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1.
RSC Adv ; 14(35): 25130-25148, 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39139248

RESUMEN

Polyethylene microplastics (PE MPs) have sparked widespread concern about their possible health implications because of their abundance, pervasiveness in the environment and in our daily life. Multiple investigations have shown that a high dosage of PE MPs may adversely impact gastrointestinal health. In tandem with the rising prevalence of Inflammatory bowel disease (IBD) in recent decades, global plastic manufacturing has risen to more than 300 million tons per year, resulting in a build-up of plastic by-products such as PE MPs in our surroundings. We have explored current advancements in the effect PE MPs on IBD in this review. Furthermore, we compared and summarized the detrimental roles of PE MPs in gut microbiota of different organisms viz., earthworms, super worm's larvae, yellow mealworms, brine shrimp, spring tails, tilapia, gilt-head bream, crucian carp, zebrafish, juvenile yellow perch, European sea bass, c57BL/6 mice and human. According to this review, PE MPs played a significant role in decreasing the diversity of gut microbiota of above-mentioned species which leads to the development of IBD and causes severe intestinal inflammation. Finally, we pinpoint significant scientific gaps, such as the movement of such hazardous PE MPs and the accompanying microbial ecosystems and propose prospective research directions.

2.
ACS Cent Sci ; 10(6): 1179-1190, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38947210

RESUMEN

Protein-based therapeutics comprise a rapidly growing subset of pharmaceuticals, but enabling their delivery into cells for intracellular applications has been a longstanding challenge. To overcome the delivery barrier, we explored a reversible, bioconjugation-based approach to modify the surface charge of protein cargos with an anionic "cloak" to facilitate electrostatic complexation and delivery with lipid nanoparticle (LNP) formulations. We demonstrate that the conjugation of lysine-reactive sulfonated compounds can allow for the delivery of various protein cargos using FDA-approved LNP formulations of the ionizable cationic lipid DLin-MC3-DMA (MC3). We apply this strategy to functionally deliver RNase A for cancer cell killing as well as a full-length antibody to inhibit oncogenic ß-catenin signaling. Further, we show that LNPs encapsulating cloaked fluorescent proteins distribute to major organs in mice following systemic administration. Overall, our results point toward a generalizable platform that can be employed for intracellular delivery of a wide range of protein cargos.

3.
J Phys Chem Lett ; 15(25): 6560-6567, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38885454

RESUMEN

Aggregation of human α-synuclein protein is regarded to be a key stage in the etiology of Parkinson's disease and numerous other neurodegenerative illnesses. Microplastics pollution can be a potential agent to promote various neurodegenerative disorders. In this study, we have employed various multispectroscopic analytical methods to investigate the binding interactions between polyethylene (PE-MPs), polyvinyl chloride (PVC-MPs), polystyrene (PS-MPs) microplastics, and human α-synuclein protein. Spectroscopic investigations using UV-vis absorption, circular dichroism, and Fourier transform infrared have indicated different alterations in α-synuclein protein's secondary structures induced by the formation of the α-synuclein protein-MP binding complex. This study suggests that PS-MPs are found to be the most effective microplastic that promote amyloidogenic oligomer emergence because of their tiny size (100 nm).


Asunto(s)
Microplásticos , alfa-Sinucleína , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Humanos , Microplásticos/química , Poliestirenos/química , Dicroismo Circular , Espectroscopía Infrarroja por Transformada de Fourier , Unión Proteica , Cloruro de Polivinilo/química , Polietileno/química , Estructura Secundaria de Proteína , Amiloide/química , Amiloide/metabolismo
4.
Comput Biol Med ; 177: 108683, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38838555

RESUMEN

G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions and are abundant in promoter regions of several oncogenes. Therefore, GQ-DNA is an important target for anticancer drugs and hence binding interactions between GQ-DNA and small molecule ligands are of great importance. Since GQ-DNA is a highly polymorphic structure, it is important to identify ligand molecules which preferentially target a particular quadruplex sequence. In this present study, we have used a FDA approved drug called imatinib mesylate (ligand) which is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia, gastrointestinal stromal tumours. Different spectroscopic techniques as well as molecular docking investigations and molecular simulations have been used to explore the interaction between imatinib mesylate with VEGF GQ DNA structures along with duplex DNA, C-Myc, H-Telo GQ DNA. We found that imatinib mesylate shows preferential interaction towards VEGF GQ DNA compared to C-Myc, H-Telo GQ and duplex DNA. Imatinib mesylate seems to be an efficient ligand for VEGF GQ DNA, suggesting that it might be used to regulate the expression of genes in cancerous cells.


Asunto(s)
Antineoplásicos , G-Cuádruplex , Mesilato de Imatinib , Simulación del Acoplamiento Molecular , Factor A de Crecimiento Endotelial Vascular , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/química , Mesilato de Imatinib/farmacología , G-Cuádruplex/efectos de los fármacos , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/genética , ADN/química , ADN/metabolismo
5.
Langmuir ; 40(19): 10157-10170, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38700902

RESUMEN

I-Motif (iM) DNA structures represent among the most significant noncanonical nucleic acid configurations. iM-forming DNA sequences are found in an array of vital genomic locations and are particularly frequent in the promoter islands of various oncogenes. Thus, iM DNA is a crucial candidate for anticancer medicines; therefore, binding interactions between iM DNA and small molecular ligands, such as flavonoids, are critically important. Extensive sets of spectroscopic strategies and thermodynamic analysis were utilized in the present investigation to find out the favorable interaction of quercetin (Que), a dietary flavonoid that has various health-promoting characteristics, including anticancer properties, with noncanonical iM DNA structure. Spectroscopic studies and thermal analysis revealed that Que interacts preferentially with HRAS1 iM DNA compared with VEGF, BCL2 iM, and duplex DNA. Que, therefore, emerged as a suitable natural-product-oriented antagonist for targeting HRAS1 iM DNA. The innovative spectroscopic as well as mechanical features of Que and its specific affinity for HRAS1 iM may be useful for therapeutic applications and provide crucial insights for the design of compounds with remarkable medicinal properties.


Asunto(s)
ADN , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas p21(ras) , Quercetina , Quercetina/química , Quercetina/farmacología , Quercetina/metabolismo , ADN/química , ADN/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Termodinámica , Humanos , Motivos de Nucleótidos , Sitios de Unión
6.
ACS Omega ; 9(19): 21668-21679, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38764694

RESUMEN

Harmaline and harmine are two structurally similar ß-carboline alkaloids with several therapeutic activities, such as anti-inflammatory, antioxidant, neuroprotective, nephroprotective, antidiabetic, and antitumor activities. It has been previously reported that the interaction between harmaline and hemoglobin (Hb) is weak in buffer media compared to harmine. Crowding agents induce a molecular crowding environment in the ex vivo condition, which is almost similar to the intracellular environment. In this present study, we have investigated the nature of the interactions of harmaline and harmine with Hb by increasing the percentage of the crowding agent in buffer solution. The results of the UV-vis and fluorescence spectroscopy analysis have showed that with an increasing proportion of crowding agents, the interaction between harmaline and Hb is steadily improving in comparison to harmine. It has been found that the binding constant of Hb-harmaline reaches 6.82 × 105 M-1 in the 40% polyethylene glycol 200-mediated crowding condition, indicating high affinity compared to very low interaction in buffer media. Steady-state fluorescence anisotropy along with fluorescence lifetime measurements further revealed that the rotational movement of harmaline is maximally restricted by Hb in high crowding environments. Stoichiometry results represent that Hb and harmaline interacts in a 1:1 ratio in different percentages of the crowding agent. The circular dichroism spectroscopic results predict stronger interaction of harmaline with Hb (secondary structure alterations) in a higher crowding environment. From the melting study, it was found that the reactions between Hb and harmaline in crowding environments are endothermic (ΔH > 0) and disordering (ΔS > 0) in nature, indicating that hydrogen bonding and van der Waals interactions are the main interacting forces between Hb and harmaline. Harmaline molecules are more reactive in molecular crowding conditions than in normal buffer condition. This study represents that the interaction between harmaline and Hb is stronger compared to the structurally similar harmine in a molecular crowding environment, which may enlighten the drug discovery process in cell-mimicking conditions.

7.
Nat Commun ; 15(1): 1810, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38418497

RESUMEN

Selective functionalization of innate sp2 C-H bonds under ambient conditions is a grand synthetic challenge in organic chemistry. Here we combine host-guest charge transfer-based photoredox chemistry with supramolecular nano-confinement to achieve selective carbonylation of styrene by tuning the dioxygen concentration. We observe exclusive photocatalytic formation of benzaldehyde under excess O2 (>1 atm) while Markovnikov addition of water produced acetophenone in deoxygenated condition upon photoexcitation of confined styrene molecules inside a water-soluble cationic nanocage. Further by careful tuning of the nanocage size, electronics, and guest preorganization, we demonstrate rate enhancement of benzaldehyde formation and a complete switchover to the anti-Markovnikov product, 2-phenylethan-1-ol, in the absence of O2. Raman spectroscopy, 2D 1H-1H NMR correlation experiments, and transient absorption spectroscopy establish that the site-selective control on the confined photoredox chemistry originates from an optimal preorganization of styrene molecules inside the cavity. We envision that the demonstrated host-guest charge transfer photoredox paradigm in combination with green atom-transfer reagents will enable a broad range of sp2 carbon-site functionalization.

8.
J Phys Chem Lett ; 14(46): 10328-10332, 2023 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-37944083

RESUMEN

In this investigation, different multispectroscopic analytical techniques have been used to explore the interaction between polyethylene microplastics (PE-MPs) and human hemoglobin (HHb), an oxygen carrier in the human blood circulatory system. Ultraviolet-visible absorption studies have demonstrated that HHb molecules may interact with PE-MPs, and thermal melting studies have indicated that PE-MPs have a stabilizing effect on HHb. Further circular dichroism and Fourier transform infrared spectroscopic studies have revealed the distinct changes in HHb's secondary structures caused by the formation of the HHb-PE-MP binding complex. These findings imply that PE-MPs could enter the blood circulation system of humans and may be hazardous to humans. This work explains the potential binding interaction of microplastics at the molecular level and offers insight into the intermolecular interaction between PE-MPs and HHb.


Asunto(s)
Microplásticos , Polietileno , Humanos , Plásticos , Dicroismo Circular , Hemoglobinas/química
9.
ACS Omega ; 8(40): 37054-37064, 2023 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-37841109

RESUMEN

Harmine and harmaline are two structurally similar heterocyclic ß-carboline plant alkaloids with various therapeutic properties, having a slight structural difference in the C3=C4 double bond. In the present study, we have reported the nature of the interaction between hemoglobin (Hb) with harmine and harmaline by employing several multispectroscopic, calorimetric, and molecular docking approaches. Fluorescence spectroscopic studies have shown stronger interaction of harmine with Hb compared to that of almost structurally similar harmaline. Steady-state anisotropy experiments further show that the motional restriction of harmine in the presence of Hb is substantially higher than that of the harmaline-Hb complex. Circular dichroism (CD) study demonstrates no conformational change of Hb in the presence of both alkaloids, but CD study in 1-cm cuvette path length also demonstrates stronger affinity of harmine toward Hb compared to harmaline. From the thermal melting study, it has been found that both harmine and harmaline slightly affect the stability of Hb. From isothermal titration calorimetry (ITC), we have found that the binding process is exothermic and enthalpy driven. Molecular docking studies indicated that both harmine and harmaline prefer identical binding sites in Hb. This study helps us to understand that slight structural differences in harmine and harmaline can alter the interaction properties significantly, and this key information may help in the drug discovery processes.

10.
ACS Omega ; 8(33): 30315-30329, 2023 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-37636929

RESUMEN

Research on the interactions of naturally existing flavonoids with various noncanonical DNA such as i-motif (IM) DNA structures is helpful in comprehending the molecular basis of binding mode as well as providing future direction for the application and invention of novel effective therapeutic drugs. IM DNA structures have been identified as prospective anticancer therapeutic targets, and flavonoids are smaller molecules with a variety of health-promoting attributes, including anticancer activities. The extensive investigation comprising a series of techniques reveals the contrasting mode of the binding behavior of fisetin and morin with various IM DNA structures. We have discovered that structural alterations of hydroxyl groups located at different places of aromatic rings influence flavonoid's reactivity. This minor structural alteration appears to be critical for fisetin and morin's capacity to interact differentially with HRAS1 and HRAS2 IM DNA. Hence, fisetin appears to be an efficient ligand for HRAS1 and morin is considered to be an efficient ligand for HRAS2 IM DNA. This novel exploration opens up the possibility of employing the strategy for regulation of gene expression in cancerous cells. Our finding also reveals the flavonoid-mediated specific interaction with IM DNA while pointing toward tangible strategies for drug discovery and other essential cellular functions.

11.
Polymers (Basel) ; 15(8)2023 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-37111997

RESUMEN

Rapid breakthroughs in nucleic acid nanotechnology have always driven the creation of nano-assemblies with programmable design, potent functionality, good biocompatibility, and remarkable biosafety during the last few decades. Researchers are constantly looking for more powerful techniques that provide enhanced accuracy with greater resolution. The self-assembly of rationally designed nanostructures is now possible because of bottom-up structural nucleic acid (DNA and RNA) nanotechnology, notably DNA origami. Because DNA origami nanostructures can be organized precisely with nanoscale accuracy, they serve as a solid foundation for the exact arrangement of other functional materials for use in a number of applications in structural biology, biophysics, renewable energy, photonics, electronics, medicine, etc. DNA origami facilitates the creation of next-generation drug vectors to help in the solving of the rising demand on disease detection and therapy, as well as other biomedicine-related strategies in the real world. These DNA nanostructures, generated using Watson-Crick base pairing, exhibit a wide variety of properties, including great adaptability, precise programmability, and exceptionally low cytotoxicity in vitro and in vivo. This paper summarizes the synthesis of DNA origami and the drug encapsulation ability of functionalized DNA origami nanostructures. Finally, the remaining obstacles and prospects for DNA origami nanostructures in biomedical sciences are also highlighted.

12.
Annu Rev Chem Biomol Eng ; 12: 241-261, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-33730514

RESUMEN

Macromolecule-drug conjugates (MDCs) occupy a critical niche in modern pharmaceuticals that deals with the assembly and combination of a macromolecular carrier, a drug cargo, and a linker toward the creation of effective therapeutics. Macromolecular carriers such as synthetic biocompatible polymers and proteins are often exploited for their inherent ability to improve drug circulation, prevent off-target drug cytotoxicity, and widen the therapeutic index of drugs. One of the most significant challenges in MDC design involves tuning their drug release kinetics to achieve high spatiotemporal precision. This level of control requires a thorough qualitative and quantitative understanding of the bond cleavage event. In this review, we highlight specific research findings that emphasize the importance of establishing a precise structure-function relationship for MDCs that can be used to predict their bond cleavage and drug release kinetic parameters.


Asunto(s)
Sistemas de Liberación de Medicamentos , Preparaciones Farmacéuticas , Portadores de Fármacos , Liberación de Fármacos , Cinética , Polímeros
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