Introduction:The α-amylase enzyme plays a critical role in the digestion of complex carbohydrates. Inhibiting this enzyme offers a promising strategy for improving glucose regulation in diabetic patients. Methods:In this study, a comprehensive computational approach, combining 3D-QSAR modeling, ADMET profiling, molecular docking, molecular dynamics, ligand transport analysis, and retrosynthesis, was used to identify novel ligands with potent inhibitory activity against various indenoquinoxaline-phenylacrylohydrazide hybrids. Results:The optimal 3D-QSAR model, developed using partial least squares (PLS) and Comparative Molecular Similarity Indices Analysis (CoMSIA), demonstrated strong correlation and predictive power (Q2=0.541, R2=0.973, SEE=0.076). ADMET analysis showed that the designed ligands possess acceptable pharmacokinetic and toxicological profiles, supporting their potential for further drug development. Molecular docking revealed that the designed ligands effectively interacted with the active site of α-amylase (PDB ID: 7TAA). Furthermore, molecular dynamics simulations (100 ns) and MM-PBSA free energy calculations confirmed the stability of ligand-enzyme complexes. Ligand transport was further examined using the CaverDock program, tracking the movement of molecules from the enzyme's active site to its surface. Finally, retrosynthetic analysis was performed to propose feasible synthesis routes for the most active compound. Conclusion:Overall, the findings highlight a promising lead compound for further in vitro and in vivo investigations targeting α-amylase inhibition.
Introduction:Lactylation, an emerging post-translational modification, modulates tumor metabolism and gene expression, thereby influencing the initiation and progression of cervical squamous cell carcinoma (CESC). This study aims to identify lactylation-associated prognostic features in CESC through the integration of transcriptomic data and single-cell RNA sequencing (scRNA-seq). Methods:Publicly available datasets were utilized for this study. Lactylation-related genes (LRGs) linked to CESC prognosis were found through analysis. Key prognostic genes include PGK1, PFKP, DDX39A, RFC4, WAS, and PFKM, with PFKP identified as a risk factor. Results:The risk model demonstrated strong predictive performance, and immune infiltration analysis revealed elevated levels of immune cells, with CD8+ T cells negatively correlating with risk. ScRNA-seq analysis identified three distinct cell types, with CD8+ T cells showing a distinct developmental trajectory, marked by a reduction in early-stage cells and an accumulation of late-stage cells within the CESC microenvironment. Moreover, the expression of prognostic genes was elevated during the later stages of CD8+ T cell differentiation. Conclusion:LRGs demonstrated significant prognostic value in CESC and accurately predicted patient outcomes. Furthermore, the study underscored the pivotal role of CD8+ T cells in the progression of CESC.
Glomerulonephritis (GN) is a heterogeneous group of kidney diseases characterized by inflammation and damage to the glomeruli. Current treatments for GN remain suboptimal, creating a pressing need for innovative therapeutic strategies. Short interfering RNAs (siRNAs) represent a promising advance in the therapeutic landscape for GN, offering targeted gene silencing that could fundamentally transform the management of this significant cause of kidney disease. siRNA therapies work by selectively silencing specific genes involved in the pathogenesis of GNs, including interferon pathways, B cell activation, TGF-β, MAPK1, HMGB1, BLYSS, and SIRT1. Preclinical evidence demonstrates improved kidney function and reduced glomerular damage in experimental models. While challenges remain in translating these findings to clinical applications, ongoing research suggests that siRNA-based therapies have the potential to transform the treatment of GN, offering new hope for patients with this challenging kidney disease. This review highlights the impact of siRNA-based therapies in GN, exploring their mechanisms, delivery systems, challenges, and preclinical and clinical evidence.
Introduction:Articular cartilage has a limited intrinsic capacity for regeneration following injury, particularly in cases of severe defects. Exosome-based therapy has emerged as a promising cell-free regenerative strategy, with increasing preclinical evidence supporting its therapeutic potential in cartilage repair. As previous studies have indicated that human adipose-derived mesenchymal stem cells (hADSCs) secrete regenerative factors, whereas human umbilical cord-derived mesenchymal stem cells (hUCMSCs) exert immunomodulatory effects, the combined use of exosomes from these two sources may have complementary therapeutic benefits. Methods:In this study, exosome-enriched extracellular vesicles (EVs) isolated from hADSCs and hUCMSCs were combined, characterized, and evaluated in a cartilage defect model. The isolated EVs displayed a characteristic cup-shaped morphology under transmission electron microscopy, a size distribution ranging from 30 to 200 nm, and high expression levels of the exosomal markers CD9, CD63, and CD81. Results:Treatment with the combined EVs formulation promoted the regeneration of medial femoral condyle defects at 12 weeks post-injury compared to untreated controls, as demonstrated by an improved macroscopic appearance and scoring, radiographic evaluation, and increased deposition of total collagen, glycosaminoglycans, and aggrecan. Conclusion:The findings provide proof-of-concept evidence that a combined hADSC- and hUCMSC-derived EVs formulation represents a feasible cell-free approach to cartilage repair.
Introduction:Diabetes mellitus (DM) being a chronic metabolic disorder, causes a major concern for the healthcare system. Among different types, type 1 DM (T1DM) results in the destruction of insulin-producing pancreatic β cells, mediated by the immune system. Studies have demonstrated that human umbilical cord derived mesenchymal stem cells (hUMSCs) exhibit great potential to regenerate β-cells. Moreover, in order to enhance the regenerative potential of MSCs, several strategies are being utilized, including preconditioning with bioactive compounds. Among these, naphthoquinones can be used for MSC preconditioning in order to augment their therapeutic potential for β-cell regeneration, as these compounds possess anti-inflammatory and anti-diabetic properties. Methods:hUMSCs were isolated, characterized, and treated with non-cytotoxic concentrations of lawsone, lapachol, or their combination. The preconditioned cells were subsequently analyzed for pancreatic β-cell differentiation at gene and protein levels. The study also explores the role of Wnt and BMP signaling pathways during the differentiation process through gene expression analysis. Binding patterns of these compounds with their respective receptors were analyzed using in silico studies. Results:Gene expression profiling showed overexpression of pancreatic β-cell-specific markers in the Law + hUMSC group, whereas downregulation of Neurogenin-3 (NGN3) was observed in all treatment groups. Immunocytochemical analysis also showed enhanced expression of insulin in Law + hUMSCs, relative to other groups. Transcriptional analysis of the wingless/integrated (Wnt) and bone morphogenetic protein (BMP) pathways showed increased Wnt and decreased BMP expression across all treatment groups. In silico analyses showed that the binding patterns of lawsone or lapachol with frizzled (FZD) and activin-like kinase 1 (ALK1) receptors share comparable sequence similarity, facilitating their binding to these receptors and regulating downstream Wnt and BMP signaling. Conclusion:The study concludes that the regulatory role of lawsone and lapachol can be exploited for preconditioning of MSCs for improved pancreatic β-cell differentiation.
Introduction:Dengue virus (DENV), transmitted by Aedes mosquitoes, remains a serious global health threat with an increasing incidence, largely due to its complex epidemiology and the impact of climate change. DENV belongs to the Flaviviridae family, comprising four serotypes (DENV-1 to DENV-4). The high mutation rate of DENV and the risk of antibody-dependent enhancement (ADE) complicate the development of a vaccine. This study aims to design a multi-epitope vaccine against DENV, with a focus on DENV-2, the strain associated with severe symptoms. Methods:First, the genome of DENV-2 was analyzed and vaccine candidate proteins were identified by examining properties such as immunogenicity, toxicity, and allergenicity. The secondary and tertiary structures of the vaccine were predicted and validated, and the vaccine interaction with MHC receptors was analyzed through docking. The stability and flexibility of the vaccine were also evaluated by molecular dynamics simulation. Finally, the vaccine gene sequence was optimized for expression in Nicotiana benthamiana and cloned into the pBI121 vector. Results:In this study, four proteins were selected from the initial 10 proteins after eliminating those that were allergens, toxins, or had homology to human or mouse proteins. Finally, protein 3 was identified as the source antigen for epitope prediction and vaccine construction. This highly immunogenic, non-toxic, and non-allergenic protein, located in the cytoplasm, was used to design a multi-epitope vaccine that includes selected epitopes, an IL-12 adjuvant, and a His tag. The designed vaccine consisted of 380 amino acids, exhibited a suitable stability index, and possessed a valid three-dimensional structure, with 95.4% of the amino acids located in the preferred region of the Ramachandran map. Docking and dynamic simulations demonstrated a stable interaction between the vaccine and MHC-I and MHC-II receptors. Also, the vaccine gene sequence was cloned into the pBI121 vector for optimal expression in N. benthamiana with a codon compatibility index of 0.78 and a GC content of 50.53%. Conclusion:This study demonstrates the potential of computational approaches for developing targeted vaccines against dengue fever. Additionally, molecular farming offers a promising, safe, and cost-effective method for large-scale production of vaccines. Future research should focus on preclinical and clinical trials to validate the safety and efficacy of the vaccine.
Breast cancer, a complex and heterogeneous disease marked by uncontrolled cell growth in breast tissue, presents a significant global health challenge due to its high mortality rate. Metastasis, a major driver of cancer progression and mortality, poses a significant challenge in clinical oncology. This complex process involves profound changes in cytoskeletal dynamics and interactions with the extracellular matrix, including integrin-mediated adhesion and the activity of matrix metalloproteinases (MMPs). Circular RNAs (circRNAs) are a type of endogenous non-coding RNA with a covalently closed-loop structure. They serve as critical regulators of gene expression and modulate essential cellular processes, including proliferation, cell cycle control, and invasion. Through intricate interactions with key signaling pathways, including Wnt/β-catenin, PI3K/AKT, TGF-β/SMAD, and the MEK-MAPK pathway, circRNAs modulate these processes, particularly epithelial-to-mesenchymal transition (EMT), which is crucial in breast cancer metastasis. Mechanistically, circRNAs activate transcription factors associated with EMT, such as Slug, Snail, Twist, and Zeb. Moreover, circRNAs have emerged as promising clinical biomarkers in breast cancer, offering new opportunities for early diagnosis, prognostic assessment, and the development of targeted therapeutic strategies. In this article, the role of circRNAs in modulating EMT-regulating signaling pathways in the context of breast cancer metastasis will be reviewed.
Introduction:Clonazepam is a long-acting benzodiazepine utilized for conditions such as seizures, panic disorder, and other neurological/psychiatric disorders. It functions by increasing GABA effects, which leads to reduced neural activity. Careful dosage titration and monitoring are necessary due to potential side effects, including drowsiness, impaired motor coordination, memory loss, and dependence. Methods:In this work, an optical probe based on a terbium (Tb) coordination polymer was developed for the quantification of clonazepam in the exhaled breath condensate (EBC). The principle of the probe was based on the interaction of clonazepam with pyridine-2,6-dicarboxylic acid -Tb coordination polymer nanoparticles, which dynamically quenches the Tb³⁺ luminescence through a collisional mechanism, as confirmed by the linear Stern-Volmer plot and the increased quenching efficiency at higher temperatures. As the increase in response intensity is proportional to clonazepam concentration, a method was offered for its determination in EBC samples. Results:This method presented a linear relationship with clonazepam concentration in the range of 0.001-1.5 µg.mL-1 with a limit of detection of 0.0002 µg.mL-1 and the intra-day and inter-day relative standard deviation of 1.8%, and 2.7%, respectively. The validated method was used for clonazepam analysis in patients receiving this medication. The recovery values, ranged from 90% to 104%, served as an indicator of the method's accuracy, and confirmed that the measured signal was attributable specifically to clonazepam with high reliability. Conclusion:By being faster, simpler, and cost-effective than traditional techniques, this method presented a valuable tool for therapeutic drug monitoring.
Introduction:Bloodstream infections (BSIs) caused by Staphylococcus aureus, particularly methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) strains, remain a critical clinical concern due to high mortality rates and delays in diagnosis. Traditional approaches, such as blood culture, are time consuming, whereas molecular methods are limited by their inability to assess bacterial viability. Dielectrophoresis (DEP)-based lab-on-a-chip (LOC) technology offers a label-free, rapid, and viability preserving alternative for pathogen isolation by exploiting differences in dielectric properties. Methods:A dual-channel microfluidic separation device was developed with independently operated pathways. The primary channel (2000×198 μm) integrated ten crown-shaped microelectrodes, while the secondary channel (1540×80 μm) incorporated eight microelectrodes. The primary channel isolated both target strains directly from whole blood; the secondary channel enabled further separation between standard Gram-positive MRSA and MSSA. Finite element modeling was performed using COMSOL Multiphysics, which integrated the Electric Currents, Creeping Flow, and Particle Tracing modules. Separation efficiency was evaluated across varying voltages, electrode geometries, and sample-to-buffer flow rate ratios at 1 Hz. Dielectric properties from published data were used to calculate the Clausius-Mossotti (CM) factor for predicting DEP behavior. Results:In the primary channel, nearly 100% separation efficiency and purity were achieved for isolating MRSA and MSSA from red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs) at 24-28 Vpp and a sample-to-buffer flow rate ratio of 1:2. The secondary channel successfully differentiated MSSA from MRSA at 42-46 Vpp and a 1:5 flow rate ratio, exploiting their distinct membrane characteristics. Crown-shaped electrodes outperformed rectangular designs by generating higher electric field gradients, thereby enhancing separation performance. Conclusion:The dual-channel LOC system enables high-efficiency, label-free separation and identification of MRSA and MSSA directly from whole blood using low-frequency negative DEP (nDEP). The optimized configuration supports rapid pathogen detection, offering substantial advantages over conventional diagnostic platforms.
Introduction:Triple-negative breast cancer demonstrated high metastasis and mortality rates in female populations. Emerging data on effective targeting and specific internalization of chemotherapeutic agents, using modified exosomes, decreased the therapeutic dosage of anti-cancer drugs in cancer cells. Methods:Herein, we developed modified exosomes by surface decoration using the Fusion protein of Respiratory Syncytial Virus (F-protein of RSV) through Click-chemistry techniques, and Dox-loaded via sonication strategy. Then, the viability and metastatic behaviors of MDA-MB-231 cells were monitored in the presence of different groups, including Dox, Exosomes (Exo), Exosomes loaded with Dox (Exo@Dox), and F-protein coupled Exosome groups (Exo-F) and (Exo-F@Dox). Results:In vitro and in vivo results verified that the F-protein coupled exosome, as a modified natural nanoplatform, possessed a biocompatible nature in blood circulation and crossing of blood barriers. After exposure to tumoral temperature (40 °C) and lysosomal PH (5.5) demonstrate amplified Dox release (around 60% at 8 h). Also, in vitro uptake results confirmed a significant increase in Exo-F internalization compared to the Exo group in MDA-MB-231 cells (P<0.0001). Correspondingly, the IC50 value of Exo-F@Dox versus free Dox showed a significant reduction (24-fold more potent) (P<0.0001). Interestingly, Dox-free modified Exo (Exo-F) showed appreciable cytotoxicity (IC50 of about 0.1 µg /mL for exosomal protein concentration) (P˂0.0001). Also, migration assay results confirmed a considerable decrease in the migrated population of MDA-MB-231 cells (10%) compared to the control group, following exposure to modified exosomes. Interestingly, an in vivo study in tumor-bearing Balb/c mice demonstrated a significantly decreased tumor size in the Exo-F groups compared to other formulations. Conclusion:In summary, F-protein modified exosomes exhibited superior anticancer efficacy by improving tumor-specific targeting, ensuring precise delivery of chemotherapeutic agents, facilitating efficient drug release, and allowing for lower therapeutic dosages.
Nanoparticles have emerged as a promising strategy in dental implantology to enhance implant integration and therapeutic functionality. Nanostructured surface modifications enable precise control over implant topography and chemistry, leading to increased surface area, improved protein adsorption, and enhanced cellular adhesion, key factors for successful osseointegration. Various nanoparticle systems, including titanium dioxide (TiO₂), hydroxyapatite, and bioactive glass, have been extensively explored for surface modification and functional enhancement of dental implants. In addition to structural benefits, nanoparticles facilitate localized and controlled drug delivery, reducing infection risk, minimizing systemic side effects, and accelerating tissue healing. Despite these advancements, challenges such as long-term stability, biocompatibility, optimization of drug release kinetics, and potential toxicity remain critical barriers to clinical translation. Therefore, further research is required to ensure safe and effective application of nanoparticle-based dental implants in clinical practice.
Introduction:Androgenic alopecia (AGA) is the most common type of hair loss that occurs due to androgens, specially, dihydrotestosterone (DHT), and the 5-alpha reductase is the key enzyme to control AGA, as it is responsible for the conversion of testosterone to DHT, the more potent form of testosterone involved in the pathogenesis of AGA. Blockers of this enzyme suppress the conversion of androgens to DHT. Dutasteride is one of the 5-alpha reductase inhibitors and is frequently used as an anti-hair loss treatment. Gamma-oryzanol (GO) is an anti-oxidant and anti-5-alpha reductase, which has been introduced as an anti-hair loss treatment by some studies. Methods:The nanostructured lipid carriers (NLCs) were developed for targeting the dutasteride and GO in hair follicles. The NLCs were prepared from herbal oils pumpkin seed oil (PSO) and saw palmetto (SP), which also have a 5-alpha reductase inhibitory effect, contributing to the therapeutic effect. NLCs in follicular targeting enable to accumulation of the drugs in the target area (hair follicle cells), reduce the absorption of dutasteride in other organs and tissues, and reduce the side effects. NLCs were prepared by adopting a hot homogenization method and were characterized by particle size analyzer, scanning electron microscope, and X-ray diffraction. An in-vivo study was conducted using C57BL/6 mice to assess NLCs ability in drug delivery and accumulation in hair follicles. Results:NLCs had great potentials for reducing the dutasteride daily dose. Moreover, the accumulation of NLCs was confirmed by histopathological images even after two weeks of the discontinued treatment. Conclusion:NLCs may have facilitated the follicular delivery of the anti-hair loss drugs. Since the NLCs have potential for accumulation in the hair follicles, the interval of formulation usage may have been increased to more than once a week which was of great interest to the practitioners aiming at developing more efficient formulations for androgenetic alopecia.
Using structured materials and special molecules, scientists can create synthetic materials that can change their properties in a controlled and efficient way, resulting in useful functions. These characteristics remind us of the most popular designs found in nature. Specifically, they can produce strong structures when needed, store information, cause movement, and hold and release therapeutic agents. These macromolecular systems can be created using three-dimensional (3D) printing technology that can respond to human physiological conditions. In this review, the reasons for this progress are explained, and the potential future developments for macromolecules with specific functions are discussed. This review delves into the advancements in 3D printing technology and polymeric nanomaterials, particularly in the diagnosis and therapy of cancer. In addition, it highlights the versatility of these materials in creating intricate scaffolds with enhanced therapeutic properties, leveraging nanotechnology to improve cell interactions.
Introduction:Recurrent implantation failure (RIF) is a complex condition that makes it one of the most challenging cases in the field of infertility. The diagnosis of this condition with the immunological etiology may be aided by determining the endometrial immune profile for the classification of these patients. Current diagnostic approaches are based on invasive endometrial biopsies to classify patients into balanced, low, or over-immune activation profiles, which have limitations for routine use and serial monitoring. This study aimed to develop and validate a minimally invasive peripheral blood-based classification system using immunological and metabolic markers to mirror endometrial immune profiles in RIF patients. Methods:Endometrial tissue and peripheral blood samples were collected during the mid-luteal phase from 163 RIF patients and 28 fertile controls. Endometrial immune profiles were determined via RT-qPCR for IL-18, IL-15, TWEAK, Fn-14, and CD56, classifying RIF into balanced, low, and over-immune activation subgroups, with sample sizes of 32, 47, and 84 women, respectively. Peripheral blood was analyzed by flow cytometry to determine the Th1/Th2 ratio and NK cell percentage; by ELISA to measure nuclear antibodies (ANA, anti-dsDNA), phospholipid-related antibodies (anticardiolipin, anti-β2-glycoprotein I, antiphospholipid antibodies), thyroid-related antibodies (anti-TPO, anti-TG), anti-tissue transglutaminase (anti-TTG), and metabolites (S1P, adiponectin, leptin, PGE2, phosphatidylserine, IGF-1); and by spectrophotometry to quantify total phospholipids. Results:The over-immune activation group showed significantly elevated Th1/Th2 ratios, NK-cell percentages, and autoantibodies (ANA, anti-phospholipid, anti-β2-glycoprotein I, anti-TG, anti-TPO) compared to balanced and low-immune activation groups. Metabolic profiles revealed higher leptin, and total phospholipids but lower adiponectin, S1P, and PGE2 in over-immune activation group. The low-activation group exhibited lower Th1/Th2 ratios, reduced leptin, but elevated adiponectin, S1P, and PGE2 versus balanced and over-immune activation groups. No significant differences were found in phosphatidylserine or IGF-1 across groups. Conclusion:Our results demonstrate that peripheral blood immunological and metabolic markers can effectively distinguish RIF immune endotypes, offering a non-invasive alternative to endometrial biopsy for personalized assisted reproductive technology (ART) management and potentially improving implantation success through targeted therapies.
Introduction:Although prophylactic vaccinations for human papillomaviruses (HPVs) have been approved, these vaccines lack therapeutic efficacy and cannot eradicate pre-existing infections. Although epitope-based vaccines represent a promising therapeutic vaccine platform, their anti-tumor efficacy has been limited due to low immunogenicity. This study aimed to apply bioinformatics tools to design a built-in adjuvant therapeutic candidate vaccine targeting HPV16 infections and associated cancers. Methods:The designed vaccine consists of HPV16 E6 and E7 epitopes conjugated to the domain 4 of pneumolysin (Ply4) from Streptococcus pneumonia, which serves as a potential toll-like receptor 4 (TLR4) agonist. In silico analyses were performed to evaluate the vaccine's physicochemical properties, antigenicity, immunogenicity, and binding interactions with the TLR4 receptor. The designed vaccine was expressed in E. coli and its expression was confirmed by SDS-PAGE and Western blot analysis. Results:In silico analysis predicted that the designed vaccine could have desirable qualities, including non-toxicity, non-allergenicity, antigenicity, immunogenicity, hydrophilicity, and stability. Docking analysis between the vaccine and the TLR4 proteins predicted a high binding capacity and efficient binding. Furthermore, immunoinformatics tools showed that the vaccine could induce robust immune responses, specifically helper and cytotoxic T-cell responses, and promote the production of IFN-γ. The vaccine was successfully expressed in the E. coli system after being cloned into the pET28a vector. SDS-PAGE and Western blotting assays confirmed the purification of the target protein. Conclusion:The novel built-in adjuvant therapeutic candidate vaccine is a rationally designed construct for eradicating pre-existing HPV infections and HPV-induced cervical cancers that warrants further preclinical evaluation.
Introduction: α-Lipoic acid (ALA) is a potent antioxidant with anticancer properties, but its clinical application is limited by poor water solubility and low bioavailability. Current nanocarrier systems for ALA delivery suffer from low encapsulation efficiency, rapid drug release kinetics, and biocompatibility concerns that restrict their therapeutic potential. This study aimed to develop and evaluate ALA-loaded D-alpha-tocopheryl polyethylene glycol succinate (TPGS) micelles as an innovative nanomedicine platform to overcome existing limitations and enhance anticancer efficacy. Methods: ALA was loaded into TPGS micelles via modified solvent evaporation method and comprehensively characterized by TEM, DLS, and FTIR examination. Drug loading and encapsulation efficiency were quantitatively determined. In vitro drug release kinetics, cellular uptake and cytotoxicity were assessed in 4T1 breast cancer cells. Gene expression analysis was performed, and in vivo antitumor efficacy was evaluated in 4T1 murine xenograft model with histopathological examination. Results: The formulation achieved superior encapsulation efficiency of 70%, with DLS analysis revealing micelles having mean diameter of 30–40 nm (polydispersity index: 0.234) and zeta potential of –1.9 mV. TEM confirmed spherical morphology. FTIR validated structural integrity with characteristic peaks. In vitro release demonstrated burst release of 52.4±2.5% (6 hours) followed by sustained release reaching 85.9±2.5% (48 hours). Flow cytometry showed 13.75-fold increased cellular uptake (15.4% vs 1.12% FL4-H+cells). MTT assay revealed dose-dependent cytotoxicity. qRT-PCR demonstrated significant upregulation of apoptotic markers: Caspase-8 (2.071-fold, 95% CI: 1.308–3.299, P<0.001) and Caspase-9 (2.86-fold, 95% CI: 1.102–7.785, P<0.001). In vivo studies in 4T1 murine xenograft model showed 10.39% reduction in tumor growth rate (8.54±3.83 mm³/day vs 9.53±1.03 mm³/day in controls) with histopathological evidence of decreased mitotic activity (28 vs 36 mitoses/10 HPF) and increased apoptosis (11 vs 5 apoptotic figures/10 HPF). All treatment groups achieved 100% survival throughout the 17-day study period with maintained body weights, confirming excellent biocompatibility. Conclusion: ALA-loaded TPGS micelles demonstrate enhanced anticancer efficacy through improved drug delivery, controlled release kinetics, and effective modulation of apoptotic pathways, supporting their potential for clinical translation in cancer therapy.
Ocular malignancies, particularly uveal and conjunctival melanoma, exemplify tumors that evolve within one of the body’s most immunologically constrained ecosystems, the eye’s immune-privileged microenvironment. The limited success of PD-1/PD-L1 and CTLA-4 blockade in these cancers underscores the need to move beyond linear checkpoint inhibition toward multidimensional immune engineering. Through the confluence of synthetic bio-nanotechnology, AI-guided immunogenomics, and spatial immunomics, this review reframes ocular immunotherapy and redefines how tolerance and immunity might be programmatically regulated within ocular tissue. We synthesize recent advances in bispecific T-cell engagers, oncolytic viro-immunotherapy, mRNA and dendritic-cell vaccines, and engineered CAR/TCR-T platforms, highlighting how they collectively reconfigure the ocular tumor microenvironment from immune-silent to immune-responsive. Logic-gated antibodies, ROS-responsive nanocarriers, and CRISPR-assisted checkpoint reprogramming are added to the notion of "precision immune engineering". These developments are intended to temporarily alter immune privilege without sacrificing visual quality. Lastly, we suggest a systems-level model for ocular immuno-oncology 2.0, where immune privilege is not an unchangeable barrier but rather a configurable circuit for therapeutic orchestration. One element of a dynamic, closed-loop immune-engineering architecture is checkpoint inhibition. This platform offers the possibility of long-lasting, vision-preserving disease treatment by combining AI-driven neoantigen detection, liquid-biopsy feedback loops, and flexible delivery biomaterials. While several of these approaches remain at a conceptual or early translational stage, they outline a plausible roadmap toward vision-preserving immunotherapy in ocular oncology.
Therapy resistance remains a formidable challenge in hematologic malignancies despite significant advances in targeted therapies. This comprehensive review examines integrin-linked kinase (ILK) as a critical molecular hub at the nexus of cell adhesion, signal transduction, and therapy resistance across leukemias, lymphomas, and multiple myeloma. Unlike in solid tumors, where ILK primarily drives invasion and metastasis, in hematologic malignancies it uniquely mediates microenvironmental protection and therapy resistance through distinct signaling networks. ILK functions as a central mediator connecting microenvironmental signals to intracellular survival pathways, with expression levels 5-20-fold higher in malignant cells compared to normal counterparts. Through systematic analysis of structural properties, expression patterns, downstream signaling, and microenvironmental interactions, we present compelling evidence for ILK as a promising therapeutic target capable of overcoming resistance mechanisms. Current data demonstrate that ILK inhibition simultaneously disrupts multiple survival pathways, sensitizes resistant cells to established therapies, and selectively targets therapy-resistant leukemic stem cells while sparing normal progenitors. This review provides a comprehensive framework for translating ILK-targeted approaches into innovative therapeutic strategies with significant potential to improve outcomes in treatment-refractory hematologic malignancies.
