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1.
Proc Natl Acad Sci U S A ; 121(30): e2322437121, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39018192

RESUMEN

In this work, we have found that a prenotched double-network (DN) hydrogel, when subjected to tensile loading in a pure-shear geometry, exhibits intriguing stick-slip crack dynamics. These dynamics synchronize with the oscillation of the damage (yielding) zone at the crack tip. Through manipulation of the loading rate and the predamage level of the brittle network in DN gels, we have clarified that this phenomenon stems from the significant amount of energy dissipation required to form the damage zone at the crack tip, as well as a kinetic contrast between the rapid crack extension through the yielding zone (slip process) and the slow formation of a new yielding zone controlled by the external loading rate (stick process).

2.
Hum Mol Genet ; 2024 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-39439404

RESUMEN

Protein aggregation of α-synuclein (αS) is a genetic and neuropathological hallmark of Parkinson's disease (PD). Studies in the model nematode Caenorhabditis elegans suggested that variation of αS aggregation depends on the genetic background. However, which genes and genetic modifiers underlie individual differences in αS pathology remains unknown. To study the genotypic-phenotypic relationship of αS aggregation, we constructed a Recombinant Inbred Line (RIL) panel derived from a cross between genetically divergent strains C. elegans NL5901 and SCH4856, both harboring the human αS gene. As a first step to discover genetic modifiers 70 αS-RILs were measured for whole-genome gene expression and expression quantitative locus analysis (eQTL) were mapped. We detected multiple eQTL hot-spots, many of which were located on Chromosome V. To confirm a causal locus, we developed Introgression Lines (ILs) that contain SCH4856 introgressions on Chromosome V in an NL5901 background. We detected 74 genes with an interactive effect between αS and the genetic background, including the human p38 MAPK homologue pmk-1 that has previously been associated with PD. Together, we present a unique αS-RIL panel for defining effects of natural genetic variation on αS pathology, which contributes to finding genetic modifiers of PD.

3.
Plant Physiol ; 194(4): 2616-2630, 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38206190

RESUMEN

The plant cuticle is essential in plant defense against biotic and abiotic stresses. To systematically elucidate the genetic architecture of maize (Zea mays L.) cuticular wax metabolism, 2 cuticular wax-related traits, the chlorophyll extraction rate (CER) and water loss rate (WLR) of 389 maize inbred lines, were investigated and a genome-wide association study (GWAS) was performed using 1.25 million single nucleotide polymorphisms (SNPs). In total, 57 nonredundant quantitative trait loci (QTL) explaining 5.57% to 15.07% of the phenotypic variation for each QTL were identified. These QTLs contained 183 genes, among which 21 strong candidates were identified based on functional annotations and previous publications. Remarkably, 3 candidate genes that express differentially during cuticle development encode ß-ketoacyl-CoA synthase (KCS). While ZmKCS19 was known to be involved in cuticle wax metabolism, ZmKCS12 and ZmKCS3 functions were not reported. The association between ZmKCS12 and WLR was confirmed by resequencing 106 inbred lines, and the variation of WLR was significant between different haplotypes of ZmKCS12. In this study, the loss-of-function mutant of ZmKCS12 exhibited wrinkled leaf morphology, altered wax crystal morphology, and decreased C32 wax monomer levels, causing an increased WLR and sensitivity to drought. These results confirm that ZmKCS12 plays a vital role in maize C32 wax monomer synthesis and is critical for drought tolerance. In sum, through GWAS of 2 cuticular wax-associated traits, this study reveals comprehensively the genetic architecture in maize cuticular wax metabolism and provides a valuable reference for the genetic improvement of stress tolerance in maize.


Asunto(s)
Estudio de Asociación del Genoma Completo , Zea mays , Zea mays/genética , Zea mays/metabolismo , Sitios de Carácter Cuantitativo/genética , Fenotipo , Agua/metabolismo , Hojas de la Planta/genética
4.
FASEB J ; 38(6): e23563, 2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38498358

RESUMEN

Acute kidney injury (AKI), a prevalent clinical syndrome, involves the participation of the nervous system in neuroimmune regulation. However, the intricate molecular mechanism that governs renal function regulation by the central nervous system (CNS) is complex and remains incompletely understood. In the present study, we found that the upregulated expression of lncTCONS_00058568 in lower thoracic spinal cord significantly ameliorated AKI-induced renal tissue injury, kidney morphology, inflammation and apoptosis, and suppressed renal sympathetic nerve activity. Mechanistically, the purinergic ionotropic P2X7 receptor (P2X7R) was overexpressed in AKI rats, whereas lncTCONS_00058568 was able to suppress the upregulation of P2X7R. In addition, RNA sequencing data revealed differentially expressed genes associated with nervous system inflammatory responses after lncTCONS_00058568 was overexpressed in AKI rats. Finally, the overexpression of lncTCONS_00058568 inhibited the activation of PI3K/Akt and NF-κB signaling pathways in spinal cord. Taken together, the results from the present study show that lncTCONS_00058568 overexpression prevented renal injury probably by inhibiting sympathetic nerve activity mediated by P2X7R in the lower spinal cord subsequent to I/R-AKI.


Asunto(s)
Lesión Renal Aguda , ARN Largo no Codificante , Receptores Purinérgicos P2X7 , Animales , Ratas , Lesión Renal Aguda/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas Sprague-Dawley , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Médula Espinal/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
5.
Nucleic Acids Res ; 51(8): 4064-4077, 2023 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-36912089

RESUMEN

CRISPR (clustered regularly interspaced short palindromic repeats) technology holds tremendous promise for gene regulation and editing. However, precise control of CRISPR editing is essential to overcome its uncontrollable reaction process and excessive activity that leads to off-target editing. To overcome this problem, we engineered a photoswitch on G-quadruplex gRNA (GqRNA) for precisely controlled gene editing and expression by embedding dicationic azobenzene derivatives (AZD++). Our results demonstrated that rational design of the G-quadruplex onto crRNA conferred higher stability and sequence recognition specificity than unmodified single guide (sgRNA). Light-induced isomerization of AZD++ quickly transformed the on state of GqRNA, which facilitated rapid activation of ribonucleoprotein activity for genome editing of on-target sites in cells with excellent editing efficiency. In turn, AZD++-GqRNA promptly refolded to an off state to inhibit genomic cleavage, and limited the generation of off-target effects and by-products. Therefore, the proposed strategy of a photo-reversible modality presents a new opportunity for CRISPR-Cas9 modulation to improve its safety and applicability.


Asunto(s)
Edición Génica , Genómica , Edición Génica/métodos , Genoma , Regulación de la Expresión Génica , Sistemas CRISPR-Cas/genética
6.
Opt Express ; 32(6): 9105-9115, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38571151

RESUMEN

The strong interaction between light and matter is one of the current research hotspots in the field of nanophotonics, and provides a suitable platform for fundamental physics research such as on nanolasers, high-precision sensing in biology, quantum communication and quantum computing. In this study, double Rabi splitting was achieved in a composite structure monolayer MoS2 and a single Ag@Au hollow nanocube (HNC) in room temperature mainly due to the two excitons in monolayer MoS2. Moreover, the tuning of the plasmon resonance peak was realized in the scattering spectrum by adjusting the thickness of the shell to ensure it matches the energy of the two excitons. Two distinct anticrossings are observed at both excitons resonances, and large double Rabi splittings (90 meV and 120 meV) are obtained successfully. The finite-difference time domain (FDTD) method was also used to simulate the scattering spectra of the nanostructures, and the simulation results were in good agreement with the experimental results. Additionally, the local electromagnetic field ability of the Ag@Au hollow HNC was proved to be stronger by calculating and comparing the mode volume of different nanoparticles. Our findings provides a good platform for the realization of strong multi-mode coupling and open up a new way to construct nanoscale photonic devices.

7.
EMBO Rep ; 23(5): e52606, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35297148

RESUMEN

Mitochondrial dysfunction can either extend or decrease Caenorhabditis elegans lifespan, depending on whether transcriptionally regulated responses can elicit durable stress adaptation to otherwise detrimental lesions. Here, we test the hypothesis that enhanced metabolic flexibility is sufficient to circumvent bioenergetic abnormalities associated with the phenotypic threshold effect, thereby transforming short-lived mitochondrial mutants into long-lived ones. We find that CEST-2.2, a carboxylesterase mainly localizes in the intestine, may stimulate the survival of mitochondrial deficient animals. We report that genetic manipulation of cest-2.2 expression has a minor lifespan impact on wild-type nematodes, whereas its overexpression markedly extends the lifespan of complex I-deficient gas-1(fc21) mutants. We profile the transcriptome and lipidome of cest-2.2 overexpressing animals and show that CEST-2.2 stimulates lipid metabolism and fatty acid beta-oxidation, thereby enhancing mitochondrial respiratory capacity through complex II and LET-721/ETFDH, despite the inherited genetic lesion of complex I. Together, our findings unveil a metabolic pathway that, through the tissue-specific mobilization of lipid deposits, may influence the longevity of mitochondrial mutant C. elegans.


Asunto(s)
Proteínas de Caenorhabditis elegans , Longevidad , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Metabolismo de los Lípidos/genética , Longevidad/genética , Mitocondrias/metabolismo
8.
Biol Res ; 57(1): 3, 2024 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-38217055

RESUMEN

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.


Asunto(s)
Exosomas , Neomicina , Neomicina/toxicidad , Neomicina/metabolismo , Exosomas/metabolismo , Células Ciliadas Auditivas , Autofagia/fisiología
9.
J Biosoc Sci ; 56(1): 155-181, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37309644

RESUMEN

This paper presents the first evidence of the causal relationship between adult children's schooling and changes in parental health in the short and long term. By using supply-side variation in schooling as an instrument for adult children's education and a representative dataset for rural China, we find that adult children' education has a positive influence on the long-term changes in parental health, with limited evidence of any short-term effect. Our results remain consistent after a variety of sensitivity tests. The heterogeneous analyses show differences in socio-economic status and gender, with low-educated parents and mothers being the primary beneficiaries of children's schooling. Potential mechanisms for the long-term effects of adult children's education on changes in parental health include better chronic disease management, improved access to health, sanitation, and clean fuel facilities, improved psychological well-being, and reduced smoking behaviours.


Asunto(s)
Hijos Adultos , Padres , Adulto , Femenino , Humanos , Padres/psicología , Escolaridad , Madres , China
10.
Int J Mol Sci ; 25(11)2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38892028

RESUMEN

Amino acid permeases (AAPs) transporters are crucial for the long-distance transport of amino acids in plants, from source to sink. While Arabidopsis and rice have been extensively studied, research on foxtail millet is limited. This study identified two transcripts of SiAAP9, both of which were induced by NO3- and showed similar expression patterns. The overexpression of SiAAP9L and SiAAP9S in Arabidopsis inhibited plant growth and seed size, although SiAAP9 was found to transport more amino acids into seeds. Furthermore, SiAAP9-OX transgenic Arabidopsis showed increased tolerance to high concentrations of glutamate (Glu) and histidine (His). The high overexpression level of SiAAP9 suggested its protein was not only located on the plasma membrane but potentially on other organelles, as well. Interestingly, sequence deletion reduced SiAAP9's sensitivity to Brefeldin A (BFA), and SiAAP9 had ectopic localization on the endoplasmic reticulum (ER). Protoplast amino acid uptake experiments indicated that SiAAP9 enhanced Glu transport into foxtail millet cells. Overall, the two transcripts of SiAAP9 have similar functions, but SiAAP9L shows a higher colocalization with BFA compartments compared to SiAAP9S. Our research identifies a potential candidate gene for enhancing the nutritional quality of foxtail millet through breeding.


Asunto(s)
Arabidopsis , Retículo Endoplásmico , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Plantas Modificadas Genéticamente , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Retículo Endoplásmico/metabolismo , Semillas/metabolismo , Semillas/genética , Semillas/crecimiento & desarrollo , Setaria (Planta)/genética , Setaria (Planta)/metabolismo , Setaria (Planta)/crecimiento & desarrollo , Sistemas de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Transporte de Proteínas , Brefeldino A/farmacología , Aminoácidos/metabolismo , Ácido Glutámico/metabolismo
11.
Molecules ; 29(17)2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39275071

RESUMEN

Oligonucleotide drugs are shining in clinical therapeutics, but efficient and safe delivery systems severely limit their widespread use. A disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the disulfide unit CSSC dihedral angle induced by different substituents directly affects the effectiveness of this technology and its stability. Previously, we constructed a trivalent low dihedral angle disulfide unit that can effectively promote the cellular uptake of small molecules. Here, we constructed a novel disulfide unit-masked oligonucleotide hybrid based on a low dihedral angle disulfide unit, motivated by prodrug design. Cellular imaging results showed that such a system exhibited superior cellular delivery efficiency than the commercial Lipo2000 without cytotoxicity. The thiol reagents significantly reduced its cellular uptake (57-74%), which proved to be endocytosis-independent. In addition, in vivo distribution experiments in mice showed that such systems can be rapidly distributed in liver tissues with a duration of action of more than 24 h, representing a potential means of silencing genes involved in the pathogenesis of liver-like diseases. In conclusion, this trivalent disulfide unit-masked system we constructed can effectively deliver large oligonucleotide drugs.


Asunto(s)
Disulfuros , Oligonucleótidos , Disulfuros/química , Animales , Oligonucleótidos/química , Ratones , Humanos , Sistemas de Liberación de Medicamentos , Hígado/metabolismo , Hígado/efectos de los fármacos
12.
J Tissue Viability ; 33(2): 208-214, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38599978

RESUMEN

OBJECTIVE: In this study, we evaluated the pH (potential of hydrogen) value of diabetic foot ulcers and explored the relationship between the pH value and infection, sinus formation, stasis dermatitis, and the process of healing. METHODS: From October 2022 to June 2023, 99 patients with 106 diabetic foot ulcers were selected. Diabetic foot ulcers were treated in a standardized manner by a professional team. The pH value, area, PUSH (Pressure Ulcer Scale for Healing) score, and the degree of infection of the wounds were compared before and after the treatment. RESULTS: The baseline wound pH value in 76.4% of the patients was in the alkaline range and was closely related to the degree of infection (P < 0.05). As the ulcers healed, the pH decreased. For moderately and severely infected diabetic foot ulcers, each unit decrease in pH was associated with a decrease in the PUSH score of approximately 4.6 points (P < 0.05). The pH values of wounds with surrounding ecchymosis dermatitis were significantly higher than those of wounds without ecchymosis dermatitis (P < 0.05). The pH value of the wound with a sinus tract was higher. After treatment, there was no significant difference in pH value between the patients with and without sinus tracts (P < 0.05). CONCLUSIONS: The measurement of pH value is efficient and simple, and the patient suffers no discomfort in the process. The change in pH helps predict the healing process of diabetic foot ulcers and quickly identify whether there are key factors such as infection and ischemia in the wound. It is suggested that dynamic pH monitoring be included in the whole course evaluation and intervention strategy development of diabetic foot.


Asunto(s)
Pie Diabético , Cicatrización de Heridas , Humanos , Pie Diabético/fisiopatología , Cicatrización de Heridas/fisiología , Masculino , Femenino , Persona de Mediana Edad , Concentración de Iones de Hidrógeno , Anciano , Anciano de 80 o más Años , Adulto
13.
BMC Genomics ; 24(1): 577, 2023 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-37759187

RESUMEN

BACKGROUND: The mechanism underlying cognitive impairment after hearing loss (HL) remains unclear. N6-methyladenosine (m6A) is involved in many neurodegenerative diseases; however, its role in cognitive impairment after HL has not yet been investigated. Therefore, we aimed to analyze the m6A modification profile of the mouse hippocampus after HL exposure. A mouse model of neomycin-induced HL was established. An auditory brainstem-response test was utilized for detecting hearing threshold. The passive avoidance test was served as the mean for evaluating cognitive function. The m6A-regulated enzyme expression levels were analyzed by using reverse transcription quantitative real-time polymerase chain reaction and western blot analyses. RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq) were performed with the aim of investigating gene expression differences and m6A modification in the mouse hippocampus. RESULTS: Neomycin administration induced severe HL in mice. At four months of age, the mice in the HL group showed poorer cognitive performance than the mice in the control group. METTL14, WTAP, and YTHDF2 mRNA levels were downregulated in the hippocampi of HL mice, whereas ALKBH5 and FTO mRNA levels were significantly upregulated. At the protein level, METTL3 and FTO were significantly upregulated. Methylated RNA immunoprecipitation sequencing analysis revealed 387 and 361 m6A hypermethylation and hypomethylation peaks, respectively. Moreover, combined analysis of mRNA expression levels and m6A peaks revealed eight mRNAs with significantly changed expression levels and methylation. CONCLUSIONS: Our findings revealed the m6A transcriptome-wide profile in the hippocampus of HL mice, which may provide a basis for understanding the association between HL and cognitive impairment from the perspective of epigenetic modifications.


Asunto(s)
Pérdida Auditiva , Animales , Ratones , Metilación , Adenosina , Hipocampo , Neomicina , ARN Mensajero
14.
BMC Plant Biol ; 23(1): 606, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38030968

RESUMEN

BACKGROUND: Dioecy, a sexual system of single-sexual (gynoecious/androecious) individuals, is rare in flowering plants. This rarity may be a result of the frequent transition from dioecy into systems with co-sexual individuals. RESULTS: In this study, co-sexual expression (monoecy and hermaphroditic development), previously thought to be polyploid-specific in Diospyros species, was identified in the diploid D. oleifeara historically. We characterized potential genetic mechanisms that underlie the dissolution of dioecy to monoecy and andro(gyno)monoecy, based on multiscale genome-wide investigations of 150 accessions of Diospyros oleifera. We found all co-sexual plants, including monoecious and andro(gyno)monoecious individuals, possessed the male determinant gene OGI, implying the presence of genetic factors controlling gynoecia development in genetically male D. oleifera. Importantly, discrepancies in the OGI/MeGI module were found in diploid monoecious D. oleifera compared with polyploid monoecious D. kaki, including no Kali insertion on the promoter of OGI, no different abundance of smRNAs targeting MeGI (a counterpart of OGI), and no different expression of MeGI between female and male floral buds. On the contrary, in both single- and co-sexual plants, female function was expressed in the presence of a genome-wide decrease in methylation levels, along with sexually distinct regulatory networks of smRNAs and their targets. Furthermore, a genome-wide association study (GWAS) identified a genomic region and a DUF247 gene cluster strongly associated with the monoecious phenotype and several regions that may contribute to andromonoecy. CONCLUSIONS: Collectively, our findings demonstrate stable breakdown of the dioecious system in D. oleifera, presumably also a result of genomic features of the Y-linked region.


Asunto(s)
Diospyros , Diospyros/genética , Diploidia , Estudio de Asociación del Genoma Completo , Genómica , Poliploidía
15.
Environ Sci Technol ; 57(41): 15523-15532, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37792456

RESUMEN

Even with particular interest in sustainable development, due to the limited types of bioavailable carbon sources that could support heterotrophic/mixotrophic growth, microalgae-derived products still suffer from inconsistent yield and high costs. This study demonstrates a successful cocultivation of the photoautotroph Chlorella vulgaris with a hydrolytic-enzyme-abundant heterotroph, Saccharomycopsis fibuligera, enabling efficient starch upcycling from water/wastewater toward enhancing microalgae-dominant biomass and lipid production. The enzymatic activities of S. fibuligera contributed to the hydrolysis of starch into glucose, generating a 7-fold higher biomass through mixotrophic/heterotrophic growth of C. vulgaris. Further, scanning transmission electron microscopy (STEM) and quantitative analysis suggested a significantly induced accumulation of lipids in C. vulgaris. Results of meta-transcriptomics revealed the critical regulatory role of illumination in interaction shifting. Gene expression for glycolysis and lipid biosynthesis of C. vulgaris were highly activated during dark periods. Meanwhile, during illumination periods, genes coding for glucoamylase and the sulfur-related activities in S. fibuligera were significantly upregulated, leading to induced starch hydrolysis and potential increased competition for sulfur utilization, respectively. This study indicates that hydrolytic organisms could collaborate to make starch bioavailable for nonhydrolytic microalgae, thus broadening the substrate spectrum and making starch a novel biotechnological feedstock for microalgae-derived products, e.g., biofuels or single-cell protein.


Asunto(s)
Chlorella vulgaris , Microalgas , Chlorella vulgaris/metabolismo , Aguas Residuales , Almidón/metabolismo , Técnicas de Cocultivo , Hidrólisis , Biomasa , Lípidos , Azufre/metabolismo , Microalgas/metabolismo , Biocombustibles
16.
Exp Cell Res ; 420(1): 113336, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36058294

RESUMEN

Elevated hepatic gluconeogenesis is a major contributor of fasting hyperglycemia in diabetes. MicroRNAs (miRNAs) are tightly linked to glucose metabolism, but their role in hepatic gluconeogenesis remains largely unkown. In this current study, miR-34a-5p expression was significantly increased in liver tissues of db/db mice. Overexpression of miR-34a-5p promoted hepatic glucose production in mouse primary hepatocytes with increased expressions of gluconeogenic genes while miR-34a-5p inhibition displayed a contrary action. MiR-34a-5p overexpression in mouse primary hepatocytes repressed SIRT1 expression. SIRT1 inhibition by EX527 blocked phosphoenolpyruvate carboxykinase (PEPCK) protein degradation and enhanced hepatic gluconeogenesis. Treatment of A485 (a CBP/p300 inhibitor) decreased miR-34a-5p and PEPCK expressions in the livers of db/db mice, but elevated SIRT1 protein expression. In mouse primary hepatocytes, A485 exhibited a similar result. Overexpression of miR-34a-5p attenuated A485-inhibited gluconeogenic gene expressions and A485-induced SIRT1 protein expression. Finally, after miR-34a-5p was inhibited in the livers of db/db mice, hepatic glucose production and gluconeogenic gene expressions were markedly lowered. Our findings highlight a critical role of miR-34a-5p in the regulation of hepatic gluconeogenesis and miR-34a-5p may be a potential target in the treatment of type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2 , MicroARNs/genética , Animales , Diabetes Mellitus Tipo 2/genética , Gluconeogénesis/genética , Glucosa/metabolismo , Glucosa/farmacología , Hígado/metabolismo , Ratones , MicroARNs/metabolismo , Fosfoenolpiruvato/metabolismo , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo
17.
Exp Cell Res ; 421(2): 113407, 2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36334793

RESUMEN

Vascular calcification (VC) is closely related to higher cardiovascular mortality and morbidity, and vascular smooth muscle cell (VSMC) switching to osteogenic-like cells is crucial for VC. LncRNA LEF1-AS1 promotes atherosclerosis and dental pulp stem cells calcification, while its role in VC remains unknown. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine regulating bone metabolism. However, the relationship between vaspin and VC is still unclear. We aimed to explore the role of LEF1-AS1 on VSMC osteogenic transition, whether vaspin inhibited LEF1-AS1-mediated osteogenic differentiation of VSMCs, and the responsible mechanism. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis indicated that LEF1-AS1 overexpression significantly upregulated osteogenic marker Runt-related transcription factor-2 (RUNX2) level and downregulated VSMC contractile marker α-smooth muscle actin (α-SMA) level. Alizarin red staining, alkaline phosphatase (ALP) staining, ALP activity assay, and calcium content assay also suggested that LEF1-AS1 overexpression promoted calcium deposition in VSMCs. However, vaspin treatment abolished this phenomenon. Mechanistically, LEF1-AS1 markedly decreased phosphorylated YAP level, while vaspin reversed LEF1-AS1-induced phosphorylated YAP decline. Our results revealed that LEF1-AS1 accelerated the osteogenic differentiation of VSMCs by regulating the Hippo/YAP pathway, while vaspin eliminated the LEF1-AS1-meditated VSMCs osteogenic phenotype switch.


Asunto(s)
ARN Largo no Codificante , Calcificación Vascular , Humanos , Músculo Liso Vascular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Osteogénesis/genética , Calcio/metabolismo , Miocitos del Músculo Liso/metabolismo , Calcificación Vascular/inducido químicamente , Diferenciación Celular/genética , Transducción de Señal , Células Cultivadas , Factor de Unión 1 al Potenciador Linfoide
18.
J Nanobiotechnology ; 21(1): 132, 2023 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-37081432

RESUMEN

Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000-1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.


Asunto(s)
Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Fototerapia/métodos , Línea Celular Tumoral , Terapia Fototérmica , Polímeros , Muerte Celular Inmunogénica , Neoplasias/tratamiento farmacológico , Técnicas Fotoacústicas/métodos
19.
Xenobiotica ; 53(5): 454-464, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37728540

RESUMEN

1. Two curcumin analogs, (1E,6E)-1,7-bis(3,5-diethyl-4-hydroxyphenyl)hepta-1,6-diene-3,5- dione (N17) and its prodrug ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2,6-diethyl-4,1- phenylene)bis(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate) (N17'), were evaluated as breast cancer resistance protein (BCRP) inhibitors.2. MDCKII-BCRP and MDCKII-WT were used to evaluate the modulation effects of N17 and N17' on BCRP and to explore the relevant mechanism. Sprague-Dawley rats were orally administered rosuvastatin (ROS), a probe substrate of BCRP, without and with N17' (100 mg/kg) to investigate the effect of N17' on ROS pharmacokinetics.3. In cell studies, N17 and N17' were substrates of BCRP, and they decreased the activity and protein expression of BCRP. In rat study, N17' increased the systemic exposure of ROS by 218% (p = 0.058).4. N17 and N17' are potential BCRP inhibitors and will be promising candidates for overcoming the BCRP-mediated multidrug resistance.

20.
Anim Biotechnol ; 34(4): 947-954, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34842492

RESUMEN

Copy number variation (CNV) is one kind of genomic structure variations and presents as gains and losses of genomic fragments. More recently, we have made an atlas of CNV maps for livestock. In the future, it is a primary focus to determine the phenotypic effects of candidate CNVs. Lysine Acetyltransferase 6 A (KAT6A) is a protein coding gene and plays a critical role in many cellular processes. However, the effects of KAT6A CNVs on sheep body measurements remains unknown. In this study, we performed quantitative polymerase chain reaction (qPCR) to detect the presences and distributions of three CNV regions within KAT6A gene in 672 sheep from four Chinese breeds. Association analysis indicated that the three CNVs of KAT6A gene were significantly associated with body measurement(s) in Small-tailed Han sheep (STH) and Hu sheep (HU) (p < 0.05), while no effects on Large-tailed Han sheep (LTH) were observed (p > 0.05) were observed. Additionally, only one CNV was significantly associated with body measurement (body length) in Chaka sheep (CK) (p < 0.05). Our study provided evidence that the CNV(s) of KAT6A gene could be used as candidate marker(s) for molecular breedings of STH, HU, and CK breeds.


Asunto(s)
Variaciones en el Número de Copia de ADN , Genoma , Ovinos/genética , Animales , Variaciones en el Número de Copia de ADN/genética , Genómica , Ganado/genética
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