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1.
J Zhejiang Univ Sci B ; : 1-16, 2024 Jul 09.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38993075

RESUMO

Grooming, as an evolutionarily conserved repetitive behavior, is common in various animals, including humans, and serves essential functions including, but not limited to, hygiene maintenance, thermoregulation, de-arousal, stress reduction, and social behaviors. In rodents, grooming involves a patterned and sequenced structure, known as the syntactic chain with four phases that comprise repeated stereotyped movements happening in a cephalocaudal progression style, beginning from the nose to the face, to the head, and finally ending with body licking. The context-dependent occurrence of grooming behavior indicates its adaptive significance. This review briefly summarizes the neural substrates responsible for rodent grooming behavior and explores its relevance in rodent models of neuropsychiatric disorders and neurodegenerative diseases with aberrant grooming phenotypes. We further emphasize the utility of rodent grooming as a reliable measure of repetitive behavior in neuropsychiatric models, holding promise for translational psychiatry. Herein, we mainly focus on rodent self-grooming. Allogrooming (grooming being applied on one animal by its conspecifics via licking or carefully nibbling) and heterogrooming (a form of grooming behavior directing towards another animal, which occurs in other contexts, such as maternal, sexual, aggressive, or social behaviors) are not covered due to space constraints.

2.
Mol Biol Evol ; 41(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38829799

RESUMO

Global climate change has led to shifts in the distribution ranges of many terrestrial species, promoting their migration from lower altitudes or latitudes to higher ones. Meanwhile, successful invaders have developed genetic adaptations enabling the colonization of new environments. Over the past 40 years, Rattus tanezumi (RT) has expanded into northern China (Northwest and North China) from its southern origins. We studied the cold adaptation of RT and its potential for northward expansion by comparing it with sympatric Rattus norvegicus (RN), which is well adapted to cold regions. Through population genomic analysis, we revealed that the invading RT rats have split into three distinct populations: the North, Northwest, and Tibetan populations. The first two populations exhibited high genetic diversity, while the latter population showed remarkably low genetic diversity. These rats have developed various genetic adaptations to cold, arid, hypoxic, and high-UV conditions. Cold acclimation tests revealed divergent thermoregulation between RT and RN. Specifically, RT exhibited higher brown adipose tissue activity and metabolic rates than did RN. Transcriptome analysis highlighted changes in genes regulating triglyceride catabolic processes in RT, including Apoa1 and Apoa4, which were upregulated, under selection and associated with local adaptation. In contrast, RN showed changes in carbohydrate metabolism genes. Despite the cold adaptation of RT, we observed genotypic and phenotypic constraints that may limit its ability to cope with severe low temperatures farther north. Consequently, it is less likely that RT rats will invade and overlap with RN rats in farther northern regions.


Assuntos
Aclimatação , Temperatura Baixa , Animais , Ratos , Aclimatação/genética , China , Fenótipo , Variação Genética , Adaptação Fisiológica/genética , Regulação da Temperatura Corporal/genética , Mudança Climática
3.
Cell Signal ; 120: 111220, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38740234

RESUMO

Synovitis and cartilage destruction are crucial characteristics of osteoarthritis (OA). Inflammatory cytokines, such as IL-1ß, are secreted by synovial macrophages, leading to cartilage destruction. Pyroptosis is a lytic form of programmed cell death, which could be triggered by the NLRP3 inflammasome of macrophages. Pyroptosis promotes the secretion of IL-1ß and is supposed as a potential biomarker for OA. However, the function of Pyroptosis and NLRP3 inflammasome and its regulatory mechanism for activation is unclear in OA. In this study, we found that Degrasyn could alleviate the GSDMD-mediated pyroptosis of macrophages and the release of IL-1ß, caspase-1, and LDH. Furthermore, it selectively impedes the form of ASC oligomer and speckle to effectively suppress the NLRP3 inflammasome during its assembly phase. Notably, Degrasyn exhibited potential chondroprotective effects in a co-culture system. Additionally, these results also indicate that Degrasyn mitigates synovitis and cartilage damage in a murine model of destabilization of the medial meniscus (DMM)-induced OA. In summary, Degrasyn emerges as a promising pharmaceutical agent for synovitis, paving the way for innovative therapeutic approaches to OA. Our findings underscore the potential of Degrasyn as a viable candidate for OA therapeutics, demonstrating its ability to regulate pyroptosis and NLRP3 inflammasome activation.


Assuntos
Condrócitos , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Osteoartrite , Proteínas de Ligação a Fosfato , Piroptose , Transdução de Sinais , Piroptose/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/tratamento farmacológico , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Proteínas de Ligação a Fosfato/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Humanos , Células RAW 264.7 , Interleucina-1beta/metabolismo , Gasderminas
4.
Nat Commun ; 15(1): 1044, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316815

RESUMO

Reinforcement learning (RL) stands as one of the three fundamental paradigms within machine learning and has made a substantial leap to build general-purpose learning systems. However, using traditional electrical computers to simulate agent-environment interactions in RL models consumes tremendous computing resources, posing a significant challenge to the efficiency of RL. Here, we propose a universal framework that utilizes a photonic integrated circuit (PIC) to simulate the interactions in RL for improving the algorithm efficiency. High parallelism and precision on-chip optical interaction calculations are implemented with the assistance of link calibration in the hybrid architecture PIC. By introducing similarity information into the reward function of the RL model, PIC-RL successfully accomplishes perovskite materials synthesis task within a 3472-dimensional state space, resulting in a notable 56% improvement in efficiency. Our results validate the effectiveness of simulating RL algorithm interactions on the PIC platform, highlighting its potential to boost computing power in large-scale and sophisticated RL tasks.

5.
Proc Natl Acad Sci U S A ; 121(3): e2319335121, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38198526

RESUMO

The phytohormone cytokinin has various roles in plant development, including meristem maintenance, vascular differentiation, leaf senescence, and regeneration. Prior investigations have revealed that cytokinin acts via a phosphorelay similar to the two-component system by which bacteria sense and respond to external stimuli. The eventual targets of this phosphorelay are type-B ARABIDOPSIS RESPONSE REGULATORS (B-ARRs), containing the conserved N-terminal receiver domain (RD), middle DNA binding domain (DBD), and C-terminal transactivation domain. While it has been established for two decades that the phosphoryl transfer from a specific histidyl residue in ARABIDOPSIS HIS PHOSPHOTRANSFER PROTEINS (AHPs) to an aspartyl residue in the RD of B-ARRs results in a rapid transcriptional response to cytokinin, the underlying molecular basis remains unclear. In this work, we determine the crystal structures of the RD-DBD of ARR1 (ARR1RD-DBD) as well as the ARR1DBD-DNA complex from Arabidopsis. Analyses of the ARR1DBD-DNA complex have revealed the structural basis for sequence-specific recognition of the GAT trinucleotide by ARR1. In particular, comparing the ARR1RD-DBD and ARR1DBD-DNA structures reveals that unphosphorylated ARR1RD-DBD exists in a closed conformation with extensive contacts between the RD and DBD. In vitro and vivo functional assays have further suggested that phosphorylation of the RD weakens its interaction with DBD, subsequently permits the DNA binding capacity of DBD, and promotes the transcriptional activity of ARR1. Our findings thus provide mechanistic insights into phosphorelay activation of gene transcription in response to cytokinin.


Assuntos
Arabidopsis , Citocininas , Ativação Transcricional , Arabidopsis/genética , Reguladores de Crescimento de Plantas , DNA
6.
Acta Pharmaceutica Sinica ; (12): 643-650, 2024.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1016629

RESUMO

Three carboline fluorescent probes F1-F3 were designed and synthesized, based on lead compound JYJ-19, an antifungal compound discovered previously by our group. The antifungal activity in vitro results showed that compound F1 had moderate antifungal activity (MIC80 = 32 μg·mL-1). The stokes shift of F1 is 70 nm. The fluorescent probe F1 has good optical properties and can be used for fluorescence imaging research. Subcellular localization experiments results showed that F1 was enriched in the mitochondria of fungal cells. The detection of intracellular reactive oxygen species levels shows that JYJ-19 enhances intracellular reactive oxygen species levels. The above results indicated that carboline compounds could exert antifungal effects by acting on fungal mitochondria.

7.
Organ Transplantation ; (6): 257-262, 2024.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1012497

RESUMO

Objective To investigate the feasibility and clinical experience of kidney transplantation from donors with Marfan syndrome (MFS). Methods Clinical data of 2 recipients undergoing kidney transplantation from the same MFS patient were retrospectively analyzed and literature review of 2 cases was conducted. Characteristics and clinical diagnosis and treatment of kidney transplantation from MFS patients were summarized. Results The Remuzzi scores of the left and right donor kidneys of the MFS patient during time-zero biopsy were 1 and 2. No significant difference was observed in the renal arteriole wall compared with other donors of brain death and cardiac death. Two recipients who received kidney transplantation from the MFS patient suffered from postoperative delayed graft function. After short-term hemodialysis, the graft function of the recipients received the left and right kidney began to gradually recover at postoperative 10 d and 20 d. After discharge, serum creatinine level of the recipient received the left kidney was ranged from 80 to 90 μmol/L, whereas that of the recipient received the right kidney kept declining, and the lowest serum creatinine level was 232 μmol/L before the submission date (at postoperative 43 d). Through literature review, two cases successfully undergoing kidney transplantation from the same MFS donor were reported. Both two recipients experienced delayed graft function, and then renal function was restored to normal. Until the publication date, 1 recipient has survived for 6 years, and the other recipient died of de novo cerebrovascular disease at postoperative 2 years. Conclusions MFS patients may serve as an acceptable source of kidney donors. However, the willingness and general conditions of the recipients should be carefully evaluated before kidney transplantation. Intraoperatively, potential risk of tear of renal arterial media should be properly treated. Extensive attention should be paid to the incidence of postoperative complications.

8.
Lett Appl Microbiol ; 76(10)2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37833237

RESUMO

The occurrence of Giardia and Cryptosporidium (oo)cysts in drinking source water poses a serious public health risk. Here, we established a method that combines membrane concentration and real-time polymerase chain reaction (PCR) to quantify Giardia and Cryptosporidium in drinking water. The water samples were filtered through a cellulose membrane to collect Giardia and Cryptosporidium, and then nucleic acids were extracted. Specific primers and probes were designed and synthesized according to the gph gene sequence of Giardia and 18S rRNA gene sequence of Cryptosporidium. The concentrations of the two targets were determined using real-time PCR technology. The sensitivity, specificity, and stability of the method were evaluated. Our findings revealed that the detection limits of real-time PCR method for detecting Giardia and Cryptosporidium were 0.926 and 0.65 copy/µL, respectively; the spiked recovery rates were above 60% and 38%, respectively, and relative standard deviations were under 0.95% and 2.26%, respectively. Therefore, this effective procedure based on the membrane concentration method and real-time PCR will be useful for detecting Giardia and Cryptosporidium in drinking water for purpose of continuous environmental monitoring.


Assuntos
Criptosporidiose , Cryptosporidium , Água Potável , Humanos , Cryptosporidium/genética , Giardia/genética , Reação em Cadeia da Polimerase em Tempo Real
9.
iScience ; 26(10): 107742, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37731619

RESUMO

For mammals that originate in the cold north, adapting to warmer environments is crucial for southwards invasion. The brown rat (Rattus norvegicus) originated in Northeast China and has become a global pest. R. n. humiliatus (RNH) spread from the northeast, where R. n. caraco (RNC) lives, to North China and diverged to form a subspecies. Genomic analyses revealed that subspecies differentiation was promoted by temperature but impeded by gene flow and that genes related to fatty acid metabolism were under the strongest selection. Transcriptome analyses revealed downregulated hepatic genes related to fatty acid metabolism and upregulated those related to pheromones in RNH vs. RNC. Similar patterns were observed in relation to cold/warm acclimation. RNH preferred mates with stronger pheromone signals intra-populationally and more genetic divergence inter-populationally. We concluded that RNH experienced reduced fat utilization and increased pheromone-mediated sexual selection during its invasion from the cold north to warm south.

10.
Oncol Lett ; 26(4): 432, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37664649

RESUMO

Gastrointestinal (GI) cancers are the most common types of tumors worldwide. The lack of cancer biomarkers and targeted drug resistance are barriers to achieving effective cancer therapy. Low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane protein that has multiple functions due to its ability to recognize different ligands; however, the role of LRP1 in GI cancer cells remains unclear. The present study aimed to investigate the role of LRP1 in GI tumors. The Cancer Genome Atlas database was used to analyze the potential correlation between expression of LRP1 and prognosis in patients with GI cancer. Bioinformatics analysis was utilized and the expression of LRP1 was simultaneously validated in GI cancer at the cellular level through western blot experiments. LRP1 was expressed at high levels in HGC-27, HepG2 and BxPC-3 cells. LRP1 expression in GI cancer cells was knocked down using lentivirus-mediated shRNA and the effects on biological functions were observed. LRP1 knockdown suppressed the proliferation, invasion and migration of GI cancer cells. LRP1 knockdown inhibited CD36 gene expression in HepG2 and BxPC-3 cells. LRP1 knockdown inhibited the proliferation, invasion and migration of GI cancer cells, suggesting that LRP1 may be a novel target for treatment of GI tumors.

11.
Radiat Oncol ; 18(1): 129, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37542246

RESUMO

PURPOSE: In this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD. PATIENTS AND METHODS: Patients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman's rank test in the matched cohort to generate a nomogram. RESULTS: There were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82). CONCLUSIONS: The incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD.


Assuntos
Carcinoma Hepatocelular , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Receptor de Morte Celular Programada 1 , Pontuação de Propensão
12.
Curr Zool ; 69(2): 143-155, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37092005

RESUMO

Dominance relationships between males and their associated traits are usually heritable and have implications for sexual selection in animals. In particular, social dominance and its related male pheromones are heritable in inbred mice; thus, we wondered whether epigenetic changes due to altered levels of DNA methylation determine inheritance. Here, we used C57BL/6 male mice to establish a social dominance-subordination relationship through chronic dyadic encounters, and this relationship and pheromone covariation occurred in their offspring, indicative of heritability. Through transcriptome sequencing and whole-genome DNA methylation profiling of the sperm of both generations, we found that differential methylation of many genes was induced by social dominance-subordination in sires and could be passed on to the offspring. These methylated genes were mainly related to growth and development processes, neurodevelopment, and cellular transportation. The expression of the genes with similar functions in whole-genome methylation/bisulfite sequencing was also differentiated by social dominance-subordination, as revealed by RNA-seq. In particular, the gene Dennd1a, which regulates neural signaling, was differentially methylated and expressed in the sperm and medial prefrontal cortex in paired males before and after dominance-subordination establishment, suggesting the potential epigenetic control and inheritance of social dominance-related aggression. We suggest that social dominance might be passed on to male offspring through sperm DNA methylation and that the differences could potentially affect male competition in offspring by affecting the development of the nervous system.

13.
Zhongguo Zhong Yao Za Zhi ; 48(6): 1642-1651, 2023 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-37005852

RESUMO

The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and ß-boswellic acid(ß-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and ß-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and ß-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of ß-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of ß-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of ß-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of ß-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.


Assuntos
Medicamentos de Ervas Chinesas , Lesões Pré-Cancerosas , Triterpenos , Ratos , Animais , Cromatografia Líquida , Espectrometria de Massas em Tandem , Triterpenos/farmacologia
14.
Nat Plants ; 9(4): 605-615, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36928775

RESUMO

Axial chirality of biaryls can generate varied bioactivities. Gossypol is a binaphthyl compound made by cotton plants. Of its two axially chiral isomers, (-)-gossypol is the bioactive form in mammals and has antispermatogenic activity, and its accumulation in cotton seeds poses health concerns. Here we identified two extracellular dirigent proteins (DIRs) from Gossypium hirsutum, GhDIR5 and GhDIR6, which impart the hemigossypol oxidative coupling into (-)- and (+)-gossypol, respectively. To reduce cotton seed toxicity, we disrupted GhDIR5 by genome editing, which eliminated (-)-gossypol but had no effects on other phytoalexins, including (+)-gossypol, that provide pest resistance. Reciprocal mutagenesis identified three residues responsible for enantioselectivity. The (-)-gossypol-forming DIRs emerged later than their enantiocomplementary counterparts, from tandem gene duplications that occurred shortly after the cotton genus diverged. Our study offers insight into how plants control enantiomeric ratios and how to selectively modify the chemical spectra of cotton plants and thereby improve crop quality.


Assuntos
Gossipol , Animais , Gossipol/toxicidade , Gossipol/análise , Gossipol/química , Edição de Genes , Gossypium/genética , Gossypium/metabolismo , Sementes/metabolismo , Mamíferos/genética
15.
Radiat Oncol ; 18(1): 48, 2023 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-36890592

RESUMO

BACKGROUND: The incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child-Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability. METHODS: Seventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis. RESULTS: Among CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child-Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child-Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674-0.926). CONCLUSIONS: The incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Lesões por Radiação , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/complicações , Radioterapia de Intensidade Modulada/efeitos adversos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/complicações , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Transaminases , Dosagem Radioterapêutica
16.
Int Immunopharmacol ; 118: 110010, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36924563

RESUMO

We investigated whether human umbilical vein endothelial cells (HUVECs) under hypoxic conditions can suppress the production of cytokines in Hut-78 cells via the HIF-1α/PD-L1/PD-1 pathway, and the intervention effect of Nivolumab. HUVECs and HuT-78 cells were monocultured or cocultured in a tri-gas incubator with or without Nivolumab pretreatment. Real-time PCR, western blotting, and protein chips were used. Transcriptional regulation of PD-L1 and PD-1 by HIF-1α was analyzed by ChIP-qPCR and luciferase reporter gene assays. Apoptosis was assessed by flow cytometry. In HuT-78 cells, hypoxic monoculture significantly increased the expression of HIF-1α, PD-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-α, and Bax, decreased the expression of Bcl-2, and resulted in increased apoptosis. In comparison to hypoxic monoculture, hypoxic coculture significantly reduced the expression of IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, and IFN-α, as well as Bcl-2, in HuT-78 cells. Meanwhile, Bax expression was significantly increased with elevated apoptosis in HuT-78 cells. However, pretreatment with Nivolumab significantly antagonized the reduction in cytokines and the elevation in apoptosis in HuT-78 cells. Chip-qPCR and luciferase reporter gene assays demonstrated that hypoxia significantly increased the binding of HIF-1α to the upstream regulatory regions of PD-1 at -63 and -66 bp and PD-L1 at -571 bp, promoting their transcription. Therefore, HUVECs under hypoxia can reduce cytokine production and inhibit their own apoptosis in co-culture with HuT-78 cells via the HIF-1α/PD-L1/PD-1 pathway. These findings provide new clues for exploring the combined use of immune checkpoint inhibitors and anti-angiogenic drugs in clinical settings.


Assuntos
Interleucina-10 , Receptor de Morte Celular Programada 1 , Humanos , Células Endoteliais da Veia Umbilical Humana , Interleucina-10/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Interleucina-8/metabolismo , Nivolumabe , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose , Hipóxia Celular , Hipóxia/metabolismo , Luciferases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
17.
J Clin Transl Hepatol ; 11(2): 341-349, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-36643048

RESUMO

Background and Aims: The study aimed to create a new staging model for radiotherapy-based treatment for prognostic hepatocellular carcinoma (HCC) classification. Methods: The training cohort comprised 658 patients receiving stereotactic body radiotherapy and external validation cohort comprised 533 patients receiving three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. We established a modified staging system as follows: stage I, solitary nodule without macrovascular invasion, or 2-3 nodules no more than 3.0 cm apart, and performance status (PS) 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with any one nodule more than 3.0-cm apart, or ≥4 nodules, and performance status 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion, regional lymph node metastasis or distant metastasis, and performance status 0-2 (IIIa: ALBI-1 grade; IIIb: ALBI-2 grade); stage IV: performance status 3-4, or performance status 0-2 with ALBI-3 grade. We analyzed long-term overall survival based on different stages. Results: The staging model showed an excellent ability to discriminate patients according to four stages and seven substages with notably different curves in the training and validation cohort. The median survival decreased from stages I to IV with 63.0 months in stage I (not reached in Ia, and 53.0 months in Ib), 24.0 months in stage II (28.0 months in IIa, and 22.0 months in IIb), 11.0 months in stage III (18.0 months in IIIa, and 9.0 months in IIIb), and less than 9.0 months in stage IV in the training cohort. Conclusions: The modified staging model may provide an alternative for clinical radiation oncologists.

18.
Chinese Pharmacological Bulletin ; (12): 1815-1818, 2023.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1013957

RESUMO

Parkinson's disease (PD) is a kind of senile neurodegenerative disease. Dopaminergic drugs and anticholinergic drugs are the two major therapeutic drugs for PD. In the past several decades, great progress has been achieved on dopamines (DAs) and their synergists including monoamine oxidase B (MAO-B) inhibitors, catechol oxygen methyl transferase inhibitors, ergot and nonergot DA receptor agonists, DA precursor drugs, cannabis and isatin. Isatin is the inhibitor of endogenous specific anti-aging enzyme MAO-B, which has a variety of pharmacological activities. Moreover, the pharmacological mechanism of isatin may be associated with the regulatory functions of various protein activities.

19.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1006317

RESUMO

Objective To preliminarily compare 6LiF-7LiF and CR39 in individual neutron dose monitoring, and to provide a reference for improving individual neutron dose monitoring. Methods According to the GBZ 128-2019, 26 radiation workers from 7 institutions received individual neutron dose monitoring with 6LiF-7LiF and CR39 at the same time. The monitoring results were analyzed. Results For most of the workers, the personal neutron dose equivalent Hp(10) was less than the minimum detectable level. The results with the two monitoring methods differed in 6 of 26 workers. Conclusion Both 6LiF-7LiF and CR39 monitoring methods can be used for individual neutron dose monitoring for radiation workers, but the difference between 6LiF-7LiF and CR39 (in threshold energy, energy response, etc.) should be considered so that different types of radiation workers receive appropriate individual neutron dose monitoring.

20.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1003567

RESUMO

With the extensive use of neutron sources in industry, medicine, and scientific research, the number of people exposed to neutron has been increasing, which highlights the importance of personal neutron dose monitoring in the field of radiation protection. In the past decades, researchers have developed and improved a variety of techniques and methods for personal neutron dose monitoring. This paper focuses on the problems and research progress of track dosimeters (solid-state nuclear track dosimeters and fluorescent nuclear track dosimeters), luminescent dosimeters (thermoluminescent dosimeters and optically stimulated luminescent dosimeters), and bubble dosimeters in personal neutron dose monitoring.

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