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1.
Biomed Pharmacother ; 177: 117105, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-39002438

RESUMEN

Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.

2.
Environ Monit Assess ; 196(8): 726, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38995468

RESUMEN

The feasibility of a simultaneous nitrification, denitrification and fermentation process (SNDF) under electric stirrer agitation conditions was verified in a single reactor. Enhanced activated sludge for phenol degradation and denitrification in pharmaceutical phenol-containing wastewater under low dissolved oxygen conditions, additional inoculation with Comamonas sp. BGH and optimisation of co-metabolites were investigated. At a hydraulic residence time (HRT) of 28 h, 15 mg/L of substrate as strain BGH co-metabolised substrate degraded 650 ± 50 mg/L phenol almost completely and was accompanied by an incremental increase in the quantity of strain BGH. Strain BGH showed enhanced phenol degradation. Under trisodium citrate co-metabolism, strain BGH combined with activated sludge treated phenol wastewater and degraded NO2--N from 50 ± 5 to 0 mg/L in only 7 h. The removal efficiency of this group for phenol, chemical oxygen demand (COD) and TN was 99.67%, 90.25% and 98.71%, respectively, at an HRT of 32 h. The bioaugmentation effect not only promotes the degradation of pollutants, but also increases the abundance of dominant bacteria in activated sludge. Illumina MiSeq sequencing research showed that strain BGH promoted the growth of dominant genera (Acidaminobacter, Raineyella, Pseudarcobacter) and increased their relative abundance in the activated sludge system. These genera are resistant to toxicity and organic matter degradation. This paper provides some reference for the activated sludge to degrade high phenol pharmaceutical wastewater under the action of biological enhancement.


Asunto(s)
Reactores Biológicos , Desnitrificación , Fermentación , Nitrificación , Eliminación de Residuos Líquidos , Aguas Residuales , Contaminantes Químicos del Agua , Reactores Biológicos/microbiología , Eliminación de Residuos Líquidos/métodos , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/análisis , Aguas Residuales/química , Fenol/metabolismo , Aguas del Alcantarillado/microbiología , Biodegradación Ambiental
4.
Eur J Pharmacol ; 977: 176716, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38849039

RESUMEN

The immune system has a strong connection to tumors. When a tumor cell is recognized as an abnormal cell by the immune system, the immune system may initiate an immune response to kill the tumor cell. In this study, RNA sequencing was performed on multiple myeloma (MM) cells treated with the proteasome inhibitor FHND6091. The transcriptional changes induced by FHND6091 in RPMI8226 cells aligned notably with immune response activation and results indicated upregulation of cGAS-STING pathway-related genes in the FHND6091-treated group. In vivo and in vitro experiments had demonstrated that FHND6091 stimulated the immunoreaction of MM cells via activation of the cyclic guanosine monophosphate-adenosine synthase/stimulator of interferon genes (cGAS-STING) pathway. This activation resulted in the generation of type-I interferons and the mobilization of natural killer (NK) cells. Notably, FHND6091 upregulated the levels of calreticulin and the protein ligands UL16-binding protein 2/5/6, MHC class I chain-related A (MICA), and MICB on the surface of MM cells. Subsequently, upon engaging with the surface activation receptors of NK cells, these ligands triggered NK cell activation, leading to the subsequent elimination of tumor cells. Thus, our findings elucidated the mechanism whereby FHND6091 exerted its immunotherapeutic activity as a STING agonist, enhancing the killing ability of NK cells against tumor cells.


Asunto(s)
Células Asesinas Naturales , Proteínas de la Membrana , Mieloma Múltiple , Inhibidores de Proteasoma , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Inhibidores de Proteasoma/farmacología , Línea Celular Tumoral , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Animales , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Ratones , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Calreticulina/metabolismo , Calreticulina/genética , Transducción de Señal/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Interferón Tipo I/metabolismo
5.
Int J Biol Macromol ; 270(Pt 2): 132441, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38761897

RESUMEN

Pest management technology has been a promising bioconversion method for waste resource utilization. Unlike many pests that consume waste, the larvae of Lucilia sericata, also known as maggots, have many outstanding advantages as following: with their strong adaption to environment and not easily infected and exhibiting a medicinal nutritional value. Herein, the potential efficacies of maggot polysaccharides (MP), as well as their underlying mechanisms, were explored in Dextran sulfate sodium (DSS)-induced colitis mice and TNF-α-elicited Caco-2 cells. We extracted two bioactive polysaccharides from maggots, MP-80 and MP-L, whose molecular weights were 4.25 × 103 and 2.28 × 103 g/mol, respectively. MP-80 and MP-L contained nine sugar residues: 1,4-α-Arap, 1,3-ß-Galp, 1,4,6-ß-Galp, 1,6-α-Glcp, 1-α-Glcp, 1,4-ß-Glcp, 1-ß-Xylp, 1,2-α-Manp, and 1-ß-Manp. We demonstrated that MP-80 and MP-L significantly ameliorated DSS-induced symptoms and histopathological damage. Immuno-analysis revealed that compared with MP-L, MP-80 could better restore intestinal barrier and reduced inflammation by suppressing NLRP3/NF-κB pathways, which might be attributed to its enriched galactose fraction. Moreover, 16S rRNA sequencing revealed that MP-80 and MP-L both improved the dysbiosis and diversity of gut microbiota and acted on multiple microbial functions. Our study sheds new light on the possibility of using maggot polysaccharides as an alternative therapy for colitis.


Asunto(s)
Colitis Ulcerosa , Sulfato de Dextran , Microbioma Gastrointestinal , Larva , Polisacáridos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Larva/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/química , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Humanos , Ratones , Células CACO-2 , Dípteros/química , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Modelos Animales de Enfermedad , Masculino
6.
BMC Microbiol ; 24(1): 145, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38671363

RESUMEN

BACKGROUND: Vibrio parahaemolyticus is the predominant etiological agent of seafood-associated foodborne illnesses on a global scale. It is essential to elucidate the mechanisms by which this pathogen disseminates. Given the existing research predominantly concentrates on localized outbreaks, there is a pressing necessity for a comprehensive investigation to capture strains of V. parahaemolyticus cross borders. RESULTS: This study examined the frequency and genetic attributes of imported V. parahaemolyticus strains among travelers entering Shanghai Port, China, between 2017 and 2019.Through the collection of 21 strains from diverse countries and regions, Southeast Asia was pinpointed as a significant source for the emergence of V. parahaemolyticus. Phylogenetic analysis revealed clear delineation between strains originating from human and environmental sources, emphasizing that underlying genome data of foodborne pathogens is essential for environmental monitoring, food safety and early diagnosis of diseases. Furthermore, our study identified the presence of virulence genes (tdh and tlh) and approximately 120 antibiotic resistance-related genes in the majority of isolates, highlighting their crucial involvement in the pathogenesis of V. parahaemolyticus. CONCLUSIONS: This research enhanced our comprehension of the worldwide transmission of V. parahaemolyticus and its antimicrobial resistance patterns. The findings have important implications for public health interventions and antimicrobial stewardship strategies, underscoring the necessity for epidemiological surveillance of pathogen at international travel hubs.


Asunto(s)
Enfermedades Transmitidas por los Alimentos , Filogenia , Vibriosis , Vibrio parahaemolyticus , Vibrio parahaemolyticus/genética , Vibrio parahaemolyticus/aislamiento & purificación , Vibrio parahaemolyticus/clasificación , Vibrio parahaemolyticus/patogenicidad , Vibrio parahaemolyticus/efectos de los fármacos , Humanos , China/epidemiología , Vibriosis/microbiología , Vibriosis/epidemiología , Enfermedades Transmitidas por los Alimentos/microbiología , Enfermedades Transmitidas por los Alimentos/epidemiología , Genoma Bacteriano/genética , Viaje , Factores de Virulencia/genética , Genómica , Farmacorresistencia Bacteriana/genética , Antibacterianos/farmacología , Alimentos Marinos/microbiología
7.
Biomater Adv ; 160: 213859, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38642515

RESUMEN

Triple-negative breast cancer (TNBC) is a highly invasive and metastatic subtype of breast cancer that often recurs after surgery. Herein, we developed a cyclodextrin-based tumor-targeted nano delivery system that incorporated the photosensitizer chlorin e6 (Ce6) and the chemotherapeutic agent lonidamine (LND) to form the R6RGD-CMßCD-se-se-Ce6/LND nanoparticles (RCC/LND NPS). This nanosystem could target cancer cells, avoid lysosomal degradation and further localize within the mitochondria. The RCC/LND NPS had pH and redox-responsive to control the release of Ce6 and LND. Consequently, the nanosystem had a synergistic effect by effectively alleviating hypoxia, enhancing the production of cytotoxic reactive oxygen species (ROS) and amplifying the efficacy of photodynamic therapy (PDT). Furthermore, the RCC/LND NPS + light weakened anoikis resistance, disrupted extracellular matrix (ECM), activated both the intrinsic apoptotic pathway (mitochondrial pathway) and extrinsic apoptotic pathway (receptor death pathway) of anoikis. In addition, the nanosystem showed significant anti-TNBC efficacy in vivo. These findings collectively demonstrated that RCC/LND NPS + light enhanced the anticancer effects, induced anoikis and inhibited tumor cell migration and invasion through a synergistic effect of chemotherapy and PDT. Overall, this study highlighted the promising potential of the RCC/LND NPS + light for the treatment of TNBC.


Asunto(s)
Anoicis , Apoptosis , Clorofilidas , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfirinas , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Humanos , Fotoquimioterapia/métodos , Femenino , Porfirinas/farmacología , Porfirinas/uso terapéutico , Animales , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Anoicis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , Apoptosis/efectos de los fármacos , Indazoles/farmacología , Indazoles/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones
8.
Heliyon ; 10(3): e25642, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38356529

RESUMEN

Vibrio parahaemolyticus is a significant cause of foodborne illness, and its incidence worldwide is on the rise. It is thus imperative to develop a straightforward and efficient method for typing strains of this pathogen. In this study, we conducted a pangenome analysis of 75 complete genomes of V. parahaemolyticus and identified the core gene mtlA with the highest degree of variation, which distinguished 44 strains and outperformed traditional seven-gene-based MLST when combined with aer, another core gene with high degree of variation. The mtlA gene had higher resolution to type strains with a close relationship compared to the traditional MLST genes in the phylogenetic tree built by core genomes. Strong positive selection was also detected in the gene mtlA (ω > 1), representing adaptive and evolution in response to the environment. Therefore, the panel of gene mtlA and aer may serve as a tool for the typing of V. parahaemolyticus, potentially contributing to the prevention and control of this foodborne disease.

9.
Int J Nanomedicine ; 19: 1809-1825, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38414523

RESUMEN

Introduction: Tumor hypoxia and invasion present significant challenges for the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC). This study developed a mitochondrial targeting strategy that combined PDT and gene therapy to promote each other and address the challenges. Methods: The positively charged amphiphilic material triphenylphosphine-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and the photosensitizer chloride e6 (Ce6) formed TPS@Ce6 nanoparticles (NPs) by hydrophobic interaction. They electrostatically condensed microRNA-34a (miR-34a) to form stable TPS@Ce6/miRNA NPs. Results: Firstly, Ce6 disrupted the lysosomal membrane, followed by successful delivery of miR-34a by TPS@Ce6/miRNA NPs. Meanwhile, miR-34a reduced ROS depletion and further enhanced the effectiveness of PDT. Consequently, the mutual promotion between PDT and gene therapy led to enhanced anti-tumor effects. Furthermore, the TPS@Ce6/miRNA NPs promoted apoptosis by down-regulating Caspase-3 and inhibited tumor cell migration and invasion by down-regulating N-Cadherin. In addition, in vitro and in vivo experiments demonstrated that the TPS@Ce6/miRNA NPs achieved excellent anti-tumor effects. These findings highlighted the enhanced anticancer effects and reduced migration of tumor cells through the synergistic effects of PDT and gene therapy. Conclusion: Taken together, the targeted co-delivery of Ce6 and miR-34a will facilitate the application of photodynamic and genic nanomedicine in the treatment of aggressive tumors, particularly TNBC.


Asunto(s)
MicroARNs , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/terapia , Fármacos Fotosensibilizantes/química , MicroARNs/genética , Modelos Animales de Enfermedad , Línea Celular Tumoral , Porfirinas/química , Nanopartículas/química
10.
mSphere ; 8(6): e0045723, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-37905831

RESUMEN

IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to multiple drugs and can cause serious infections. In recent years, one of the most widespread strains of MRSA worldwide has been the clonal complex 5 (CC5) type. Sequence type 5 (ST5) and ST764 are two prevalent CC5 strains. Although ST5 and ST764 are genotypically identical, ST764 is classified as a hybrid variant of ST5 with characteristics of community-associated MRSA (CA-MRSA). In contrast to ST5, ST764 lacks the tst and sec genes but carries the staphylococcal enterotoxin B (seb) gene. Vancomycin is commonly used as the first-line treatment for MRSA infections. However, it is currently unclear whether the genetic differences between the ST5 and ST764 strains have any impact on the efficacy of vancomycin in treating MRSA infections. We conducted a prospective observational study comparing the efficacy of vancomycin against ST5-MRSA and ST764-MRSA in five hospitals in China. There were significant differences in bacteriological efficacy between the two groups, with virulence genes, such as the tst gene, being a risk factor for bacterial persistence (adjusted odds ratio, 4.509; 95% confidence interval, 1.216 to 16.724; P = 0.024). In the future, it may be necessary to consider personalized vancomycin treatment strategies based on the genetic characteristics of MRSA isolates.


Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Adulto , Humanos , Vancomicina/farmacología , Vancomicina/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Virulencia
11.
Front Mol Neurosci ; 16: 1149906, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37822967

RESUMEN

Peroxisome proliferator-activated receptor PPARγ coactivator-α (PGC-1α) is concentrated in inhibitory interneurons and plays a vital role in neuropsychiatric diseases. We previously reported some characteristic features of schizophrenia (SZ) in GABAergic neuron-specific Pgc-1alpha knockout (KO) mice (Dlx5/6-Cre: Pgc-1alphaf/f). However, there is a fundamental gap in the molecular mechanism by which the Pgc-1alpha gene is involved in the neurobehavioral abnormalities of SZ. The loss of critical period (CP) triggers-maturations of parvalbumin interneurons (PVIs) and brakes-and the formation of perineuronal nets (PNNs) implicates mistimed trajectories during adult brain development. In this study, using the Pgc-1alpha KO mouse line, we investigated the association of Pgc-1alpha gene deletion with SZ-like behavioral deficits, PVI maturation, PNN integrity and synaptic ultrastructure. These findings suggest that Pgc-1alpha gene deletion resulted in a failure of CP onset and closure, thereby prolonging cortical plasticity timing. To determine whether the manipulation of the PNN structure is a potential method of altering neuronal plasticity, GM6001, a broad-spectrum matrix metalloproteinase (MMP)-inhibitor was applied. Here we confirmed that the treatment could effectively correct the CP plasticity window and ameliorate the synaptic ultrastructure in the Pgc-1alpha KO brain. Moreover, the intervention effect on neuronal plasticity was followed by the rescue of short-term habituation deficits and the mitigation of aberrant salience, which are some characteristic features of SZ. Taken collectively, these findings suggest that the role of PGC-1α in regulating cortical plasticity is mediated, at least partially, through the regulation of CP onset/closure. Strategically introduced reinforcement of molecular brakes may be a novel preventive therapy for psychiatric disorders associated with PGC-1α dysregulation.

12.
Cancer Cell Int ; 23(1): 194, 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37670265

RESUMEN

OBJECTIVES: Lung adenocarcinoma (LUAD) exhibits a higher fatality rate among all cancer types worldwide, yet the precise mechanisms underlying its initiation and progression remain unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) exert significant regulatory roles in cancer development and progression. Nevertheless, the precise involvement of lncRNA CYP4A22-AS1 in LUAD remains incompletely comprehended. METHODS: Bioinformatics analyses evaluated the expression level of CYP4A22-AS1 in lung adenocarcinoma and paracancer. The LUAD cell line with a high expression of CYP4A22-AS1 was constructed to evaluate the role of CYP4A22-AS1 in the proliferation and metastasis of LUAD by CCK8, scratch healing, transwell assays, and animal experiments. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. Luciferase reporter gene analyses, west-blotting, and qRT-PCR were carried out to reveal the interaction between CYP4A22-AS1, miR-205-5p/EREG, and miR-34c-5p/BCL-2 axes. RESULTS: CYP4A22-AS1 expression was significantly higher in LUAD tissues than in the adjacent tissues. Furthermore, we constructed a LUAD cell line with a high expression of CYP4A22-AS1 and noted that the high expression of CYP4A22-AS1 significantly enhanced the proliferation and metastasis of LUAD. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. CYP4A22-AS1 increased the expression of EREG and BCL-2 by reducing the expression of miR-205-5p and miR-34-5p and activating the downstream signaling pathway of EGFR and the anti-apoptotic signaling pathway of BCL-2, thereby triggering the proliferation and metastasis of LUAD. The transfection of miR-205-5p and miR-34-5p mimics inhibited the role of CYP4A22-AS1 in enhancing tumor progression. CONCLUSION: This study elucidates the molecular mechanism whereby CYP4A22-AS1 overexpression promotes LUAD progression through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

13.
Appl Microbiol Biotechnol ; 107(22): 6911-6922, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37704771

RESUMEN

The Food and Agriculture Organization of the United Nations (FAO) has identified hybrid rice as ideal for addressing food scarcity in poor nations. A comprehensive investigation of the endophytic bacteria in hybrid rice seeds is essential from a microecological perspective to illuminate the mechanisms underlying its high yield, high quality, and multi-resistance. The endophytic bacterial diversity and community structures of 11 genetically correlated hybrid rice seeds with different rice blast resistance levels were studied using high-throughput sequencing (HTS) on the Illumina MiSeq platform to reveal their "core microbiota" and explore the effect of genotypes, genetic relationships, and resistance. Proteobacteria (78.15-99.15%) represented the most abundant group in the 11 hybrid rice cultivars, while Pantoea, Pseudomonas, and Microbacterium comprised the "core microbiota." Hybrid rice seeds with different genotypes, genetic correlations, and rice blast resistance displayed endophytic bacterial community structure and diversity variation. In addition, the network relationships between the rice seed endophytic bacteria of "the same female parent but different male parents" were more complex than those from "the same male parent but different female parents." Matrilineal inheritance may be the primary method of passing on endophytic bacteria in rice from generation to generation. The endophytic bacterial interaction network in rice blast-resistant hybrid rice seed varieties was more complicated than in susceptible varieties. In summary, this study demonstrated that the genotype, genetic relationship, and rice blast resistance were important factors affecting the community structures and diversity of endophytic bacteria in hybrid rice seeds, which was vital for revealing the interaction between endophytic bacteria and the host. KEY POINTS: • Pantoea, Pseudomonas, and Microbacterium represent the main endophytic bacteria in hybrid rice seeds. • Genotype is the primary factor affecting endophytic bacterial diversity in hybrid rice seeds. • The diversity of the endophytic bacterial community in hybrid rice seeds is related to their genotypes, genetic relationships, and rice blast resistance.

14.
Eur J Drug Metab Pharmacokinet ; 48(5): 595-614, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37528327

RESUMEN

BACKGROUND AND OBJECTIVES: Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research. METHODS: The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated. RESULTS: Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed. CONCLUSION: Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.


Asunto(s)
Sistema Enzimático del Citocromo P-450 , Inhibidores de Proteínas Quinasas , Ratones , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Administración Oral , Citocromo P-450 CYP3A/metabolismo
15.
Aging (Albany NY) ; 15(16): 8220-8236, 2023 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-37606987

RESUMEN

Multiple myeloma (MM) is the second most common hematological malignancy, in which the dysfunction of the ubiquitin-proteasome pathway is associated with the pathogenesis. The valosin containing protein (VCP)/p97, a member of the AAA+ ATPase family, possesses multiple functions to regulate the protein quality control including ubiquitin-proteasome system and molecular chaperone. VCP is involved in the occurrence and development of various tumors while still elusive in MM. VCP inhibitors have gradually shown great potential for cancer treatment. This study aims to identify if VCP is a therapeutic target in MM and confirm the effect of a novel inhibitor of VCP (VCP20) on MM. We found that VCP was elevated in MM patients and correlated with shorter survival in clinical TT2 cohort. Silencing VCP using siRNA resulted in decreased MM cell proliferation via NF-κB signaling pathway. VCP20 evidently inhibited MM cell proliferation and osteoclast differentiation. Moreover, exosomes containing VCP derived from MM cells partially alleviated the inhibitory effect of VCP20 on cell proliferation and osteoclast differentiation. Mechanism study revealed that VCP20 inactivated the NF-κB signaling pathway by inhibiting ubiquitination degradation of IκBα. Furthermore, VCP20 suppressed MM cell proliferation, prolonged the survival of MM model mice and improved bone destruction in vivo. Collectively, our findings suggest that VCP is a novel target in MM progression. Targeting VCP with VCP20 suppresses malignancy progression of MM via inhibition of NF-κB signaling pathway.


Asunto(s)
Exosomas , Mieloma Múltiple , Animales , Ratones , ATPasas Asociadas con Actividades Celulares Diversas , Diferenciación Celular , Proliferación Celular , FN-kappa B , Osteoclastos , Complejo de la Endopetidasa Proteasomal , Transducción de Señal , Ubiquitinas , Proteína que Contiene Valosina
16.
Int J Nanomedicine ; 18: 4023-4042, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37520302

RESUMEN

Introduction: Mitochondria are a significant target of lonidamine (LND). However, its limited solubility and inability to specifically target mitochondria, LND can lead to hepatic toxicity and has shown only modest anticancer activity. The objective of this study is to establish a glutathione programmed mitochondria targeted delivery of LND for the effective treatment of triple negative breast cancer (TNBC). Methods: In this study, LND was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) wrapped with mitochondria-targeting short-chain triphenylphosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and tumor-targeting long-chain 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-S-S-polyethylene glycol-R6RGD (DSPE-S-S-PEG2000-R6RGD, DSSR), which were designated as LND-PLGA/TPS/DSSR NPs. The release behavior was evaluated, and cellular uptake, in vitro and in vivo antitumor activity of nanoparticles were investigated. The mechanism, including apoptosis of tumor cells and mitochondrial damage and respiratory rate detection, was also further investigated. Results: LND-PLGA/TPS/DSSR NPs were successfully prepared, and characterization revealed that they are globular particles with smooth surfaces and an average diameter of about 250 nm. Long-chain DSSR in LND-PLGA/TPS/DSSR NPs prevented positively charged LND-PLGA/TPS NPs from being cleared by the reticuloendothelial system. Furthermore, LND release rate from NPs at pH 8.0 was significantly higher than that at pH 7.4 and 5.5, which demonstrated specific LND release in mitochondria and prevented LND leakage in cytoplasm and lysosome. NPs could locate in mitochondria, and the released LND triggered apoptosis of tumor cells by damaging mitochondria and releasing apoptosis-related proteins. In addition, in TNBC mice model, programmed mitochondria targeted NPs improved efficacy and reduced LND toxicity. Conclusion: LND-PLGA/TPS/DSSR NPs may be a useful system and provide an effective approach for the treatment of TNBC.


Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Línea Celular Tumoral , Nanopartículas/química , Mitocondrias/metabolismo , Glutatión/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/metabolismo
17.
Int Orthop ; 47(8): 2065-2071, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37270455

RESUMEN

PURPOSE: The purpose of this study is to compare the effect of buttress plate and cannulated screw in the treatment of anteromedial coronoid fracture with posteromedial rotatory instability (PMRI). METHODS: We retrospectively evaluated patients who were diagnosed with O'Driscoll type 2 fractures combined with elbow posteromedial rotatory instability and underwent surgery for anteromedial coronoid fracture between August 2014 and March 2019. They were divided into buttress plate (n=16) and cannulated screw (n=11) groups. The elbow range of motion, visual analog scale (VAS), Mayo elbow performance score (MEPS), and disabilities of the arm, shoulder, and hand score (DASH) were used for clinical outcome assessment. RESULT: There were no significant differences in clinical outcomes. However, the surgical time was significantly shorter in cannulated screw group (85.45±4.156) compared to the buttress plate group (93.81±8.863, P=0.008), and the surgical time was associated with internal fixation (P=0.008). CONCLUSION: Although there was selection of cases in that small fragments were treated with buttress plate and large fragments with cannulated screw, the buttress plate and cannulated screw have comparable functional outcomes on fixation of the anteromedial coronoid fracture with elbow PMRI. The fixation of the anteromedial coronoid fracture with large fragments using the cannulated screw has a shorter operation time.


Asunto(s)
Articulación del Codo , Fracturas Óseas , Fracturas del Cúbito , Humanos , Codo , Fracturas del Cúbito/complicaciones , Fracturas del Cúbito/diagnóstico por imagen , Fracturas del Cúbito/cirugía , Estudios Retrospectivos , Fracturas Óseas/complicaciones , Articulación del Codo/diagnóstico por imagen , Articulación del Codo/cirugía , Fijación Interna de Fracturas/efectos adversos , Tornillos Óseos , Rango del Movimiento Articular , Resultado del Tratamiento
18.
Z Naturforsch C J Biosci ; 78(9-10): 345-352, 2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37354002

RESUMEN

A systematic chemical study of the secondary metabolites of the marine fungus, Penicillium chrysogenum (No. Y20-2), led to the isolation of 21 compounds, one of which is new (compound 3). The structures of the 21 compounds were determined by conducting extensive analysis of the spectroscopic data. The pro-angiogenic activity of each compound was evaluated using a zebrafish model. The results showed that compounds 7, 9, 16, and 17 had strong and dose-dependent pro-angiogenic effects, with compound 16 demonstrating the strongest pro-angiogenic activity, compounds 6, 12, 14, and 18 showing moderate activity, and compounds 8, 13, and 19 exhibiting relatively weak activity.


Asunto(s)
Penicillium chrysogenum , Penicillium , Animales , Penicillium chrysogenum/química , Penicillium chrysogenum/metabolismo , Pez Cebra , Penicillium/química , Estructura Molecular
19.
Zootaxa ; 5257(1): 123-130, 2023 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-37044617

RESUMEN

The druid fly genus Clusia was firstly recorded from China, including two new species: C. luteimacula sp. nov. from Yintiaoling Nature Reserve of Chongqing and C. sinensis sp. nov. from Wanglang of Sichuan and Mt. Taibai of Shaanxi. A key to all species of Clusia globally is presented.


Asunto(s)
Clusia , Dípteros , Animales , Distribución Animal , China
20.
Zootaxa ; 5257(1): 115-122, 2023 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-37044618

RESUMEN

Three species of the genus Phyllomyza Fallén from Yintiaoling National Nature Reserve are described as new to science: P. fuscusagenis sp. nov., P. hirtipes sp. nov. and P. obtususa sp. nov. An updated key to the species of Phyllomyza from China is presented. The specimens are deposited in the Insect Collection of Henan Agricultural University.


Asunto(s)
Dípteros , Animales , Distribución Animal , China
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