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1.
Int J Mol Sci ; 25(9)2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38732260

RESUMEN

Peptides show high promise in the targeting and intracellular delivery of next-generation biotherapeutics. The main limitation is peptides' susceptibility to proteolysis in biological systems. Numerous strategies have been developed to overcome this challenge by chemically enhancing the resistance to proteolysis. In nature, amino acids, except glycine, are found in L- and D-enantiomers. The change from one form to the other will change the primary structure of polypeptides and proteins and may affect their function and biological activity. Given the inherent chiral nature of biological systems and their high enantiomeric selectivity, there is rising interest in manipulating the chirality of polypeptides to enhance their biomolecular interactions. In this review, we discuss the first examples of up-and-down homeostasis regulation by two enantiomeric drugs: immunostimulant Thymogen (L-Glu-L-Trp) and immunosuppressor Thymodepressin (D-Glu(D-Trp)). This study shows the perspective of exploring chirality to remove the chiral wall between L- and D-biomolecules. The selected clinical result will be discussed.


Asunto(s)
Péptidos , Humanos , Estereoisomerismo , Animales , Péptidos/química , Péptidos/farmacología , Inmunosupresores/química , Inmunosupresores/farmacología
2.
Biofabrication ; 16(2)2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38471160

RESUMEN

Bioprinting has evolved into a thriving technology for the fabrication of cell-laden scaffolds. Bioinks are the most critical component for bioprinting. Recently, microgels have been introduced as a very promising bioink, enabling cell protection and the control of the cellular microenvironment. However, the fabrication of the bioinks involves the microfluidic production of the microgels, with a subsequent multistep process to obtain the bioink, which so far has limited its application potential. Here we introduce a direct coupling of microfluidics and 3D-printing for the continuous microfluidic production of microgels with direct in-flow printing into stable scaffolds. The 3D-channel design of the microfluidic chip provides access to different hydrodynamic microdroplet formation regimes to cover a broad range of droplet and microgel diameters. After exiting a microtubing the produced microgels are hydrodynamically jammed into thin microgel filaments for direct 3D-printing into two- and three-dimensional scaffolds. The methodology enables the continuous on-chip encapsulation of cells into monodisperse microdroplets with subsequent in-flow cross-linking to produce cell-laden microgels. The method is demonstrated for different cross-linking methods and cell lines. This advancement will enable a direct coupling of microfluidics and 3D-bioprinting for scaffold fabrication.


Asunto(s)
Bioimpresión , Microgeles , Andamios del Tejido , Impresión Tridimensional , Microfluídica , Línea Celular , Ingeniería de Tejidos , Hidrogeles
3.
PLoS One ; 16(6): e0253684, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34138967

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0247022.].

4.
PLoS One ; 16(2): e0247022, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33577570

RESUMEN

Electron cryo-microscopy (Cryo-EM) is a powerful method for visualizing biological objects with up to near-angstrom resolution. Instead of chemical fixation, the method relies on very rapid freezing to immobilize the sample. Under these conditions, crystalline ice does not have time to form and distort structure. For many practical applications, the rate of cooling is fast enough to consider sample immobilization instantaneous, but in some cases, a more rigorous analysis of structure relaxation during freezing could be essential. This difficult yet important problem has been significantly under-reported in the literature, despite spectacular recent developments in Cryo-EM. Here we use Brownian dynamics modeling to examine theoretically the possible effects of cryo-immobilization on the apparent shapes of biological polymers. The main focus of our study is on tubulin protofilaments. These structures are integral parts of microtubules, which in turn are key elements of the cellular skeleton, essential for intracellular transport, maintenance of cell shape, cell division and migration. We theoretically examine the extent of protofilament relaxation within the freezing time as a function of the cooling rate, the filament's flexural rigidity, and the effect of cooling on water's viscosity. Our modeling suggests that practically achievable cooling rates are not rapid enough to capture tubulin protofilaments in conformations that are incompletely relaxed, suggesting that structures seen by cryo-EM are good approximations to physiological shapes. This prediction is confirmed by our analysis of curvatures of tubulin protofilaments, using samples, prepared and visualized with a variety of methods. We find, however, that cryofixation may capture incompletely relaxed shapes of more flexible polymers, and it may affect Cryo-EM-based measurements of their persistence lengths. This analysis will be valuable for understanding of structures of different types of biopolymers, observed with Cryo-EM.


Asunto(s)
Microtúbulos/ultraestructura , Tubulina (Proteína)/ultraestructura , Algoritmos , Animales , Microscopía por Crioelectrón , Congelación , Microtúbulos/metabolismo , Simulación de Dinámica Molecular , Multimerización de Proteína , Tubulina (Proteína)/metabolismo
5.
Nat Commun ; 11(1): 3765, 2020 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-32724196

RESUMEN

Microtubules are dynamic tubulin polymers responsible for many cellular processes, including the capture and segregation of chromosomes during mitosis. In contrast to textbook models of tubulin self-assembly, we have recently demonstrated that microtubules elongate by addition of bent guanosine triphosphate tubulin to the tips of curving protofilaments. Here we explore this mechanism of microtubule growth using Brownian dynamics modeling and electron cryotomography. The previously described flaring shapes of growing microtubule tips are remarkably consistent under various assembly conditions, including different tubulin concentrations, the presence or absence of a polymerization catalyst or tubulin-binding drugs. Simulations indicate that development of substantial forces during microtubule growth and shortening requires a high activation energy barrier in lateral tubulin-tubulin interactions. Modeling offers a mechanism to explain kinetochore coupling to growing microtubule tips under assisting force, and it predicts a load-dependent acceleration of microtubule assembly, providing a role for the flared morphology of growing microtubule ends.


Asunto(s)
Microtúbulos/metabolismo , Modelos Biológicos , Tubulina (Proteína)/metabolismo , Animales , Microscopía por Crioelectrón , Tomografía con Microscopio Electrónico , Microtúbulos/efectos de los fármacos , Microtúbulos/ultraestructura , Simulación de Dinámica Molecular , Polimerizacion/efectos de los fármacos , Porcinos , Tubulina (Proteína)/aislamiento & purificación , Tubulina (Proteína)/ultraestructura , Moduladores de Tubulina/farmacología
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