Physicochemical Studies on Amino Acid Based Metallosurfactants in Combination with Phospholipid.

Dicarboxylate metallosurfactants (AASM), synthesized by mixing N-dodecyl aminomalonate, -aspartate and -glutamate with CaCl2, MnCl2 and CdCl2, were characterized by XRD, FTIR, and NMR spectroscopy. Layered structures, formed by metallosurfactants, were evidenced from differential scanning calorimetry and thermogravimetric analyses. Solvent-spread monolayer of AASM in combination with soyphosphatidylcholine (SPC) and cholesterol (CHOL) were studied using Langmuir surface balance. With increasing mole fraction of AASM mean molecular area increased and passed through maxima at ~60 mol% of AASMs, indicating molecular packing reorganization. Systems with 20 and 60 mol% AASM exhibited positive deviations from ideal behavior signifying repulsive interaction between the AASM and SPC, while synergistic interactions were established from the negative deviation at other combinations. Dynamic surface elasticity increased with increasing surface pressure signifying formation of rigid monolayer. Transition of monolayer from gaseous to liquid expanded to liquid condensed state was established by Brewster angle microscopic studies. Stability of the hybrid vesicles, formed by AASM+SPC+CHOL, was established by monitoring their size, zeta potential and polydispersity index values over 100 days. Size and spherical morphology of hybrid vesicles were confirmed by transmission electron microscopic studies. Biocompatibility of the hybrid vesicles were established by cytotoxicity studies revealing their possible applications in drug delivery and imaging.

A hydrogel based on Fe(II)-GMP demonstrates tunable emission, self-healing mechanical strength and Fenton chemistry-mediated notable antibacterial properties.

Supramolecular hydrogels serve as an excellent platform to enable in situ reactive oxygen species (ROS) generation while maintaining controlled localized conditions, thereby mitigating cytotoxicity. Herein, we demonstrate hydrogel formation using guanosine-5'-monophosphate (GMP) with tetra(4-carboxylphenyl) ethylene (1) to exhibit aggregation-induced emission (AIE) and tunable mechanical strength in the presence of divalent metal ions such as Ca2+, Mg2+, and Fe2+. The addition of divalent metal ions leads to structural transformation in the metallogels (M-1GMP). Furthermore, the incorporation of Fe2+ ions into the hydrogel (Fe-1GMP) promotes the Fenton reaction that could be upregulated upon adding ascorbic acid (AA), demonstrating antibacterial efficacy via ROS generation. In vitro studies on AA-loaded Fe-1GMP demonstrate excellent bacterial killing efficacy against E. coli, S. aureus and vancomycin-resistant enterococci (VRE) strains. Finally, in vivo studies involving topical administration of Fe-1GMP to Balb/c mice with skin infections further suggest the potential antibacterial efficacy of the hydrogel. Taken together, the hydrogel with its unique combination of mechanical tunability, ROS generation capability and antibacterial efficacy can be used for biomedical applications, particularly in wound healing and infection control.

Surface Chemistry of Gold Nanoparticles Modulates Cytokines and Nanomechanical Properties in Pancreatic Cancer Cell Lines: A Correlative Study.

Surface chemistry of nanoparticles play significant role in their cellular interaction. Along with other group, we previously demonstrated that dynamic alteration of cell membrane during uptake of gold nanoparticles can be thoroughly probed by nanomechanical properties of cell membrane. Additionally, endocytosis influences intracellular cytokines expression that also impact membrane stiffness. Hence, we have hypothesized that surface chemistry of gold nanoparticles influences intracellular cytokines which in turn imparts dynamic alteration of nanomechanical properties of cellular membrane of pancreatic cancer cells. Various gold nanoparticles decorated with targeting peptide, polyethylene glycol or their combinations have been used to treat two pancreatic cancer cell lines, Panc-1 and AsPC1, for 1 and 24 hours. Atomic force microscope is used to measure linear and nonlinear nanomechanical properties of cell membrane. Intracellular cytokine has been measured using real time polymeric chain reaction. We evaluated several criteria such as receptor dependent vs independent, PEGylated vs non-PEGylated and different timepoints, to deduce correlations between cytokines and nanomechanical attributes. We have identified unique relationship pro-tumorigenic cytokines with both linear and non-linear nanomechanical properties of Panc-1 and AsPC1 cell membrane during uptake of pristine gold nanoparticles or for PEGylation and for targeting peptide conjugation at the nanoparticle surface.

An investigation for phylogenetic characterization of human Pancreatic cancer microbiome by 16SrDNA Sequencing and Bioinformatics techniques.

Pancreatic cancer is a significant public health concern, with increasing incidence rates and limited treatment options. Recent studies have highlighted the role of the human microbiome, particularly the gut microbiota, in the development and progression of this disease. Microbial dysbiosis, characterized by alterations in the composition and function of the gut microbiota, has been implicated in pancreatic carcinogenesis through mechanisms involving chronic inflammation, immune dysregulation, and metabolic disturbances. Researchers have identified specific microbial signatures associated with pancreatic cancer, offering potential biomarkers for early detection and prognostication. By leveraging advanced sequencing and bioinformatics tools, scientists have delineated differences in the gut microbiota between pancreatic cancer patients and healthy individuals, providing insights into disease pathogenesis and potential diagnostic strategies. Moreover, the microbiome holds promise as a therapeutic target in pancreatic cancer treatment. Interventions aimed at modulating the microbiome, such as probiotics, prebiotics, and fecal microbiota transplantation, have demonstrated potential in enhancing the efficacy of existing cancer therapies, including chemotherapy and immunotherapy. These approaches can influence immune responses, alter tumor microenvironments, and sensitize tumors to treatment, offering new avenues for improving patient outcomes and overcoming therapeutic resistance. Overall, understanding the complex interplay between the microbiome and pancreatic cancer is crucial for advancing our knowledge of disease mechanisms and identifying innovative therapeutic strategies. Here we report phylogenetic analysis of the 16S microbial sequences of the pancreatic cancer mice microbiome and corresponding age matched healthy mice microbiome. We successfully identified differentially abundance of microbiota in the pancreatic cancer.

Machine learning-based approach for automated classification of cell and extracellular matrix using nanomechanical properties.

Fibrosis characterized by excess accumulation of extracellular matrix (ECM) due to complex cell-ECM interactions plays a pivotal role in pathogenesis. Herein, we employ the pancreatic ductal adenocarcinoma (PDAC) model to investigate dynamic alterations in nanomechanical attributes arising from the cell-ECM interactions to study the fibrosis paradigm. Several segregated studies performed on cellular and ECM components fail to recapitulate their complex collaboration. We utilized collagen and fibronectin, the two most abundant PDAC ECM components, and studied their nanomechanical attributes. We demonstrate alteration in morphology and nanomechanical attributes of collagen with varying thicknesses of collagen gel. Furthermore, by mixing collagen and fibronectin in various stoichiometry, their nanomechanical attributes were observed to vary. To demonstrate the dynamicity and complexity of cell-ECM, we utilized Panc-1 and AsPC-1 cells with or without collagen. We observed that Panc-1 and AsPC-1 cells interact differently with collagen and vice versa, evident from their alteration in nanomechanical properties. Further, using nanomechanics data, we demonstrate that ML-based techniques were able to classify between ECM as well as cell, and cell subtypes in the presence/absence of collagen with higher accuracy. This work demonstrates a promising avenue to explore other ECM components facilitating deeper insights into tumor microenvironment and fibrosis paradigm.

A Stimuli-Responsive Dual-Emitting Covalent Organic Framework Shows Selective Sensing of Highly Corrosive Acidic Media via Fluorescence Turn-On Signal with White Light Emission.

Luminescent covalent organic frameworks (LCOFs) have been employed as platforms for sensing analytes. Judicial incorporation of appropriate functional units inside the framework leads to the different electronic states in the presence of external stimuli, e.g., temperature, pH, etc. We report herein a new COF (TPEPy) as a solid-state acid sensor specific for the highly acidic environments that range from pH ∼0.5 to ∼3.0. This COF shows a protonation-induced reversible color change from bright yellow to deep red upon decreasing the pH from 3 to 0.5 and vice versa. No visual color change was, however, observed above pH 3.0. Photoluminescence (PL) studies show that the intrinsic emission peak of the TPEPy COF at 530 nm is shifted to 420 nm owing to the N-protonation of the imine nitrogen of COF within this pH range. Extensive studies demonstrate that the protonation behavior of the COF is counterion dependent. This was revealed when different acids, e.g., HCl, HNO3, HBr, and HI, were employed. The intensity of the proton-induced emission peak at 420 nm depends significantly upon the counterions with the order of HCl > HNO3 > HBr > HI. These anions interact with the protonated TPEPy COF by cation-anion and H-bonding interactions. Further, the pristine COF showed near white light emission at a particular pH of 2.5 (CIE coordinates 0.27, 0.32). From the PL spectrophotometric titrations, the deprotonation pKa was experimentally found to be 1.8 ± 0.02 for the TPEPy COF. The sensor reported herein is reversible, reusable, and regenerable and is useful for assessing pH fluctuations within a strongly acidic range via digital signaling.

Dual Circularly Polarized Luminescence (CPL) and Piezoelectric Responses in Self-Assembled Chiral Nanostructures Derived from a Dipeptide Based Piezorganogel.

Next-generation medical and consumer electrical devices require soft, flexible materials. Piezoelectric materials, capable of converting mechanical stress into electrical energy, are of interest across various fields. Chiral nanostructures, with inherent chirality, have emerged as potential piezoelectric materials. Peptide-based materials, known for self-assembly and stimuli responsiveness, hold promise for the utilization of chiral nanostructures. When combined with luminescent chromophores, peptides can generate aggregation-induced chiroptical effects like Circularly Polarized Luminescence (CPL) and Circular Dichroism (CD). In this study, a chiral organogel, L,L-1 is synthesized, and its self-assembly, mechanical properties, and chiroptical features are examined. The organogel exhibits thermo-reversible and thixotropic behavior, forming fibrillar networks and 2D-sheets upon cooling. CD spectroscopy reveals aggregation-induced chirality on pyrene chromophore, resulting in CPL with glum values of 3.0 (± 0.2) × 10-3 and 3.1 (± 0.2) × 10-3 for L,L-1 and D,D-1, respectively. Notably, the 2D-sheets exhibit an enhanced piezoelectric response (d33 ≈76.0 pm V-1) compared to the fibrillar network (d33 ≈64.1 pm V-1). Introducing an electron-deficient molecule into the solution forms a Charge-transfer (CT) complex, modulating the piezoelectric response to d33 ≈52.44 pm V-1. This study offers a promising approach to optoelectronics design, presenting a chiral system with both CPL and piezoelectric responses, opening new possibilities for innovative applications.

Structure-activity relationship of drug conjugated polymeric materials against uropathogenic bacteria colonization under in vitro and in vivo settings.

The human world has been plagued with different kinds of bacterial infections from time immemorial. The increased development of resistance towards commercial antibiotics has made these bacterial infections an even more critical challenge. Bacteria have modified their mode of interactions with different types of commercial drugs by bringing changes to the receptor proteins or by other resisting mechanisms like drug efflux. Various chemical approaches have been made to date to fight against these smart adapting species. Towards this, we hypothesize chemically modifying the commercial antibacterial drugs in order to deceive the bacteria and destroy the bacterial biomass. In this study, different molecular weight polyethyleneimines are taken and conjugated with some well-known commercial drugs like penicillin and chloramphenicol to explore their antibacterial properties against some of the laboratory and uro-pathogenic strains of Gram-positive and Gram-negative bacteria. A detailed structure-activity relationship of these polymeric prodrug-like materials has been evaluated to determine the optimum formulation. The standardized system not only shows significant ∼90% bacterial killing in liquid broth culture, but also demonstrates promising bacterial inhibition towards biofilm formation for the pathogenic strains on inanimate surfaces like urinary catheters and on an in vivo mouse skin abrasion model. The reported bioactive polymeric materials can be successfully used for widespread therapeutic applications with promising medical relevance.

An in silico approach to evaluate the bindings of natural flavonoids and RNA-DNA hybrids.

Flavonoids, low molecular weight polyphenolic compounds, are important natural products that belong to plant secondary metabolites. They have diverse biomedical applications such as antioxidative, anti-inflammatory, enzyme inhibitory, antimutagenic, anticarcinogenic, aromatase inhibitory effects, etc. Some of the flavonoids have been exported for bindings with certain DNA and tRNA structures both experimentally and computationally. RNA-DNA hybrid (RDH) falls into an important category of noncanonical nucleic acid structures that have many important biological functions. We have investigated the interaction of RDH structures with some of the dietary flavonoids with the aid of computational methods such as docking and molecular dynamics simulation. The presence of the - OH group on the ligand and the availability of a proper binding pocket in the macromolecule are the two main factors driving the binding preference. Thus, this computationally guided report explains the binding of the flavonoids with RDH structures to assist the researchers in designing noncanonical nucleic acid-targeted drug molecules.Communicated by Ramaswamy H. Sarma.

Advances in Glioblastoma Therapy: An Update on Current Approaches.

Glioblastoma multiforme (GBM) is a primary malignant brain tumor characterized by a high grade of malignancy and an extremely unfavorable prognosis. The current efficacy of established treatments for GBM is insufficient, necessitating the prompt development of novel therapeutic approaches. The progress made in the fundamental scientific understanding of GBM is swiftly translated into more advanced stages of therapeutic studies. Despite extensive efforts to identify new therapeutic approaches, GBM exhibits a high mortality rate. The current efficacy of treatments for GBM patients is insufficient due to factors such as tumor heterogeneity, the blood-brain barrier, glioma stem cells, drug efflux pumps, and DNA damage repair mechanisms. Considering this, pharmacological cocktail therapy has demonstrated a growing efficacy in addressing these challenges. Towards this, various forms of immunotherapy, including the immune checkpoint blockade, chimeric antigen receptor T (CAR T) cell therapy, oncolytic virotherapy, and vaccine therapy have emerged as potential strategies for enhancing the prognosis of GBM. Current investigations are focused on exploring combination therapies to mitigate undesirable side effects and enhance immune responses against tumors. Furthermore, clinical trials are underway to evaluate the efficacy of several strategies to circumvent the blood-brain barrier (BBB) to achieve targeted delivery in patients suffering from recurrent GBM. In this review, we have described the biological and molecular targets for GBM therapy, pharmacologic therapy status, prominent resistance mechanisms, and new treatment approaches. We also discuss these promising therapeutic approaches to assess prospective innovative therapeutic agents and evaluated the present state of preclinical and clinical studies in GBM treatment. Overall, this review attempts to provide comprehensive information on the current status of GBM therapy.

Correction: Kalvala et al. Cannabidiol-Loaded Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Paclitaxel-Induced Peripheral Neuropathy. Pharmaceutics 2023, 15, 554.

"Yan Li" was not included as an author in the original publication [...].

Analysis of Differential Gene Expression and Core Canonical Pathways Involved in the Epithelial to Mesenchymal Transition of Triple Negative Breast Cancer Cells by Ingenuity Pathway Analysis.

Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cells of epithelial origin that promotes metastasis, drug resistance and cancer stem cell formation. Since the information regarding differential gene expression in TNBC cells and cell signaling events leading to EMT is limited, this investigation was done by comparing transcriptomic data generated by RNA isolation and sequencing of a EMT model TNBC cell line in comparison to regular TNBC cells. RNA sequencing and Ingenuity Pathway Software Analysis (IPA) of the transcriptomic data revealed several upregulated and downregulated gene expressions along with novel core canonical pathways including Sirtuin signaling, Oxidative Phosphorylation and Mitochondrial dysfunction events involved in EMT changes of the TNBC cells.

Hydrogel Nanocomposite Towards Optical Sensing of Spermine in Biomedical and Real-Life Food Samples and Remediation of Toxic Dyes from Wastewater.

Nanocomposites such as graphene oxide (GO) have been incorporated into hydrogels to enhance conventional hydrogels' properties and develop new functions. Unique and strong molecular interactions between GO and low molecular weight gelators allow the fabrication of various functional hydrogels suitable for different applications. In the present study, we report a stable and soft nanocomposite hydrogel comprising a pyrene-based chiral amphipath having an amino acid (l-phenylalanine) core with pendant oligo-oxyethylene hydrophilic chains and GO. The mechanical and viscoelastic properties of the nanocomposite hydrogel were thoroughly studied using various spectroscopic, microscopic, and mechanical techniques. Even without GO, native hydrogels could form a self-supported thermoreversible and thixotropic hydrogel composed of the fibrillar network. Unlike native hydrogels, the morphological investigation of nanocomposite gels shows the presence of cross-linked nanosheet-like structures. The combined effect of π-π stacking and H-bonding interactions is the driving force for the formation of such composite hydrogels. Moreover, the nanocomposite hydrogels possess significantly superior mechanical stiffness than the native hydrogels. Interestingly, the thixotropic properties observed with the parent gel were retained even in the presence of carbon nanomaterials (GO). The nanocomposite hydrogel could be employed in the optical sensing of a biogenic polyamine, spermine, resulting in a visible gel-to-sol transition. The superior electrostatic interaction between the GOs and spermine molecules might have led to the release of entrapped fluorogenic dyes from the hydrogel network and a turn-on emission response. The sensory system was employed to analyze spermine content in human urine samples and decomposed food items. A gel-coated paper strip was also developed for onsite detection of the spermine. The nanocomposite hydrogel was further utilized to remove toxic organic dyes such as methylene blue (MB) and rhodamine B (RhB) from the aqueous media. The nanocomposite hydrogel thus showed excellent dye removal capabilities and was also found to be recyclable. Calculations of different mechanical parameters suggest that the dye removal efficiency of the nanocomposite hydrogel was better for MB than for RhB.

New Xanthone Derivatives as Potent G-Quadruplex Binders for Developing Anti-Cancer Therapeutics.

Xanthone is an important scaffold for various medicinally relevant compounds. However, it has received scant attention in the design of agents that are cytotoxic to cancer cells via targeting the stabilization of G-quadruplex (G4) nucleic acids. Specific G4 DNA recognition against double-stranded (ds) DNA is receiving epoch-making interest for the development of G4-mediated anticancer agents. Toward this goal, we have synthesized xanthone-based derivatives with various functionalized side-arm substituents that exhibited significant selectivity for G4 DNA as compared to dsDNA. The specific interaction has been demonstrated by performing various biophysical experiments. Based on the computational study as well as the competitive ligand binding assay, it is inferred that the potent compounds exhibit an end-stacking mode of binding with G4 DNA. Additionally, compound-induced conformational changes in the flanking nucleotides form the binding pocket for effective interaction. Selective action of the compounds on cancer cells suggests their effectiveness as potent anti-cancer agents. This study promotes the importance of structure-based screening approaches to get molecular insights for new scaffolds toward desired specific recognition of non-canonical G4 DNA structures.

Demand-induced regime shift in fishery: A mathematical perspective.

Though overfishing and climate change are the primary reasons for a regime shift in the fishery, we demonstrate here a different reason for the regime shift, not reported earlier to the best of our knowledge. We show that high demand for fish may cause a regime shift in a fishery in a shorter time. For this, a four-dimensional bioeconomic fishery model is considered and analyzed to explore the system's dynamic behavior. The objective is to demonstrate how increasing demand may cause a catastrophic change in the fish and fishery. We provide the local and global stabilities of different equilibrium points, guaranteeing the stable coexistence of ecological and economic states. Our bifurcation analysis revealed that the demand parameter might play positive and negative roles in the system dynamics. Demand can make an unstable fishery stable. It can also help remove the infection from the system. On the flip side, high demand may cause a regime shift from a harvested state to a non-harvested state, making the price unbounded. Using Pontryagin's maximum principle, we further discussed optimal revenue generation.

Cannabidiol-Loaded Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Paclitaxel-Induced Peripheral Neuropathy.

In cancer patients, chronic paclitaxel (PTX) treatment causes excruciating pain, limiting its use in cancer chemotherapy. The neuroprotective potential of synthetic cannabidiol (CBD) and CBD formulated in extracellular vesicles (CBD-EVs) isolated from human umbilical cord derived mesenchymal stem cells was investigated in C57BL/6J mice with PTX-induced neuropathic pain (PIPN). The particle size of EVs and CBD-EVs, surface roughness, nanomechanical properties, stability, and release studies were all investigated. To develop neuropathy in mice, PTX (8 mg/kg, i.p.) was administered every other day (four doses). In terms of decreasing mechanical and thermal hypersensitivity, CBD-EVs treatment was superior to EVs treatment or CBD treatment alone (p < 0.001). CBD and CBD-EVs significantly reduced mitochondrial dysfunction in dorsal root ganglions and spinal homogenates of PTX-treated animals by modulating the AMPK pathway (p < 0.001). Studies inhibiting the AMPK and 5HT1A receptors found that CBD did not influence the neurobehavioral or mitochondrial function of PIPN. Based on these results, we hypothesize that CBD and CBD-EVs mitigated PIPN by modulating AMPK and mitochondrial function.

[2,1,3]-Benzothiadiazole-Spaced Co-Porphyrin-Based Covalent Organic Frameworks for O2 Reduction.

Designing N-coordinated porous single-atom catalysts (SACs) for the oxygen reduction reaction (ORR) is a promising approach to achieve enhanced energy conversion due to maximized atom utilization and higher activity. Here, we report two Co(II)-porphyrin/ [2,1,3]-benzothiadiazole (BTD)-based covalent organic frameworks (COFs; Co@rhm-PorBTD and Co@sql-PorBTD), which are efficient SAC systems for O2 electrocatalysis (ORR). Experimental results demonstrate that these two COFs outperform the mass activity (at 0.85 V) of commercial Pt/C (20%) by 5.8 times (Co@rhm-PorBTD) and 1.3 times (Co@sql-PorBTD), respectively. The specific activities of Co@rhm-PorBTD and Co@sql-PorBTD were found to be 10 times and 2.5 times larger than that of Pt/C, respectively. These COFs also exhibit larger power density and recycling stability in Zn-air batteries compared with a Pt/C-based air cathode. A theoretical analysis demonstrates that the combination of Co-porphyrin with two different BTD ligands affords two crystalline porous electrocatalysts having different d-band center positions, which leads to reactivity differences toward alkaline ORR. The strategy, design, and electrochemical performance of these two COFs offer a pyrolysis-free bottom-up approach that avoids the creation of random atomic sites, significant metal aggregation, or unpredictable structural features.

Design and Synthesis of Xanthone Analogues Conjugated with Aza-aromatic Substituents as Promising G-Quadruplex Stabilizing Ligands and their Selective Cancer Cell Cytotoxic Action.

We have examined the stabilization of higher-order noncanonical G-quadruplex (G4) DNA structures formed by the G-rich sequences in the promoter region of oncogenes such as c-MYC, c-KIT, VEGF and BCl2 by newly synthesized, novel nitrogen-containing aromatics conjugated to xanthone moiety. Compounds with N-heterocyclic substituents such as pyridine (XNiso), benzimidazole (XBIm), quinoxaline (XQX) and fluorophore dansyl (XDan) showed greater effectiveness in stabilizing the G4 DNA as well as selective cytotoxicity for cancer cells (mainly A549) over normal cells both in terms of UV-Vis spectral titrations and cytotoxicity assay. Both fluorescence spectral titrimetric measurements and circular dichroism (CD) melting experiments further substantiated the G4 stabilization phenomenon by these small-molecular ligands. In addition, these compounds could induce the formation of parallel G4 structures in the absence of any added salt condition in Tris⋅HCl buffer at 25 °C. In a polymerase stop assay, the formation of stable G4 structures in the promoter of oncogenes and halting of DNA synthesis in the presence of the above-mentioned compounds was demonstrated by using oncogene promoter as the DNA synthesis template. Apoptosis-mediated cell death of the cancer cells was proved by Annexin V-PI dual staining assay and cell-cycle arrest occurred in the S phase of the cell cycles. The plausible mode of binding involves the stacking of the xanthone core on the G4 DNA plane with the possibility of interaction with the 5'-overhang as indicated by molecular dynamics simulation studies.

Biophysical, Molecular and Proteomic Profiling of Human Retinal Organoid-Derived Exosomes.

PURPOSE: There is a growing interest in extracellular vesicles (EVs) for ocular applications as therapeutics, biomarkers, and drug delivery vehicles. EVs secreted from mesenchymal stem cells (MSCs) have shown to provide therapeutic benefits in ocular conditions. However, very little is known about the properties of bioreactor cultured-3D human retinal organoids secreted EVs. This study provides a comprehensive morphological, nanomechanical, molecular, and proteomic characterization of retinal organoid EVs and compares it with human umbilical cord (hUC) MSCs. METHODS: The morphology and nanomechanical properties of retinal organoid EVs were assessed using Nanoparticle tracking analysis (NTA) and Atomic force microscopy (AFM). Gene expression analysis of exosome biogenesis of early and late retinal organoids were compared using qPCR. The protein profile of the EVs were analyzed with proteomic tools. RESULTS: NTA indicated the average size of EV as 100-250 nm. A high expression of exosome biogenesis genes was observed in late retinal organoids EVs. Immunoblot analysis showed highly expressed exosomal markers in late retinal organoids EVs compared to early retinal organoids EVs. Protein profiling of retinal organoid EVs displayed a higher differential expression of retinal function-related proteins and EV biogenesis proteins than hUCMSC EVs, implicating that the use of retinal organoid EVs may have a superior therapeutic effect on retinal disorders. CONCLUSION: This study provides supplementary knowledge on the properties of retinal organoid EVs and suggests their potential use in the diagnostic and therapeutic treatments for ocular diseases.

Deciphering the Binding Insights of Novel Disubstituted Anthraquinone Derivatives with G-Quadruplex DNA to Exhibit Selective Cancer Cell Cytotoxicity.

Anthraquinone-based compounds are well-known as duplex DNA as well as G-quadruplex DNA binders. Implications of various anthraquinone derivatives for specific recognition of G-quadruplex DNA over duplex DNA is a 'challenging' research work that requires adequate experience with molecular design. To address this important issue, we designed and synthesized ten new 2,6-disubstituted anthraquinone-based derivatives with different functionalized piperazinyl side-chains. Among these, particular compounds with certain distant groups have shown selective and significant binding affinities toward the c-MYC and c-KIT G-quadruplex DNA over the duplex DNA, as noticed from various biophysical experiments. The structural difference of quadruplex and duplex DNA was utilized to probe these derivatives for the end-stacking mode of binding with G-quadruplex DNA. The ability of the ligands to halt DNA synthesis by stabilizing G-quadruplex structures is one of the crucial points to further apply them for quadruplex-mediated anti-cancer therapeutics. Interestingly, these ligands trigger apoptosis to exhibit selective cytotoxicity toward cancer cells over normal cells. This was further evidenced by ligand-induced cell cycle arrest as well as cellular apoptotic morphological changes. These blood-compatible ligands provided detailed structure-activity relationship approaches for the molecular design of anthraquinone-based G-quadruplex binders.