ameliorated the toxicity of PMB towards human embryonic kidney cells(HEK 293)and pulmonary microvascular endothelial cells(HULEC-5a).What is more,HA-PMB@H effectively managed severe pneumonia induced by CRKP samples from clinical patients diagnosed with CRKP infection in vivo,substantially enhancing the survival rate of mice.Consequently,this nano-delivery system holds promising clinical significance in the combat against drug-resistant bacterial infections.
基金Supported by Taif University,Taif,Saudi Arabia(TU-DSPP-2024-05).
文摘AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
文摘Background:Diabetes mellitus(DM)is a prevalent chronic metabolic condition characterized by high blood sugar levels,resulting from insufficient insulin production or ineffective insulin use,posing substantial global health issues.Research on the relationship between glycemic status and the ratio of neutrophils to lymphocytes(NLR)and monocytes to lymphocytes(MLR)is limited.This study aimed to fill these knowledge gaps by examining the connection between DM and inflammatory markers within the Asir region.Methods:Data from 3545 participants were retrospectively analyzed.The dataset,gathered between 2021 and 2023,comprises 38 laboratory tests obtained from the Future Lab Pioneer database.The study's inclusion criteria focused on diabetes profile tests(glycated hemoglobin[HbA1c]and fasting blood glucose[FBG])and manually computed inflammatory markers(NLR and MLR),which were stratified by age and sex.Results:This study demonstrated significant differences in NLR levels compared with FBG levels across all adult age groups and adult female participants(p<0.0001),as well as among all elderly age groups(p=0.0006)and elderly women(p=0.01).MLR levels were significant in all adult age groups(p=0.04)and in adult women(p=0.02).When NLR and MLR were compared to HbA1c levels,a significant difference in the mean NLR was found in adult women(p=0.005).Additionally,the mean MLR levels were significant in all adult age groups(p=0.04)and adult women(p=0.02).Conclusion:Although a larger sample size is necessary for this research,the results indicate that NLR and MLR could serve as valuable indicators for evaluating inflammation in people with disrupted glucose metabolism,particularly in adult and female populations.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of adenomas in the colon during the second decade of life.If prophylactic colectomy is not performed,most patients eventually develop colorectal cancer(CRC).CASE SUMMARY We present the mutational profile of a case of FAP that progressed to CRC.A 45-year-old Saudi man presented with intestinal obstruction and underwent a total colectomy.The colon showed hundreds of polyps and two infiltrative ulcerative lesions,which proved to be adenocarcinoma according to histopathology.We performed next-generation sequencing and found mutations in the TP53,NRAS,EGFR PDGFR,MET,KIT,ERBB2,and GUSP genes.CONCLUSION To the best of our knowledge,this case report is the first to sheds the light on the mutation profile of FAP that progressed to CRC in Saudi Arabia.
文摘The interest in using the Datura stramonium plant is due to its natural products,which are used in many pharmaceutical industries.The objective of the current study was to assess the therapeutic and cytotoxic effects of the D.stramonium plant on two types of human cancer cell models(MCF7 and HT29)in vitro.A soxhlet apparatus was used to obtain methanolic extract from dried plant leaves.The recovered crude,after the solvent had evaporated,was then dispersed at varied concentrations of extract 100,50,20,and 0.0µg/mL and tested to see how the cells responded.Also,the cancer-testis antigen(CTA)gene transcription in the two cell types exposed to the plant extract was examined using a semi-quantitative real-time polymerase chain reaction.Gas chromatography–mass spectrometry(GC-MS)results produced the significant main metabolites Nonanoic acid,Tropine N-Oxide,3,6-Ditigloyloxy-7-hydroxytropane,Hexadecanoic acid,2-Pentadecanone,6,10,14-trimethyl-,Carvenone,methyl ester,Phytol,Aposcopolamine,Hyoscyamine,4,8,12,16-Tetramethylheptadecan-4-olide,Scopolamine,Alpha.-Tocospiro A,1,2-Cycloheptanedione,3,3,7,7-tetramethyl-,dihydrazone,Campesterol,Stigmasterol,Gamma-Sitosterol and dl-.alpha.-Tocopherol.The results showed that the two types of cell lines impacted by D.stramonium extract,through untreated type 1 cells(MCF7)gave a highly significant transcription according to all applicable genes.All implemented analyses cleared the strong genetic impacts of Datura extract on cancer cells’genomes.TGIF2LY and C2orf63 transcript accumulation were also significantly elevated when exposed to plant extract at a level of 50µg/mL in cell line type 2(HT29),but TGIF2LY and P53 had the lowest relative expression at a level of 100µg/mL when treated the same cell line type.
文摘The increasing incidence of neurodegenerative diseases(NDs)and the constraints of existing treatment methods have spurred a keen interest in investigating alternative therapies.Medicinal plants,renowned for their long-standing use in traditional medicine,offer a hopeful avenue for discovering new neuroprotective agents.This study emphasizes the potential neuroprotective characteristics of edible fruit plants in Bangladesh,specifically focusing on their traditional folk medicine uses for neurological disorders.This study provides an in-depth overview of the different types of edible fruit trees in Bangladesh and their phytochemicals,including flavonoids,terpenoids,and phenolic acids.This work examines the scientific data supporting the neuroprotective properties of bioactive chemicals from plants.It further explores the mechanisms by which these compounds work to counteract oxidative stress,decrease inflammation,and stimulate neurogenesis.Moreover,the study investigates toxicological characteristics and bioactive components of some fruits,emphasizing the importance of further investigation to measure their safety profile comprehensively.This thorough study highlights the potential benefits of Bangladesh's edible fruit trees as a rich source of neuroprotective chemicals.It also shows that additional research might lead to novel approaches for improving brain functioning and preventing NDs.
