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Extensibility is beyond the paradigm of classical soft glassy materials, and more broadly, yield-stress fluids. Recently, model yield-stress fluids with significant extensibility have been designed by adding polymeric phases to classically viscoplastic dispersions [Nelson et al., J. Rheol., 2018, 62, 357; Nelson et al., Curr. Opin. Solid State Mater. Sci., 2019, 23, 100758; Dekker et al., J. Non-Newtonian Fluid Mech., 2022, 310, 104938]. However, fundamental questions remain about the design of and coupling between the shear and extensional rheology of such systems. In this work, we propose a model material, a mixture of soft glassy microgels and solutions of high molecular weight linear polymers. We establish systematic criteria for the design and thorough rheological characterization of such systems, in both shear and extension. Using our material, we show that it is possible to dramatically change the behavior in extension with minimal change in the shear yield stress and elastic modulus, thus enabling applications that exploit orthogonal modulation of shear and extensional material properties.
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We describe the 3-iodopropyl acetal moiety as a simple cleavable unit that undergoes acid catalyzed hydrolysis to liberate HI (p Ka â¼ -10) and acrolein stoichiometrically. Integrating this unit into linear and network polymers gives a class of macromolecules that undergo a new mechanism of degradation with an acid amplified, sigmoidal rate. This trigger-responsive self-amplified degradable polymer undergoes accelerated rate of degradation and agent release.
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AIM: Exploring the efficacy of ß-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics. MATERIALS AND METHODS: We synthesized a series of 1-Aryl-N-substituted-ß-carboline-3-carboxamide compounds and evaluated their cytotoxicity against human lung carcinoma (A549) cells using the MTT assay. Normal lung fibroblast cells (WI-38) were used to assess compound selectivity. The mechanism of action of MJ-211 was elucidated through Western blot analysis of key pro-apoptotic and cell cycle regulatory proteins. Additionally, the inhibitory effect of MJ-211 on multicellular 3D spheroid growth of A549 cells was evaluated. KEY FINDINGS: Lead compound MJ-211 exhibited remarkable cytotoxicity against A549 cells with an IC50 of 4.075 µM at 24 h treatment and IC50 of 1.7 nM after 72 h of treatment, while demonstrating selectivity towards normal WI-38 cells. MJ-211 activated pro-apoptotic factors Bim and p53, and suppressed Cyclin B1, Phospho HSP 27, BubR1, Mad 2, ERK1/2, and NF-κB, indicating its potent antimitotic and pro-apoptotic effects. MJ-211 significantly suppressed the migration of cells and inhibited the growth of A549 cell-derived multicellular 3D spheroids, highlighting its efficacy in a more physiologically relevant model. SIGNIFICANCE: Cytotoxic effect of MJ-211 against cancer cells, selectivity towards normal cells, and ability to modulate key regulatory proteins involved in apoptosis and cell cycle progression underscore its potential as a promising template for further anticancer lead optimization. Moreover, the inhibitory effect of MJ-211 on multicellular spheroid growth suggests its efficacy in combating tumor heterogeneity and resistance mechanisms, thereby offering a promising avenue for future anticancer drug development.
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Carbolinas , Microtúbulos , FN-kappa B , Humanos , Carbolinas/farmacología , FN-kappa B/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Células A549 , Antimitóticos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
Venom in medicine is well documented in the chronicles of ancient Greece and the Roman Empire and persisted into the Renaissance and even into the modern era. Venoms were not always associated with detrimental consequences. Since ancient times, the curative capacity of venom has been recognized, portraying venom as a metaphor for pharmacy and medicine. Venom proteins and peptides' antimicrobial potential has not undergone systematic exploration despite the huge literature on natural antimicrobials. In light of the escalating challenge of antimicrobial resistance and the diminishing effectiveness of antibiotics, there is a pressing need for innovative antimicrobials capable of effectively addressing illnesses caused by multidrug-resistant microorganisms. This review adds to our understanding of the effectiveness of different venom components against a host of pathogenic microorganisms. The aim is to illuminate the various antimicrobials present in venom and venom peptides, thereby emphasizing the unexplored medicinal potential for antimicrobial properties. We have presented a concise summary of the molecular examination of the venom peptides' functioning processes, as well as the current clinical and preclinical progress of venom antimicrobial peptides.
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Bioengineered composite hydrogel platforms made of a supramolecular coassembly have recently garnered significant attention as promising biomaterial-based healthcare therapeutics. The mechanical durability of amyloids, in conjunction with the structured charged framework rendered by biologically abundant key ECM component glycosaminoglycan, enables us to design minimalistic customized biomaterial suited for stimuli responsive therapy. In this study, by harnessing the heparin sulfate-binding aptitude of amyloid fibrils, we have constructed a pH-responsive extracellular matrix (ECM) mimicking hydrogel matrix. This effective biocompatible platform comprising heparin sulfate-amyloid coassembled hydrogel embedded with polyphenol functionalized silver nanoparticles not only provide a native skin ECM-like conductive environment but also provide wound-microenvironment responsive on-demand superior antibacterial efficacy for effective diabetic wound healing. Interestingly, both the cytocompatibility and antibacterial properties of this bioinspired matrix can be fine-tuned by controlling the mutual ratio of heparin sulfate-amyloid and incubated silver nanoparticle components, respectively. The designed biomaterial platform exhibits notable effectiveness in the treatment of chronic hyperglycemic wounds infected with multidrug-resistant bacteria, because of the integration of pH-responsive release characteristics of the incubated functionalized AgNP and the antibacterial amyloid fibrils. In addition to this, the aforementioned assemblage shows exceptional hemocompatibility with significant antibiofilm and antioxidant characteristics. Histological evidence of the incised skin tissue sections indicates that the fabricated composite hydrogel is also effective in controlling pro-inflammatory cytokines such as IL6 and TNFα expressions at the wound vicinity with significant upregulation of angiogenesis markers like CD31 and α-SMA.
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Amiloide , Antibacterianos , Matriz Extracelular , Heparina , Hidrogeles , Nanopartículas del Metal , Plata , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Heparina/química , Heparina/farmacología , Plata/química , Plata/farmacología , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Nanopartículas del Metal/química , Amiloide/química , Amiloide/metabolismo , Animales , Humanos , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Hydrogels are soft materials engineered to suit a multitude of applications that exploit their tunable mechanochemical properties. Dynamic hydrogels employing noncovalent, physically cross-linked networks dominated by either enthalpic or entropic interactions enable unique rheological and stimuli-responsive characteristics. In contrast to enthalpy-driven interactions that soften with increasing temperature, entropic interactions result in largely temperature-independent mechanical properties. By engineering interfacial polymer-particle interactions, we can induce a dynamic-to-covalent transition in entropic hydrogels that leads to biomimetic non-ergodic aging in the microstructure without altering the network mesh size. This transition is tuned by varying temperature and formulation conditions such as pH, which allows for multivalent tunability in properties. These hydrogels can thus be designed to exhibit either temperature-independent metastable dynamic cross-linking or time-dependent stiffening based on formulation and storage conditions, all while maintaining structural features critical for controlling mass transport, akin to many biological tissues. Such robust materials with versatile and adaptable properties can be utilized in applications such as wildfire suppression, surgical adhesives, and depot-forming injectable drug delivery systems.
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Hidrogeles , Hidrogeles/química , Materiales Biomiméticos/química , Concentración de Iones de Hidrógeno , Temperatura , Reología , Biomimética/métodosRESUMEN
The escalation of bacterial resistance against existing therapeutic antimicrobials has reached a critical peak, leading to the rapid emergence of multidrug-resistant strains. Stringent pathways in novel drug discovery hinder our progress in this survival race. A promising approach to combat emerging antibiotic resistance involves enhancing conventional ineffective antimicrobials using low-toxicity small molecule adjuvants. Recent research interest lies in weak membrane-perturbing agents with unique cyclic hydrophobic components, addressing a significant gap in antimicrobial drug exploration. Our study demonstrates that quinoline-based amphipathic small molecules, SG-B-52 and SG-B-22, significantly reduce MICs of selected beta-lactam antibiotics (ampicillin and amoxicillin) against lethal methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, membrane perturbation, depolarization, and ROS generation drive cellular lysis and death. These molecules display minimal in vitro and in vivo toxicity, showcased through hemolysis assays, cell cytotoxicity analysis, and studies on albino Wistar rats. SG-B-52 exhibits impressive biofilm-clearing abilities against MRSA biofilms, proposing a strategy to enhance beta-lactam antibiosis and encouraging the development of potent antimicrobial potentiators.
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Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Quinolinas , beta-Lactamas/farmacología , beta-Lactamas/uso terapéutico , Sinergismo Farmacológico , Antiinfecciosos/farmacología , Quinolinas/farmacologíaRESUMEN
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.
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Distrofia Muscular de Duchenne , Quinazolinas , Quinolinas , Receptores de Hidrocarburo de Aril , Utrofina , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Utrofina/metabolismo , Quinolinas/farmacología , Quinolinas/química , Humanos , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Animales , Ratones , Quinazolinas/farmacología , Quinazolinas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Relación Estructura-Actividad , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
The emergence of antimicrobial resistance, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), poses a grave threat to public health globally. Over time, MRSA has evolved resistance to multiple antibiotics, challenging conventional treatment strategies. The relentless adaptability of MRSA underscores the urgent need for innovative and targeted antimicrobial approaches to combat this resilient pathogen. Ancient knowledge and practices, along with scientific evidence, have established that metallic copper, and its organic coordination complexes can act as potential antibacterial substances. In search of a smart and effective antimicrobial against MRSA, we designed, synthesized, and characterized a bidentate copper(II) ligand complex (SG-Cu) utilizing a comprehensive array of analytical techniques, including ESI-MS, elemental analysis, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, and others. Antibacterial efficacy and mechanism of action of the complex were assessed through bacterial growth analyses, bacterial membrane perturbation assays, ROS elicitation assays, and field emission scanning electron microscopy. SG-Cu was found to maintain robust biocompatibility against the mammalian cell lines HEK-293, WI-38, and NIH/3T3. Remarkably, SG-Cu demonstrated significant biofilm disruptive tendency evidenced by the retardation of sliding motility, reduction in slime production, reduction in biofilm viability, and enhanced biofilm eradication, both in vitro and in urinary catheters. In vivo studies on murine excisional wounds, with SG-Cu impregnated in a palmitic acid conjugated NAVSIQ hexapeptide (PA-NV) hydrogel, revealed the sustained release of SG-Cu from the gel matrix, facilitating accelerated wound healing and effective wound disinfection. This multifaceted investigation highlights the potential of SG-Cu as a versatile option for combating MRSA infections and promoting wound healing, solidifying its claim to be developed into a viable therapeutic.
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Antibacterianos , Cobre , Hidrogeles , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Quinolinas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Cobre/química , Cobre/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Animales , Quinolinas/química , Quinolinas/farmacología , Ligandos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Biopelículas/efectos de los fármacos , Tamaño de la Partícula , Cicatrización de Heridas/efectos de los fármacos , Ensayo de Materiales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Estructura MolecularRESUMEN
Antimicrobial cationic peptides are intriguing and propitious antibiotics for the future, even against multidrug-resistant superbugs. Venoms serve as a source of cutting-edge therapeutics and innovative, unexplored medicines. In this study, a novel cationic peptide library consisting of seven sequences was designed and synthesized from the snake venom cathelicidin, batroxicidin (BatxC), with the inclusion of the FLPII motif at the N-terminus. SP1V3_1 demonstrated exceptional antibacterial effectiveness against Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae and destroyed the bacteria by depolarizing, rupturing, and permeabilizing their membranes, as evident from fluorescence assays, atomic force microscopy, and scanning electron microscopy. SP1V3_1 was observed to modulate the immune response in LPS-elicited U937 cells and exhibited good antibiofilm activity against MRSA and K. pneumoniae. The peptide promoted wound healing and disinfection in the murine model. The study demonstrated that SP1V3_1 is an exciting peptide lead and may be explored further for the development of better therapeutic peptides.
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Antiinfecciosos , Desinfectantes , Staphylococcus aureus Resistente a Meticilina , Ratones , Animales , Pruebas de Sensibilidad Microbiana , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Antibacterianos/farmacología , Cicatrización de Heridas , Venenos de Serpiente , Escherichia coliRESUMEN
Multidrug-resistant (MDR) superficial bacterial infections caused by carbapenem-resistant Enterobacter sp. and Klebsiella sp. have emerged as major threats toward global health care management. In search of a novel antimicrobial, our main objectives were to explore the antimicrobial, antibiofilm, and wound healing potential of glutathione and citrate-capped copper oxide nanoparticles (CuNPs) against gram-negative MDR pathogens Klebsiella quasipneumoniae and Enterobacter sp., ensuring the lowest possible host cell nano-cytotoxicity and minimum susceptibility of the CuNPs toward oxidation. The CuNPs were found to elicit reactive oxygen species (ROS) generation within bacterial cells, inhibiting the bacterial growth and division. They contributed to the remodeling of the bacterial lipopolysaccharide, induced membrane lysis, and promoted antibiofilm activities by reduced cell-cell aggregation and matrix destabilization while displaying excellent biocompatibility against HEK-293 and HeLa cell lines. The CuNPs were also instrumental in preventing postsurgical wound infections and aiding in wound closure in the murine excisional wound model, as observed in albino Wistar rats, forcing us to believe that the CuNPs are bioactive in wound therapy. The results are encouraging and demands further experimental exploitation of the particles in treating other MDR gram-negative infections, irrespective of their resistance status.
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Antibacterianos/farmacología , Enterobacter/efectos de los fármacos , Klebsiella/efectos de los fármacos , Nanopartículas del Metal/química , Infección de la Herida Quirúrgica/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Animales , Biopelículas/efectos de los fármacos , Agregación Celular , Cobre/química , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Glutatión/química , Células HEK293 , Células HeLa , Humanos , Lipopolisacáridos/metabolismo , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Especies Reactivas de OxígenoRESUMEN
A new type of base-triggered self-amplifying degradable polyurethane is reported that degrades under mild conditions, with the release of increasing amounts of amine product leading to self-amplified degradation. The polymer incorporates a base-sensitive Fmoc-derivative into every repeating unit to enable highly sensitive amine amplified degradation. A sigmoidal degradation curve for the linear polymer was observed consistent with a self-amplifying degradation mechanism. An analogous cross-linked polyurethane gel was prepared and also found to undergo amplified breakdown. In this case, a trace amount of localized base initiates the degradation, which in turn propagates through the material in an amplified manner. The results demonstrate the potential utility of these new generation polyurethanes in enhanced disposability and as stimuli responsive materials.