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1.
Heliyon ; 10(20): e39334, 2024 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-39498024

RESUMO

Objective: Filamin B (FLNB) encodes an actin-binding protein that is known to function as a novel RNA-binding protein involved in cell movement and signal transduction and plays a pivotal role in bone growth. This study aimed to investigate possible FLNB function in the skeletal system by characterizing the effecs of FLNB knockdown in mouse preosteoblast cells. Methods: Stable FLNB MC3T3-E1 knockdown cells were constructed for RNA-seq and alternative splicing event (ASE) analysis of genes involved in osteoblast differentiation and function that may be regulated by FLNB. Standard transwell, MTT, ALP, qPCR, Western blot, and alizarin red staining assays were used to assess functional changes of FLNB-knockdown MC3T3-E1 cells. Results: Analysis of differentially expressed genes (DEGs) in FLNB knockdown cells revealed enrichment for genes related to osteoblast proliferation, differentiation and migration, such as ITGA10, Cebpß, Grem1, etc. Alternative splicing (AS) analysis showed changes in the predominant mRNA isoforms of skeletal development-related genes, especially Tpx2 and Evc. Functional asslysis indicated that proliferation, migration, and differentiation were all inhibited upon FLNB knockdown in MC3T3-E1 cells compared to that in vector control cells. Conclusions: FLNB participates in regulating the transcription and AS of genes required for osteoblast development and function, consequently affecting growth and development in MC3T3-E1 cells.

2.
Plant Mol Biol ; 114(6): 119, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39485577

RESUMO

Bread wheat is an important crop for the human diet, but the increasing soil salinization is reducing the yield. The Ca2+ signaling events at the early stages of the osmotic phase of salt stress are crucial for the acclimation response of the plants through the performance of calcium-sensing proteins, which activate or repress transcription factors (TFs) that affect the expression of downstream genes. Physiological, genetic mapping, and transcriptomics studies performed with the contrasting genotypes Syn86 (synthetic, salt-susceptible) and Zentos (elite cultivar, salt-tolerant) were integrated to gain a comprehensive understanding of the salt stress response. The MACE (Massive Analysis of cDNA 3'-Ends) based transcriptome analysis until 4 h after stress exposure revealed among the salt-responsive genes, the over-representation of genes coding for calcium-binding proteins. The functional and structural diversity within this category was studied and linked with the expression levels during the osmotic phase in the contrasting genotypes. The non-EF-hand category from calcium-binding proteins was found to be enriched for the susceptibility response. On the other side, the tolerant genotype was characterized by a faster and higher up-regulation of genes coding for proteins with EF-hand domain, such as RBOHD orthologs, and TF members. This study suggests that the interplay of calcium-binding proteins, WRKY, and AP2/ERF TF families in signaling pathways at the start of the osmotic phase can affect the expression of downstream genes. The identification of SNPs in promoter sequences and 3' -UTR regions provides insights into the molecular mechanisms controlling the differential expression of these genes through differential transcription factor binding affinity or altered mRNA stability.


Assuntos
Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Estresse Salino , Fatores de Transcrição , Triticum , Triticum/genética , Triticum/metabolismo , Triticum/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Salino/genética , Perfilação da Expressão Gênica , Genótipo , Pressão Osmótica
3.
Bioorg Chem ; 153: 107901, 2024 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-39447347

RESUMO

Herein, we investigated the stereochemical effects of 4'-methyl substitution on A3 adenosine receptor (A3AR) ligands by synthesizing and evaluating a series of truncated 4'-thioadenosine derivatives featuring 4'-α-methyl, 4'-ß-methyl, and 4',4'-dimethyl substitutions. We successfully synthesized these derivatives, using the stereoselective addition of an organometallic reagent, KSAc-mediated sulfur cyclization, and Vorbrüggen condensation. Binding assays demonstrated that the 4'-ß-methyl substitution conferred the highest affinity for A3AR, with compound 1 h exhibiting a Ki = 3.5 nM, followed by the 4',4'-dimethyl and 4'-α-methyl substitutions. Notably, despite the absence of the 5'-OH group, compound 1 h unexpectedly displayed partial agonism. Computational docking studies indicated that compound 1 h, the ß-methyl derivative, adopted a South conformation and maintained strong interactions within the receptor, including a critical interaction with Thr94, a residue known to be notable for agonistic effects. Conversely, compound 2 h, the α-methyl derivative, also adopted a South conformation but resulted in a flattened structure that hindered interactions with Thr94 and Asn250. The dimethyl derivative 3 h exhibited steric clashes with Thr94, contributing to a reduction in binding affinity. However, the docking results for 3 h indicated a North conformation, suggesting that the change in sugar conformation due to the additional 4'-methyl group altered the angle between the α-methyl group and the sugar plane, enabling binding despite the increased steric bulk. These findings suggest that not only do the substituents and their stereochemistry influence receptor-ligand interactions, but the conformation and the resulting spatial orientation of the substituents also play a crucial role in modulating receptor-ligand interaction. This stereochemical insight offers a valuable framework for the design of new, selective, and potent A3AR ligands, potentially facilitating the development of novel therapeutics for A3AR-related diseases such as glaucoma, inflammation, and cancer.

4.
AoB Plants ; 16(5): plae049, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39450414

RESUMO

Flavonoids in Musaceae are involved in pigmentation and stress responses, including cold resistance, and are a component of the healthy human diet. Identification and analysis of the sequence and copy number of flavonoid biosynthetic genes are valuable for understanding the nature and diversity of flavonoid evolution in Musaceae species. In this study, we identified 71-80 flavonoid biosynthetic genes in chromosome-scale genome sequence assemblies of Musaceae, including those of Ensete glaucum, Musella lasiocarpa, Musa beccarii, M. acuminata, M. balbisiana and M. schizocarpa, checking annotations with BLAST and determining the presence of conserved domains. The number of genes increased through segmental duplication and tandem duplication. Orthologues of both structural and regulatory genes in the flavonoid biosynthetic pathway are highly conserved across Musaceae. The flavonoid 3',5'-hydroxylase gene F3'5'H was amplified in Musaceae and ginger compared with grasses (rice, Brachypodium, Avena longiglumis, and sorghum). One group of genes from this gene family amplified near the centromere of chromosome 2 in the x = 11 Musaceae species. Flavonoid biosynthetic genes displayed few consistent responses in the yellow and red bracts of Musella lasiocarpa when subjected to low temperatures. The expression levels of MlDFR2/3 (dihydroflavonol reductase) increased while MlLAR (leucoanthocyanidin reductase) was reduced by half. Overall, the results establish the range of diversity in both sequence and copy number of flavonoid biosynthetic genes during evolution of Musaceae. The combination of allelic variants of genes, changes in their copy numbers, and variation in transcription factors with the modulation of expression under cold treatments and between genotypes with contrasting bract-colours suggests the variation may be exploited in plant breeding programmes, particularly for improvement of stress-resistance in the banana crop.

5.
Drug Metab Dispos ; 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39433436

RESUMO

Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect P450 function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs lies in their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230) exposure. As CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs, and to a lesser extent by non-EPFR particles. As EPFR-mediated inhibition was more robust at subsaturating NADPH-cytochrome P450 reductase (POR) concentrations, disruption of POR·CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 were inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR CuO-Si. When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. Significance Statement Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR·CYP2E1 complex or inhibition of electron transfer, but due to uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of ROS. These results show that EPFRs block the metabolism of foreign compounds, and also synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.

6.
mLife ; 3(3): 445-458, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39359676

RESUMO

Quorum sensing (QS) inhibition has emerged as a promising target for directed drug design, providing an appealing strategy for developing antimicrobials, particularly against infections caused by drug-resistant pathogens. In this study, we designed and synthesized a total of 33 ß-nitrostyrene derivatives using 1-nitro-2-phenylethane (NPe) as the lead compound, to target the facultative anaerobic bacterial pathogen Serratia marcescens. The QS-inhibitory effects of these compounds were evaluated using S. marcescens NJ01 and the reporter strain Chromobacterium violaceum CV026. Among the 33 new ß-nitrostyrene derivatives, (E)-1-methyl-4-(2-nitrovinyl)benzene (m-NPe, compound 28) was proven to be a potent inhibitor that reduced biofilm formation of S. marcescens NJ01 by 79%. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) results revealed that treatment with m-NPe (50 µg/ml) not only enhanced the susceptibility of the formed biofilms but also disrupted the architecture of biofilms by 84%. m-NPe (50 µg/ml) decreased virulence factors in S. marcescens NJ01, reducing the activity of protease, prodigiosin, and extracellular polysaccharide (EPS) by 36%, 72%, and 52%, respectively. In S. marcescens 4547, the activities of hemolysin and EPS were reduced by 28% and 40%, respectively, outperforming the positive control, vanillic acid (VAN). The study also found that the expression levels of QS- and biofilm-related genes (flhD, fimA, fimC, sodB, bsmB, pigA, pigC, and shlA) were downregulated by 1.21- to 2.32-fold. Molecular dynamics analysis showed that m-NPe could bind stably to SmaR, RhlI, RhlR, LasR, and CviR proteins in a 0.1 M sodium chloride solution. Importantly, a microscale thermophoresis (MST) test revealed that SmaR could be a target protein for the screening of a quorum sensing inhibitor (QSI) against S. marcescens. Overall, this study highlights the efficacy of m-NPe in suppressing the virulence factors of S. marcescens, identifying it as a new potential QSI and antibiofilm agent capable of restoring or improving antimicrobial drug sensitivity.

7.
Curr Res Toxicol ; 7: 100195, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39429948

RESUMO

Aims: Cytochrome P450 2E1 (CYP2E1) is a mammalian monooxygenase expressed at high levels in the liver that metabolizes low molecular weight pollutants and drugs, as well as endogenous fatty acids and ketones. Although CYP2E1 has been mainly studied in the endoplasmic reticulum (ER, microsomal fraction), it also localizes in significant amounts to the mitochondria, where it has been far less studied. We investigated the effects of CYP2E1 expression in mitochondria, endoplasmic reticulum, or both organelles in transgenic HepG2 cells exposed to free oleic and palmitic acid, including effects on cytotoxicity, lipid storage, respiration, and gene expression. Results: We found that HepG2 cells expressing CYP2E1 in both the ER and mitochondria have exacerbated levels of palmitic acid cytotoxicity and inhibited respiration. CYP2E1 expression did not impact lipid accumulation from fatty acid exposures, but mitochondrial CYP2E1 expression promoted lipid droplet depletion during serum starvation. In contrast to HepG2 cells, differentiated HepaRG cells express abundant CYP2E1, but they are not sensitive to palmitic acid cytotoxicity. Oleic acid exposure prompted less cytotoxicity, and CYP2E1 expression in the ER prevented an oleic-acid-induced increase in respiration. HepG2 cells exposed to mixtures of palmitic and oleic acid are protected from palmitic acid cytotoxicity. Additionally, we identified that CYP2E1 was decreased at the gene and protein level in hepatocellular carcinoma. Moreover, patients with tumors that had higher CYP2E1 expression had a better prognosis compared to patients with lower CYP2E1 expression. Innovation: This study has demonstrated that transgenic CYP2E1 subcellular localization plays an important role in sensitivity to cytotoxicity, lipid storage, and respiration in the hepatoma cell line HepG2 exposed to palmitic and oleic acid. HepaRG cells, in contrast, were insensitive to palmitic acid. This work demonstrates the clear importance of CYP2E1 in dictating lipotoxicity and differential roles for the mitochondrial and ER forms of the enzyme. Additionally, our data supports a potentially unique role for CYP2E1 in cancer cells. Conclusion: There lies a role for CYP2E1 in altering lipotoxicity, and since CYP2E1 is known to be upregulated in both liver disease and hepatocellular carcinoma, it is important to better define how the role of CYP2E1 changes during disease progression.

8.
J Agric Food Chem ; 72(42): 23246-23257, 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39391963

RESUMO

The aim of this study was to determine the osteogenic activity and mechanism of soybean peptide VVELLKAFEEKF (SOP) and the potential relationship between SOP and transforming growth factor-ß1 (TGF-ß1). The results show that SOP promotes MC3T3-E1 cell proliferation by altering cell progression. SOP induced cell differentiation and mineralization in a dose-dependent manner at 0.7-7 µM. Moreover, SOP stimulates osteoblast differentiation, which may be achieved through the activation of p38-MAPK and Smad2/3 signaling pathways. Furthermore, treatment with a TßRI inhibitor (SB525334) inhibited the phosphorylation levels of p38 and Smad2/3, which indicates the involvement of TßRI in the process of osteoblast differentiation caused by SOP. Besides, in non-FBS-cultured MC3T3-E1 cells, SOP and TGF-ß1 promoted the phosphorylation of Smad2/3 and alkaline phosphatase (ALP) activity, but the effect was lost when SOP was incubated separately, indicating that SOP stimulated osteoblast differentiation by promoting TGF-ß1 activity. In vivo, SOP significantly restores bone mineral density loss and behavioral deficits in a model of glucocorticoid-induced osteoporosis (GIOP) in zebrafish. These results suggest that SOP may have the function of promoting bone remodeling and may be used as a potential active factor for functional food development to prevent osteoporosis.


Assuntos
Diferenciação Celular , Glycine max , Osteoblastos , Osteogênese , Proteínas de Soja , Fator de Crescimento Transformador beta1 , Osteoblastos/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proteínas de Soja/química , Proteínas de Soja/farmacologia , Glycine max/química , Osteogênese/efeitos dos fármacos , Peixe-Zebra , Humanos , Transdução de Sinais/efeitos dos fármacos , Peptídeos/farmacologia , Peptídeos/química , Proteína Smad2/metabolismo , Proteína Smad2/genética , Fosforilação/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína Smad3/metabolismo , Proteína Smad3/genética , Proteínas Smad/metabolismo , Proteínas Smad/genética , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo
9.
J Anal Psychol ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39410778

RESUMO

The symbolic nature of taboo is examined as a container that differentiates developmental stages between the social values order/disorder through a ritual, liminal process of separating order as clean/blessed/safety and disorder as polluted/disassociated/risky. Unconscious/conscious taboos embody that perilous journey across margins in rites of passage and their emotional value and intensity in the form of symptomology varies cross-culturally. Two clinical cases are presented to illustrate the influence of taboo on obsessive compulsions and anorexia nervosa. Particular attention is given as to whether dirt as disorder/rubbish can be recycled at the margins between safety and risk and value redistributed to the intrapsychic and psychosocial anomalous bits and pieces that are discarded as rubbish.


La nature symbolique du tabou est étudiée en tant que contenant différenciant les stades de développement entre les valeurs sociales par un processus rituel et liminal de séparation de l'ordre ­ propre/béni/sécurité ­ et du désordre ­pollué/dissocié/risqué. Les tabous inconscients/conscients incarnent ce voyage périlleux à travers les limites dans les rites de passage, leur valeur et leur intensité émotionnelle, sous forme de sémiologie variant d'une culture à l'autre. Deux cas cliniques sont présentés pour illustrer l'influence du tabou sur les compulsions obsessionnelles et l'anorexie mentale. Une attention particulière est accordée à la question de savoir si la saleté en tant que désordre/déchet peut être recyclée à la marge entre la sécurité et le risque, et si de la valeur peut être redistribuée aux « morceaux ¼ intrapsychiques et psychosociaux étranges qui sont considérés comme des déchets.


Se examina la naturaleza simbólica del tabú como un contenedor que permite diferenciar etapas de desarrollo entre valores sociales a través de un proceso ritual y liminal de separación entre el orden como limpio/bendito/seguro y el desorden como contaminado/disociado/arriesgado. Los tabúes inconscientes/conscientes encarnan ese peligroso viaje a través de los márgenes en los ritos de pasaje; y su valor emocional e intensidad, en forma de sintomatología, varía a través de las distintas culturas. Se presentan dos casos clínicos para ilustrar la influencia del tabú en las compulsiones obsesivas y la anorexia nerviosa. Se presta especial atención a si la suciedad como trastorno/basura puede ser reciclada en las márgenes entre la seguridad y el riesgo, y el valor ser redistribuido entre los trozos y piezas psicosociales anómalos e intrapsíquicos, que se desechan como basura.

10.
J Anal Psychol ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39410837

RESUMO

One of Jung's most significant contributions concerns the mysterious, inexplicable and always out-of-reach nature of the self. In this paper, I will focus on the borders of the self and their nature, location and dynamics of maintenance and change in geographically, historically, and culturally situated subjects. Reflecting on the refugee experience, I intend to gain more insights into our psychic functioning and the dynamics of the self in relation to itself, the other and groups. The experiences of some refugees, marked bysignificant trauma and migration, shed light on how the boundaries of the self are frequently contested and perpetually negotiated with others, and how our subjectivity is shaped by ongoing dynamics of occupation, dispute and/or negotiation, conducted at various levels of our social and individual existence. My argument is that these processes occur at a specific site: the boundaries of the self, involving intrapsychic, interpersonal and group psychological dynamics, with reverberations in the socio-political and cultural spheres, and reciprocal influences between all these levels. This paper aims to concentrate on the shifts in these boundaries, illustrated through clinical vignettes.


L'une des contributions les plus précieuses de Jung concerne la nature du soi. Celle­ci est mystérieuse, inexplicable et toujours inaccessible. Dans cet article, réfléchissant à l'expérience de certains réfugiés et essayant d'en extraire plus de connaissances sur notre fonctionnement psychique et la dynamique du soi en relation avec le soi, l'autre et les groupes, je me concentrerai sur les frontières du soi et leur nature, leur localisation, et sur la dynamique de leur maintien et de leur changement chez des sujets géographiquement, historiquement et culturellement situés. L'expérience de certains réfugiés, qui combine un traumatisme majeur et l'expérience de la migration, est particulièrement éclairante sur la façon dont les limites de soi sont souvent contestées et toujours négociées avec les autres, et sur la façon dont notre subjectivité est le résultat de dynamiques continues d'occupation, de conflit et/ou de négociation, menées à différents niveaux de nos vies sociales et individuelles. Mon argument est que ces processus se produisent aux frontières du soi, impliquant des dynamiques psychologiques intrapsychiques, interpersonnelles et de groupe, avec des répercussions dans les sphères sociopolitiques et culturelles, avec des influences réciproques entre tous ces niveaux. L'objectif est de se concentrer sur les changements dans ces limites, en les illustrant par des vignettes cliniques.


Una de las contribuciones más valiosas de Jung se refiere a la naturaleza misteriosa, inexplicable e inalcanzable del self. En este artículo, me centraré en las fronteras del self y su naturaleza, localización y dinámicas de mantenimiento y cambio en sujetos geográfica, histórica y culturalmente situados, reflexionando sobre la experiencia de algunos refugiados e intentando extraer de ella más conocimiento sobre nuestro funcionamiento psíquico y la dinámica del self con relación a sí mismo, el otro y los grupos. La experiencia de algunos refugiados, que combina traumas de gravedad y la experiencia de la migración, es particularmente esclarecedora de cómo los límites del self, a menudo son disputados y siempre negociados con otros, y de cómo nuestra subjetividad es el resultado de dinámicas continuas de ocupación, disputa y/o negociación, llevadas a cabo en diferentes niveles de nuestras vidas sociales e individuales. Mi argumento es que estos procesos ocurren en las fronteras del self, involucrando dinámicas psicológicas grupales, intrapsíquicas e interpersonales, con repercusiones en las esferas sociopolítica y cultural, con influencias recíprocas entre todos estos niveles. La intención es hacer foco en los cambios en estas fronteras, ilustrándolos con viñetas clínicas.

11.
Biochem Biophys Res Commun ; 734: 150735, 2024 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-39357336

RESUMO

Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system.


Assuntos
Animais Geneticamente Modificados , Caenorhabditis elegans , Citocromo P-450 CYP2E1 , Etanol , Locomoção , Mitocôndrias , Animais , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/genética , Etanol/farmacologia , Ratos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Locomoção/efeitos dos fármacos , Células PC12 , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos
12.
Toxicol In Vitro ; 102: 105952, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39395750

RESUMO

Carcinogenic N-nitroso compounds, especially N-nitroso dimethylamine, increase the risk of gastric cancer development. Cytochrome P450-2E1 metabolizes this compound, thus generating an oxidant microenvironment. We aimed to evaluate in gastric adenocarcinoma cells if its effect on CYP2E1 and ROS affects signaling pathways associated with gastric cancer oncogenesis. The impact of N- nitroso dimethylamine upon CYP2E1 and ROS activation/secretion was evaluated by the DCFDA assay protocol, TER measurements, Stat3, pSTAT3, ERK1/2, and pERK1/2 expression, claudins-1 and -6 expression, and finally mRNA values of IL-1ß IL-6, IL-8 and TNFα. Our results showed that exposure to N- N-nitroso dimethylamine disrupts the regulation of Stat3 and Erk1/2, alters the expression of claudin-1 and claudin-6 tight junction proteins, and increases the secretion of pro-inflammatory cytokines. These alterations induce a continuous local inflammatory process, an event identified as a gastric cancer promoter. In summary, N-nitroso dimethylamine can disrupt cell mechanisms associated with gastric cancer oncogenesis.

13.
Front Pharmacol ; 15: 1434024, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39415831

RESUMO

Organ-specific aging is increasingly recognized for its research significance, with liver aging demonstrating particular relevance due to its central role in metabolism. We have pioneered the discovery that the expression of ESRRG in the liver positively correlates with age and have established its association with clinical characteristics, including hepatic edema. Our findings link liver aging to a shift in oxidative stress states, where ESRRG, a crucial nuclear receptor responsive to oxidative stress, may be modulated by various small molecules. Through virtual screening of a natural medicinal molecule database followed by further validation, we confirmed that the natural compound Tanshinone IIA mitigates oxidative stress-induced damage in the liver via the ESRRG/Cyp2e1 pathway, thus decelerating liver aging. Importantly, our study also explores the dynamic impact of Tanshinone IIA on ESRRG conformation, providing a profound understanding of its molecular interactions with ESRRG and laying a foundation for the rational design of small molecules based on natural compounds.

14.
Clin Exp Pharmacol Physiol ; 51(11): e13923, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39358837

RESUMO

Adipocyte enhancer-binding protein 1 (AEBP1) is closely implicated in osteoblastic differentiation and bone fracture; this research aimed to investigate the effect of AEBP1 on restoring osteoblastic differentiation under dexamethasone (Dex) treatment, and its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pre-osteoblastic MC3T3-E1 cells were cultured in osteogenic medium and treated by Dex to mimic steroid-induced osteonecrosis cellular model. They were then further transfected with control or AEBP1-overexpressed lentiviral vectors. Finally, cells were treated with the PI3K inhibitor LY294002, with or without AEBP1-overexpressed lentiviral vectors. AEBP1 expression showed a downward trend in MC3T3-E1 cells under Dex treatment in a dose-dependent manner. AEBP1-overexpressed lentiviral vectors increased relative cell viability, alkaline phosphatase (ALP) staining, Alizarin red staining and osteoblastic differentiation markers including osteocalcin (OCN), osteopontin (OPN), collagen type I alpha 1 (COL1A1), runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), but decreased cell apoptosis rate in MC3T3-E1 cells under Dex treatment; besides, AEBP1-overexpressed lentiviral vectors positively regulated p-PI3K and p-AKT expressions. Furthermore, LY294002 treatment decreased relative cell viability, Alizarin red staining, osteoblastic differentiation markers including OCN, OPN, RUNX2 and BMP, increased cell apoptosis rate and did not affect ALP staining in MC3T3-E1 cells under Dex treatment; meanwhile, LY294002 treatment weakened the effect of AEBP1 overexpression vectors on the above cell functions. AEBP1 restores osteoblastic differentiation under Dex treatment by activating the PI3K/AKT pathway.


Assuntos
Carboxipeptidases , Dexametasona , Osteoblastos , Proteínas Proto-Oncogênicas c-akt , Proteínas Repressoras , Transdução de Sinais , Animais , Camundongos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Dexametasona/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Carboxipeptidases/genética , Carboxipeptidases/metabolismo
15.
Int Immunopharmacol ; 143(Pt 1): 113302, 2024 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-39388889

RESUMO

Periodontitis is associated with multiple systemic diseases and can cause bone loss. Porphyromonas gingivalis (P. gingivalis) is one of the most virulent periodontal pathogens. Icariin is a flavonoid extracted from the traditional Chinese herbal medicine Herba Epimedii, and can regulate bone metabolism. However, its effects on promoting bone metabolism have not been fully elucidated. In this experiment, we infected MC3T3-E1 cells with P. gingivalis. Flow cytometry results show that persistent bacterial infection does not affect cell proliferative activity. Western blotting, ALP activity detection, mineral content determination, and immunofluorescence blotting confirmed that icariin improved osteogenic differentiation in the inflammatory state, and this effect may be more obvious in the early stage of osteogenic differentiation. The antibacterial assays, ROS and MMP fluorescence assays demonstrated that icariin exerted a significant inhibitory effect on bacterial growth and attenuated the inflammatory response in bacterial-infected conditions. The results of in vivo experiments in animals further validated the excellent properties exerted by icariin in the repair of bone defects. Additionally, in the P. gingivalis-infected state, icariin exert a regulatory effect on EphA2-RhoA signaling pathway to augment osteogenic differentiation. These exciting findings suggest that icariin holds significant potential for therapeutic application in the management of periodontal bone loss.


Assuntos
Infecções por Bacteroidaceae , Regeneração Óssea , Diferenciação Celular , Flavonoides , Osteogênese , Porphyromonas gingivalis , Transdução de Sinais , Animais , Porphyromonas gingivalis/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Camundongos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Infecções por Bacteroidaceae/tratamento farmacológico , Infecções por Bacteroidaceae/microbiologia , Regeneração Óssea/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismo , Linhagem Celular , Periodontite/tratamento farmacológico , Periodontite/microbiologia , Masculino , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Humanos
16.
Sci Rep ; 14(1): 26008, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39472638

RESUMO

Polyether sulfone sulfamic acid (PES-NHSO3H) was prepared by simple sulfonation of a modified polyether sulfone. The number of acidic sites (SO3H) was determined to be 4.23 mmol H+/g by acid-base titration and 4.29 mmol H+/g by barium sulfate test. PES-NHSO3H was used as an efficient acidic catalytic system for the preparation of functionalized furan-2-ones and 2',5-dioxo-5 H-spiro[furan-2,3 ' -indoline]-3-carboxylate derivatives via the three-component reaction of anilines, aldehydes/1-ethylindoline-2,3-dione, and diethyl acetylene dicarboxylate in high yields (85-97%). The effect of polar and non-polar solvents on the productivity of the reaction was investigated. The catalyst was recovered 11 times without losses in catalytic potential.

17.
IDCases ; 38: e02087, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39469502

RESUMO

Chikungunya fever is an arboviral disease caused by the Chikungunya virus (CHIKV), which is classified into three genotypes, namely Asian, West African, and East/Central/South African (ECSA). Due to the frequency and severity of CHIKV outbreaks, it is crucial to genetically characterize the virus, especially in non-endemic regions. This report describes a case and genome characterization of CHIKV from a case that was detected in Jeddah (in 2021) during the COVID-19 pandemic. CHIKV was identified in a 32-year-old male patient in Jeddah, originally from India, who presented with fever, myalgia, malaise, and fatigue and was initially suspected of having dengue. The patient had no history of travel in the fortnight prior to his presentation. Treatment included paracetamol, saline, and vitamin C, which is important for the host immune response and detoxification of viral products. The genome of CHIKV was sequenced using various techniques and bioinformatics tools. Amino acid mutations were studied. Phylogenetic analysis showed that the CHIKV strain detected in 2021 was genetically distinct from those reported in 2018. The 2021 virus shared ancestry with CHIKV strains reported in India. This strain possessed E1-K211E, E2-V264A, and E1-I317V mutations. Novel substitutions were identified. The CHIKV re-emergence in 2021 in Jeddah belonged to the Indian subcontinent/Southeast Asia clade of ECSA. More molecular epidemiological information is needed to better understand and evaluate the prevalence of CHIKV in Saudi Arabia.

18.
BMC Cancer ; 24(1): 1333, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39472827

RESUMO

BACKGROUND: Chemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance. METHODS: Small RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays. RESULTS: We identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC. CONCLUSIONS: Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.


Assuntos
Cisplatino , Ciclina E , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Proteínas Oncogênicas , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , MicroRNAs/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Amplificação de Genes
19.
Phytomedicine ; 135: 156106, 2024 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-39366156

RESUMO

BACKGROUND: The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP. METHODS: In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection. RESULTS: Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC-MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels. CONCLUSION: AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.

20.
Adv Rheumatol ; 64(1): 79, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39385260

RESUMO

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.


Assuntos
Adenosina Desaminase , Doenças Raras , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Síndrome de Cogan/complicações , Síndrome de Susac/complicações , Síndrome de Susac/diagnóstico , Vasculite Sistêmica/diagnóstico , Agamaglobulinemia/complicações , Mutação , Vasculite , Peptídeos e Proteínas de Sinalização Intercelular
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