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1.
J Neurosci ; 44(28)2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38866482

RESUMEN

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.


Asunto(s)
Antígenos Ly , Queratodermia Palmoplantar , Ratones Noqueados , Activador de Plasminógeno de Tipo Uroquinasa , Animales , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Activador de Plasminógeno de Tipo Uroquinasa/genética , Ratones , Femenino , Antígenos Ly/genética , Antígenos Ly/metabolismo , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Umbral del Dolor/fisiología
2.
Carbohydr Polym ; 340: 122215, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38857996

RESUMEN

The healing of diabetic wounds is significantly impeded due to severe oxidative stress and hindered angiogenesis, presenting a major challenge to clinical treatment. In this context, we introduces a novel hydrogel dressing strategy that uniquely combines α-lipoic acid-modified chitosan (LAMC) and melanin nanoparticles (MNPs). This innovative hydrogel, LAMC@MNPs, is formulated to gel under ultraviolet (UV) light without the need for a photoinitiator, simplifying the preparation process and potentially enhancing safety. Our experimental results demonstrate that the LAMC@MNPs hydrogel not only exhibits superior skin adhesion, with an average strength of 56.59 ± 3.16 KPa, but also effectively alleviates oxidative stress and accelerates vascular regeneration and wound healing. This is achieved by promoting cell migration and scavenging free radicals, addressing the critical barriers in diabetic wound care. The combination of these materials and their functional benefits presents a promising new approach to diabetic wound treatment.


Asunto(s)
Quitosano , Diabetes Mellitus Experimental , Hidrogeles , Melaninas , Ácido Tióctico , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Ácido Tióctico/química , Ácido Tióctico/farmacología , Animales , Melaninas/química , Hidrogeles/química , Hidrogeles/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Nanopartículas/química , Ratones , Estrés Oxidativo/efectos de los fármacos , Masculino , Humanos , Movimiento Celular/efectos de los fármacos , Piel/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
3.
Small ; 20(26): e2310194, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38279612

RESUMEN

Spinal cord injury (SCI) often leads to cell death, vascular disruption, axonal signal interruption, and permanent functional damage. Currently, there are no clearly effective therapeutic options available for SCI. Considering the inhospitable SCI milieu typified by ischemia, hypoxia, and restricted neural regeneration, a novel injectable hydrogel system containing conductive black phosphorus (BP) nanosheets within a lipoic acid-modified chitosan hydrogel matrix (LAMC) is explored. The incorporation of tannic acid (TA)-modified BP nanosheets (BP@TA) into the LAMC hydrogel matrix significantly improved its conductivity. Further, by embedding a bicyclodextrin-conjugated tazarotene drug, the hydrogel showcased amplified angiogenic potential in vitro. In a rat model of complete SCI, implantation of LAMC/BP@TA hydrogel markedly improved the recovery of motor function. Immunofluorescence evaluations confirmed that the composite hydrogel facilitated endogenous angiogenesis and neurogenesis at the injury site. Collectively, this work elucidates an innovative drug-incorporated hydrogel system enriched with BP, underscoring its potential to foster vascular and neural regeneration.


Asunto(s)
Hidrogeles , Regeneración Nerviosa , Fósforo , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Animales , Hidrogeles/química , Hidrogeles/farmacología , Regeneración Nerviosa/efectos de los fármacos , Fósforo/química , Ratas , Ratas Sprague-Dawley , Nanoestructuras/química , Neovascularización Fisiológica/efectos de los fármacos , Inyecciones
4.
Biotechnol Bioeng ; 120(7): 1784-1796, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37203999

RESUMEN

Chondroitin sulfate A (CSA) is a valuable glycosaminoglycan that has great market demand. However, current synthetic methods are limited by requiring the expensive sulfate group donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and inefficient enzyme carbohydrate sulfotransferase 11 (CHST11). Herein, we report the design and integration of the PAPS synthesis and sulfotransferase pathways to realize whole-cell catalytic production of CSA. Using mechanism-based protein engineering, we improved the thermostability and catalytic efficiency of CHST11; its Tm and half-life increased by 6.9°C and 3.5 h, respectively, and its specific activity increased 2.1-fold. Via cofactor engineering, we designed a dual-cycle strategy of regenerating ATP and PAPS to increase the supply of PAPS. Through surface display engineering, we realized the outer membrane expression of CHST11 and constructed a whole-cell catalytic system of CSA production with an 89.5% conversion rate. This whole-cell catalytic process provides a promising method for the industrial production of CSA.


Asunto(s)
Sulfatos de Condroitina , Fosfoadenosina Fosfosulfato , Sulfatos de Condroitina/metabolismo
5.
Vet Res ; 53(1): 87, 2022 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-36273217

RESUMEN

Muscle larvae of Trichinella spiralis parasitize the host intestinal epithelium. The mechanisms of exosomes participating in the invasion of T. spiralis muscle larvae are unclear. Hence, the purpose of this study was to explore the effect of exosomes derived from T. spiralis infective larvae (TsExos) on the barrier function of porcine small intestinal epithelial cells (IPEC-J2). First, TsExos were successfully obtained, and their ingestion by epithelial cells was validated. Furthermore, the optimal induction condition was determined by the CCK8 kit, and we found that exposure to 150 µg/mL TsExos for 12/24 h decreased the viability of IPEC-J2 cells by 30%. Based on this outcome, the effects of TsExos on cell biological processes and tight junctions were studied. After coincubation of TsExos and IPEC-J2 cells, the results showed a significant increase in the content of FITC-dextran and in the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS). The rate of apoptosis increased by 12.57%, and nuclear pyknosis and nuclear rupture were observed. After the cells were induced by TsExos, the expression of IL-1 was upregulated, but the expression of IL-10, TGF-ß, TLR-5, MUC-1 and MUC-2 was downregulated. TsExo induction also led to a decrease in the levels of ZO-1, CLDN-3, and OCLN. In conclusion, TsExos are involved in several cellular biological processes, and they function by disrupting physiological and biochemical processes, hyperactivating innate immunity, and damaging tight junctions.


Asunto(s)
Exosomas , Trichinella spiralis , Porcinos , Animales , Trichinella spiralis/fisiología , Interleucina-10/metabolismo , Interleucina-10/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptor Toll-Like 5/metabolismo , Mucosa Intestinal , Células Epiteliales/metabolismo , Larva/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Lactato Deshidrogenasas/metabolismo , Interleucina-1/metabolismo
6.
Vet Res ; 53(1): 18, 2022 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-35241168

RESUMEN

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum can cause an endoplasmic reticulum stress (ERS) response. If ERS continues or cannot be alleviated, it will cause the production of proapoptotic factors and eventually lead to apoptosis. Therefore, this study mainly explored whether Trichinella spiralis Kazal-type serine protease inhibitor (TsKaSPI) contributed to the invasion of intestinal epithelial cells during the infectious stage of T. spiralis by regulating ERS. First, in the T. spiralis infection model, H&E staining was used to analyse the damage to jejunum tissue, a TUNEL assay was used to examine cell apoptosis, and the expression of ERS-related and apoptosis-related molecules was also measured. The results showed that ERS occurred during the intestinal phase of T. spiralis infection, while remission began during the cyclic phase. Then, we selected TsKaSPI, one of the important components of T. spiralis ES antigens, for in vitro experiments. The results showed that TsKaSPI could induce apoptosis in a porcine small intestinal epithelial cell line (IPEC cells) by activating ERS and promote activation of the NF-κB signalling pathway. Inhibition experiments confirmed that the occurrence of ERS was accompanied by the activation of NF-κB, and the two processes regulated each other. Finally, we conducted in vivo experiments and administered TsKaSPI to mice. The results confirmed that TsKaSPI could activate ERS and lead to apoptosis in intestinal epithelial cells. In conclusion, T. spiralis infection and TsKaSPI can promote cell apoptosis by activating the ERS response in intestinal epithelial cells and activate the NF-κB signalling pathway to promote the occurrence and development of inflammation.


Asunto(s)
Trichinella spiralis , Animales , Estrés del Retículo Endoplásmico , Células Epiteliales/metabolismo , Intestinos , Ratones , Inhibidores de Serina Proteinasa/genética , Inhibidores de Serina Proteinasa/metabolismo , Porcinos
7.
Parasitol Res ; 119(9): 2837-2850, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32757109

RESUMEN

Fasciola hepatica (F. hepatica) is a well-known zoonotic parasite that is crucial for economic and public health worldwide. Quantitative proteomics studies have been performed on proteins expressed by F. hepatica to investigate the differential expression of proteomes in different growth phases. And the screening of several marker proteins for use as early diagnostic antigens is essential. In this study, high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted to analyze the differences in the expression of F. hepatica somatic proteins in different growth phases. Furthermore, gene ontology (GO) functional annotation, KEGG metabolic pathway, and clustering analyses were also performed. LC-MS/MS identified 629, 2286, 2254, and 2192 proteins in metacercariae, juvenile flukes 28dpi, immature flukes 59dpi, and adult phases, respectively. GO analysis revealed that differentially expressed proteins (DEPs) were mainly involved in transport, localization, metabolism, enzyme regulation, protein folding and binding, and nucleoside and nucleotide binding. The DEPs were enriched in cells, intracellular components, organelles, cytoplasm, vesicles, and membranes. KEGG pathway annotation results showed that the DEPs were involved in metabolism, genetic information processing, environmental information processing, cellular processes, organismal systems, and other processes. These findings provide a theoretical basis for vaccine development and establishing early diagnostic methods in the future.


Asunto(s)
Fasciola hepatica/crecimiento & desarrollo , Fasciola hepatica/genética , Proteoma/análisis , Animales , Cromatografía Liquida , Análisis por Conglomerados , Biología Computacional , Fascioliasis/parasitología , Perfilación de la Expresión Génica , Proteoma/genética , Proteómica/métodos , Espectrometría de Masas en Tándem
8.
Curr Opin Biotechnol ; 66: 18-26, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32569960

RESUMEN

Microbial cell factory performance is significantly affected by the cell morphology and membrane homeostasis. It is important to ensure that cell factories are able to regulate cell morphology and maintain membrane homeostasis. Cell morphology can be controlled by regulating the formation of elongasomes and divisomes, which change the shapes of cells from rods to fibers, large spheres, or mini-cells. Membrane homeostasis can also be controlled by regulating the homeostasis of membrane lipids and proteins, thereby improving the robustness of microbes in toxic environments. In the present review, we discuss promising developments in cell morphology and membrane homeostasis engineering that have improved microbial cell factory performance.


Asunto(s)
Microbiología Industrial , Ingeniería Metabólica , Homeostasis
9.
Biotechnol Lett ; 42(11): 2123-2133, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32562135

RESUMEN

OBJECTIVES: We evaluated the effects of miR-140-3p on EMT, cellular migration, and invasion in TGF-ß1 treated human OS cells. Human fresh OS tissue and normal bone tissue specimens were gathered from 42 patients (29 male and 13 female, 11 to 24 years of age with a mean age of 17.5 ± 2.3 years) diagnosed with OS by pathology. By targeting TRAF6, miR-140-3p inhibits TGF-ß1-induced human osteosarcoma epithelial-to-mesenchymal transition, migration, and invasion. RESULTS: In this study, we found microRNA (miR)-140-3p to be down-regulated and tumor necrosis factor receptor-associated factor 6 (TRAF6) to be up-regulated in patient OS samples. Lower levels of miR-140-3p and higher levels of TRAF6 were found in the advanced Enneking stage of OS. Furthermore, both mRNA and protein levels of TRAF6 were negatively associated with miR-140-3p mRNA expression in human OS tissue. TRAF6 was verified as a direct target of miR-140-3p in TGF-ß1-treated human U2OS cells. Further, a miR-140-3p mimic dramatically inhibited while a miR-140-3p inhibitor enhanced TGF-ß1-induced epithelial-to-mesenchymal transition, migration, and invasion of U2OS cells. Small interfering RNA was found to silence TRAF6 and to partly reverse the effects of the miR-140-3p inhibitor on TGF-ß1-treated U2OS cells in vitro. CONCLUSION: These results demonstrate miR-140-3p to function as a tumor inhibitor of human OS cells by decreasing TRAF6 expression. miR-140-3p and TRAF6 may be valuable and novel biomarkers for diagnosis and treatment of OS.


Asunto(s)
Neoplasias Óseas/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , MicroARNs/genética , Osteosarcoma/patología , Factor de Crecimiento Transformador beta1/metabolismo , Adolescente , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Niño , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Invasividad Neoplásica , Estadificación de Neoplasias , Osteosarcoma/genética , Osteosarcoma/metabolismo , Adulto Joven
10.
Pharmaceuticals (Basel) ; 9(4)2016 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-27983625

RESUMEN

Ion channels of the Transient Receptor Potential (TRP) family mediate the influx of monovalent and/or divalent cations into cells in response to a host of chemical or physical stimuli. In the skin, TRP channels are expressed in many cell types, including keratinocytes, sensory neurons, melanocytes, and immune/inflammatory cells. Within these diverse cell types, TRP channels participate in physiological processes ranging from sensation to skin homeostasis. In addition, there is a growing body of evidence implicating abnormal TRP channel function, as a product of excessive or deficient channel activity, in pathological skin conditions such as chronic pain and itch, dermatitis, vitiligo, alopecia, wound healing, skin carcinogenesis, and skin barrier compromise. These diverse functions, coupled with the fact that many TRP channels possess pharmacologically accessible sites, make this family of proteins appealing therapeutic targets for skin disorders.

11.
Pain ; 156(4): 656-665, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25790456

RESUMEN

The skin epidermis is densely innervated by peripheral sensory nerve endings. Nociceptive neurons, whose terminals are in close contact with epidermal keratinocytes, can be activated directly by noxious physical and chemical stimuli to trigger pain. However, whether keratinocytes can signal acutely to sensory nerve terminals to initiate pain in vivo remains unclear. Here, using the keratin 5 promoter to selectively express the capsaicin receptor TRPV1 in keratinocytes of TRPV1-knockout mice, we achieved specific stimulation of keratinocytes with capsaicin. Using this approach, we found that keratinocyte stimulation was sufficient to induce strong expression of the neuronal activation marker, c-fos, in laminae I and II of the ipsilateral spinal cord dorsal horn and to evoke acute paw-licking nocifensive behavior and conditioned place aversion. These data provide direct evidence that keratinocyte stimulation is sufficient to evoke acute nociception-related responses.


Asunto(s)
Queratinocitos/fisiología , Vías Nerviosas/fisiología , Nocicepción/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina/farmacología , Células Cultivadas , Condicionamiento Operante/efectos de los fármacos , Antagonistas de Estrógenos/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Transgénicos , Vías Nerviosas/efectos de los fármacos , Nocicepción/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Médula Espinal/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Factores de Tiempo
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