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1.
Cancer Manag Res ; 14: 1663-1670, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547598

RESUMO

Aim: To study the impact of All-trans-retinoic acid (ATRA) plus FOLFOX4 compared to FOLFOX4 alone in patients with advanced hepatocellular carcinoma (HCC) with pulmonary metastasis. Methods: The data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, Zhejiang Sian International Hospital and Fujian Cancer Hospital were retrospectively analyzed. The survival outcomes in the 2 groups were compared. Results: From May 2014 to July 2020, 66 patients were suitable to enter into this study. The median survival (14.0 vs 8.0 months, p=0.012), and the median time to progression in the ATRA plus FOLFOX4 group were both significantly longer than those in the FOLFOX4 group (8.7 vs 3.2 months, p=0.002). The 6 month-, 1 year- and 2 year- overall survival rates were also significantly better in the ATRA plus FOLFOX4 group (100.0%, 64.7% and 20.5%; respectively) than the FOLFOX4 group (59.4%, 21.9%, and 12.5%, respectively; p<0.001). Leukocytopenia, fatigue, anorexia, nausea, were the most common acute toxicities, but these were mostly NCI CTCAE Grade 1 or 2. There was no significant difference in adverse events between the two groups. Conclusion: ATRA plus FOLFOX4 significantly improved the survival outcomes in patients with advanced HCC with pulmonary metastasis.

2.
Neurosci Bull ; 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35570233

RESUMO

Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties. It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere, consequently imposing devastating social, economic, and health burdens worldwide. However, the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown, and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce. This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action, including neural circuit dysfunction and neuroinflammation. We discuss recent progress in the development of pharmacological interventions, anti-fentanyl vaccines, anti-fentanyl/heroin conjugate vaccines, and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression. However, translational studies and clinical trials are still lacking. Considering the present opioid crisis, the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.

3.
Addiction ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35491750

RESUMO

BACKGROUND AND AIMS: Genomic and transcriptomic findings greatly broaden the biological knowledge regarding substance use. However, systematic convergence and comparison evidence of genome-wide findings is lacking for substance use. Here, we combined all the genome-wide findings from both substance use behavior and disorder (SUBD) and identified common and distinguishing genetic factors for different SUBDs. METHODS: Systemic literature search for genome-wide association (GWAS) and RNA-seq studies of alcohol/nicotine/drug use behavior (partially meets or not reported diagnostic criteria) and alcohol use behavior and disorder (AUBD), nicotine use behavior and disorder (NUBD) and drug use behavior and disorder (DUBD) was performed using PubMed and the GWAS catalog. Drug use was focused upon cannabis, opioid, cocaine and methamphetamine use. GWAS studies required case-control or case/cohort samples. RNA-seq studies were based on brain tissues. The genes which contained significant single nucleotide polymorphism (P ≤ 1 × 10-6 ) in GWAS and reported as significant in RNA-seq studies were extracted. Pathway enrichment was performed by using Metascape. Gene interaction networks were identified by using the Protein Interaction Network Analysis database. RESULTS: Total SUBD-related 2910 genes were extracted from 75 GWAS studies (2 773 889 participants) and 17 RNA-seq studies. By overlapping the genes and pathways of AUBD, NUBD and DUBD, four shared genes (CACNB2, GRIN2B, PLXDC2 and PKNOX2), four shared pathways [two Gene Ontology (GO) terms of 'modulation of chemical synaptic transmission', 'regulation of trans-synaptic signaling', two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of 'dopaminergic synapse', 'cocaine addiction'] were identified (significantly higher than random, P < 1 × 10-5 ). The top shared KEGG pathways (Benjamini-Hochberg-corrected P-value < 0.05) in the pairwise comparison of AUBD versus DUBD, NUBD versus DUBD, AUBD versus NUBD were 'Epstein-Barr virus infection', 'protein processing in endoplasmic reticulum' and 'neuroactive ligand-receptor interaction', respectively. We also identified substance-specific genetic factors: i.e. ADH1B and ALDH2 were unique for AUBD, while CHRNA3 and CHRNA4 were unique for NUBD. CONCLUSIONS: This systematic review identifies the shared and unique genes and pathways for alcohol, nicotine and drug use behaviors and disorders at the genome-wide level and highlights critical biological processes for the common and distinguishing vulnerability of substance use behaviors and disorders.

4.
Hematology ; 27(1): 530-534, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35544613

RESUMO

OBJECTIVES: The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation. METHODS: In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed. RESULTS: MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037). CONCLUSION: MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Doenças Mieloproliferativas-Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Prognóstico , Receptores de Trombopoetina/genética , Estudos Retrospectivos
5.
J Mater Chem B ; 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35537197

RESUMO

Cardiovascular diseases have become one of the leading causes of mortality worldwide. Stents and artificial grafts have been used to treat cardiovascular diseases. Thrombosis and restenosis seriously impact the clinical outcome of stents and artificial vascular grafts. For the purpose of antithrombosis and anti-restenosis, numerous strategies have been developed to construct highly hemocompatible surfaces, enhance endothelialization, and inhibit intimal hyperplasia. Rapid endothelialization and inhibited intimal hyperplasia play an important role in artery repair after stent implantation and coronary artery bypass graft surgery. This review focuses on the recently developed strategies for improving the hemocompatibility and endothelialization of cardiovascular devices. We also introduce drug, gene and RNA delivery technologies for inhibiting intimal hyperplasia. The challenges and future perspectives about promoting endothelialization are also briefly discussed with the hope to help inspire further innovations.

6.
Fish Shellfish Immunol ; 125: 212-219, 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35569778

RESUMO

Normal dissolved oxygen in water is essential for maintaining the physiological functions of fish, but environmental pollution, such as eutrophication can lead to a decrease in oxygen content in water. How this reduction of dissolved oxygen in water affects the immune functions of fish and the potential regulatory mechanisms have not been thoroughly elucidated. In this study, we made full use of the aquatic model animal zebrafish to explore this question. In a model of LPS-induced inflammation, we found that hypoxia induced by infusing nitrogen into water increased the expression of pro-inflammatory cytokines, such as il-1ß, il-6, and il-8. In vivo imaging also showed that hypoxia significantly increased neutrophil migration to the site of caudal fin injury in the transgenic line. Subsequently, we found that the phosphorylation level of ERK protein was significantly activated upon hypoxia and proved the roles of ERK signaling in the expression of pro-inflammatory cytokines and neutrophil migration in zebrafish. This study indicated that reduced water oxygen significantly increases the inflammatory response of the zebrafish.

7.
Front Chem ; 10: 877469, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35433627

RESUMO

The emergence of antibiotic resistance in Staphylococcus aureus has necessitated the development of innovative anti-infective agents acting on novel targets. Alpha-hemolysin (Hla), a key virulence factor of S. aureus, is known to cause various cell damage and death. In this study, with bioassay-guided fractionation, a pair of unusual epimeric lignan trimers, ligustchuanes A and B (1 and 2), were isolated from the rhizomes of Ligusticum chuanxiong Hort, together with two known phthalides being identified by UPLC-QTOF-MS. To the best of our knowledge, trimers with rare C8-C9″-type neolignan and ferulic acid fragments have not been identified in any natural product. Both of them were isolated as racemic mixtures, and their absolute configurations were determined by comparing experimental and calculated ECD spectra after enantioseparation. Ligustchuane B exhibited an outstanding inhibitory effect on α-hemolysin expression in both MRSA USA300 LAC and MSSA Newman strains at concentrations of 3 and 6 µM, respectively. Notably, a mouse model of infection further demonstrated that ligustchuane B could attenuate MRSA virulence in vivo.

8.
Oncogenesis ; 11(1): 16, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418575

RESUMO

Alginate oligosaccharide (AOS) has the function to inhibit tumor progression and the sulfated modification can enhance the antitumor activity. To date, the function and mechanism of sulfated AOS (AOS-SO4) in tumors remain largely elusive. We prepared AOS by the enzymatic degradation of alginate, collected AOS-SO4 by sulfating following the canonical procedure. Using these materials, in vitro assays showed that both AOS and AOS-SO4 elicited antitumor effects in osteosarcoma cells. Sulfated modification significantly enhanced the antitumor activity. In addition, AOS-SO4 had obvious effects on cell cycle arrest, apoptosis, and autophagy induction in vitro and in vivo. Mechanistically, we observed that AOS-SO4 treatment triggered proapoptotic autophagy by inhibiting MEK1/ERK/mTOR signaling. The ERK activator reversed AOS-SO4-induced autophagy. More importantly, we found that KSR1 interacted with MEK1 and functioned as a positive regulator of MEK1 protein in osteosarcoma cells. High KSR1 expression was significantly associated with poor survival in osteosarcoma patients. Together, these results suggest that AOS-SO4 has a better antitumor effect in osteosarcoma by inhibiting MEK1/ERK/mTOR signaling, which is KSR1-dependent; thus, AOS-SO4 can be a new potential therapeutic candidate for the treatment of osteosarcoma.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(2): 539-542, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35395993

RESUMO

OBJECTIVE: To investigate the difference of therapeutic effects on children with thalassemia at different age after hematopoietic stem cell transplantation. METHODS: The clinical data of children with thalassemia treated in our hospital were retrospectively analyzed. The children were divided into 2-5 years old group and 6-12 years old group. The success rate of implantation, transplant-related mortality, GVHD incidence, and other transplant-related complications, as well as thalassemia-free survival (TFS) were compared between the two groups. RESULTS: The incidence of GVHD, hemorrhagic cystitis and severe oral mucositis after transplantation in the 2-5 years old group were significantly lower than those in the 6-12 years old group, while there was no statistically significant difference in the TFS between the two groups. CONCLUSION: Children in the low age (2-5 years old) group show fewer complications and higher quality of life after transplantation, therefore, stem cell transplantation at 2-5 years old is more conducive to rehabilitation of the children with thalassemia.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Talassemia , Talassemia beta , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/complicações , Humanos , Qualidade de Vida , Estudos Retrospectivos , Talassemia/terapia , Talassemia beta/terapia
10.
Front Psychiatry ; 13: 874090, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401246

RESUMO

Introduction: Autism spectrum disorder (ASD) is a lifelong condition. Autistic symptoms can persist into adulthood. Studies have reported that autistic symptoms generally improved in adulthood, especially restricted and repetitive behaviors and interests (RRBIs). We explored brain networks that are related to differences in RRBIs in individuals with ASDs among different ages. Methods: We enrolled 147 ASD patients from the Autism Brain Imaging Data Exchange II (ABIDEII) database. The participants were divided into four age groups: children (6-9 years old), younger adolescents (10-14 years old), older adolescents (15-19 years old), and adults (≥20 years old). RRBIs were evaluated using the Repetitive Behaviors Scale-Revised 6. We first explored differences in RRBIs between age groups using the Kruskal-Wallis test. Associations between improvements in RRBIs and age were analyzed using a general linear model. We then analyzed RRBIs associated functional connectivity (FC) links using the network-based statistic method by adjusting covariates. The association of the identified FC with age group, and mediation function of the FC on the association of age-group and RRBI were further analyzed. Results: Most subtypes of RRBIs improved with age, especially stereotyped behaviors, ritualistic behaviors, and restricted behaviors (p = 0.012, 0.014, and 0.012, respectively). Results showed that 12 FC links were closely related to overall RRBIs, 17 FC links were related to stereotyped behaviors. Among the identified 29 FC links, 15 were negatively related to age-groups. The mostly reported core brain regions included superior occipital gyrus, insula, rolandic operculum, angular, caudate, and cingulum. The decrease in FC between the left superior occipital lobe and right angular (effect = -0.125 and -0.693, respectively) and between the left insula and left caudate (effect = -0.116 and -0.664, respectively) might contribute to improvements in multiple RRBIs with age. Conclusion: We identified improvements in RRBIs with age in ASD patients, especially stereotyped behaviors, ritualistic behaviors, and restricted behaviors. The decrease in FC between left superior occipital lobe and right angular and between left insula and left caudate might contribute to these improvements. Our findings improve our understanding of the pathogenesis of RRBIs and suggest potential intervention targets to improve prognosis in adulthood.

11.
Sci Total Environ ; 831: 154924, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35364178

RESUMO

Rainwater harvesting (RWH) projects in a decentralized way are significant measures to deal with the water scarcity dilemma in rural areas of the karst mountains in Southwest China at present. Due to the differences in cistern construction features and geomorphological positions, the water sources of cisterns were characterized by marked spatial variability, and the recharge stability of cisterns was strongly influenced by precipitation seasonality. Nevertheless, in hydrological processes on karst hillsides, the identification of different runoff types of RWH has not been sufficiently studied. The stable isotopes of hydrogen and oxygen of eleven cisterns and epikarst springs in subtropic cockpit karst landforms were monitored from 2020 to 2021 to investigate the runoff characteristics in RWH. Evaporative fractionation in different hydrological cycles is the predominant factor regulating the stable isotopic signature of cistern water. The results indicated that the typical roles that occurred in the recharge process contributed differently to water harvesting, with surface runoff (SR) and subsurface runoff (SSR) contributing much more than rainwater (RW) and epikarst runoff (ER). Three mixing patterns were proposed by end-member analysis in which SR + SSR, ER, and RW were three end members with indicators of isotopic value and the total dissolved solids (TDS). The recharge of SR + SSR was the predominated source, which contributed to 64% of the total water resources collected through RWH in the rainy season. In addition, the influence of various runoffs on the recharge stability of the cistern can be reflected by the multiple statistical analysis of isotopic fluctuation. Poor recharge stability is caused by excessive SR + SSR, whereas a higher percentage of ER and RW leads to better recharge stability. The applied method of hydrological process analysis is significant to the cistern water resources management in rural areas of the karst mountains.

12.
Foods ; 11(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35406990

RESUMO

This study aimed to compare ozone-microbubble-washing (OM) performed by domestic equipment with conventional water-washing (CW) regarding resultant quality attributes of muscle foods. For this purpose, muscle microstructure and lipid and protein oxidation were evaluated in pork and fish samples after OM and CW treatments. The assessment of muscle microstructure showed that OM treatment did not damage the microstructure of muscle fibers in both pork and fish samples. Thiobarbituric acid reactive substances (TBARS) values were not detected in both treatment groups, and they were substantially below the generally acceptable threshold (1 mg MDA/kg). The methylglyoxal (MGO) level of OM-treated fish samples was significantly higher than that of CW-treated fish samples. However, glyoxal (GO) and MGO levels of OM-treated pork samples were significantly lower than that of CW-treated pork samples. Similar types and sites of oxidative modification and similar numbers of modified peptides, as well as no significant difference in the concentration of total and most of the free amino acids (FAA) between treatment groups, indicated that OM treatment did not accelerate protein oxidation.

13.
Metab Brain Dis ; 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35420377

RESUMO

Vascular dementia (VaD) is the second cause of dementia after Alzheimer's disease. Ligustilide (LIG) is one of the main active ingredients of traditional Chinese medicines, such as Angelica. Studies have reported that LIG could protect against VaD. However, the mechanism is still confused. In this study, we employed a bilateral common carotid artery occlusion rat model to study. LIG (20 or 40 mg/kg/day) and Nimodipine (20 mg/kg) were orally administered to the VaD rats for four weeks. Morris water maze test showed that LIG effectively ameliorated learning and memory impairment in VaD rats. LIG obviously reduced neuronal oxidative stress damage and the level of homocysteine in the brain of VaD rats. Western blot results showed that pro-apoptotic protein Bax and cleaved caspase 3 increased and anti-apoptotic protein Bcl-2 decreased in the hippocampi of VaD rats. But after LIG treatment, these changes were reversed. Moreover, Nissl staining result showed that LIG could reduce neuronal degeneration in VaD rats. Furthermore, LIG enhanced the expressions of P-AMPK and Sirtuin1(SIRT1) in VaD rats. In conclusion, these studies indicated that LIG could ameliorate cognitive impairment in VaD rats, which might be related to AMPK/SIRT1 pathway activation.

14.
Vaccine ; 40(22): 3046-3054, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35450782

RESUMO

BACKGROUND: Vaccination is an important preventive measure against the coronavirus disease 19 (COVID-19) pandemic. We aimed to examine the willingness to vaccination and influencing factors among college students in China. METHODS: From March 18 to April 26, 2021, we conducted a cross-sectional online survey among college students from 30 universities in Wuhan, Hubei Province, China. The survey was composed of the sociodemographic information, psychological status, experience during pandemic, the willingness of vaccination and related information. Students' attitudes towards vaccination were classified as 'vaccine acceptance', 'vaccine hesitancy', and 'vaccine resistance'. Multinomial logistic regression analyses were performed to identify the influencing factors associated with vaccine hesitancy and resistance. RESULTS: Among 23,143 students who completed the survey, a total of 22,660 participants were included in the final analysis with an effective rate of 97.9% after excluding invalid questionnaires. A total of 60.6% of participants would be willing to receive COVID-19 vaccine, 33.4% were hesitant to vaccination, and 6.0% were resistant to vaccination. Social media platforms and government agencies were the main sources of information vaccination. Worry about the efficacy and adverse effects of vaccine were the top two common reason of vaccine hesitancy and resistance. Multiple multinomial logistic regression analysis identified that participants who worried about the adverse effects of vaccination were more likely to be vaccine hesitancy (aOR = 2.44, 95% CI = 2.30, 2.58) and resistance (aOR = 2.71, 95% CI = 2.40, 3.05). CONCLUSION: More than half of college students are willing to receive the COVID-19 vaccine, whereas nearly one-third college students are still hesitant or resistant. It is crucial to provide sufficient and scientific information on the efficacy and safety of vaccine through social media and government agencies platforms to promote vaccine progress against COVID-19 and control the pandemic in China.


Assuntos
COVID-19 , Vacinas , COVID-19/prevenção & controle , Vacinas contra COVID-19 , China , Estudos Transversais , Humanos , SARS-CoV-2 , Estudantes , Vacinação
15.
Thromb Res ; 214: 8-15, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35421682

RESUMO

INTRODUCTION: Excessive activation of the coagulation cascades leads to life-threatening disseminated intravascular coagulation (DIC) in sepsis. Two recent studies by our group and others have both demonstrated the noncanonical inflammasome is pivotal for the endotoxin or gram-negative bacterial-induced coagulation. Based on this, we further evaluated the function of the NLRP3 inflammasome, the most studied inflammasome, in endotoxin-induced coagulation. MATERIALS AND METHODS: We established an endotoxin-induced coagulation model by intraperitoneal injection of sublethal doses of LPS in mice. Mice were sacrificed 8 h after injection and blood was collected for thrombin-antithrombin (TAT), plasminogen activator inhibitor-1 (PAI-1), prothrombin time (PT), D-dimer, IL-1ß and tissue factor (TF) measurements by commercial ELISA. Lungs and livers were examined via HE staining images to determine injury scores and immunohistochemistry for TF expression and fibrin deposits. The role of NLRP3 activation was evaluated in wild-type (WT), Nlrp3-/-, Asc-/- (apoptosis-associated speck-like protein containing a CARD), Caspase-11-/- mice and 30 min after treatment with MCC950, a potent inhibitor of NLRP3. Western blotting and Q-PCR were performed to assess TF expression in the lungs and livers. To uncover the different effects of NLRP3 and Caspase-11, we also compared the time-dependent IL-1ß release in LPS-treated Nlrp3-/- and Caspase-11-/- mice. Correlation analysis of TAT, PAI-1 were estimated the relationship of coagulation and release of IL-1ß, as well as IL-1ß and TF. RESULTS: Inhibition of NLRP3 by MCC950 as well as NLRP3 or ASC deficiency decreased TAT, PAI-1, PT, D-dimer, and TF levels in blood and impaired the thrombus formation and fibrin deposition, as well as declined expression of TF in the liver and lung in endotoxin-induced coagulation but not caspase-11 deficiency. Impressively, IL-1ß release is increased in LPS-treated Caspase-11-/- mice, but not in Nlrp3-/- mice. Moreover, the correlation analysis is indicated that downstream of the NLRP3 inflammasome, IL-1ß expression, is positively correlated with TAT, PAI-1 and TF in blood circulation. CONCLUSIONS: The NLRP3 inflammasome contributes to endotoxin-induced coagulation by promoting TF expression at least in part through the induction of IL-1ß release. These findings broadened our understanding of the mechanism of coagulation and implicated a possible therapeutic strategy for preventing coagulation in sepsis.


Assuntos
Inflamassomos , Sepse , Animais , Caspases , Endotoxinas , Fibrina , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inibidor 1 de Ativador de Plasminogênio
16.
Nat Commun ; 13(1): 1700, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361799

RESUMO

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.


Assuntos
Endopeptidases , Complexos Endossomais de Distribuição Requeridos para Transporte , Imunoterapia , Neoplasias , Microambiente Tumoral , Ubiquitina Tiolesterase , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Endopeptidases/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética
17.
Molecules ; 27(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35408754

RESUMO

Functional nanoprobes which detect specific food hazards quickly and simply are still in high demand in the field of food-safety inspection research. In the present work, a dual-emission metal-organic framework-based ratiometric fluorescence probe was integrated to detect Cu2+ and Pb2+ with rapidness and ease. Specifically, quantum dots (QDs) and carbon quantum dots (CQDs) were successfully embedded into zeolitic imidazolate framework-67 (ZIF-67) to function as a novel ratiometric fluorescent sensing composite. The ratiometric fluorescence signal of CQDs/QDs@ZIF-67 was significantly aligned with the concentration of metal ions to give an extremely low detection limit of 0.3324 nM. The highly sensitive and selective CQDs/QDs@ZIF-67 composite showed potential for the rapid and cost-effective detection of two metal ions.


Assuntos
Estruturas Metalorgânicas , Pontos Quânticos , Carbono , Corantes Fluorescentes , Íons , Limite de Detecção
18.
Artigo em Inglês | MEDLINE | ID: mdl-35471760

RESUMO

In this study, we examined the sources and temporal variability of 16 polycyclic aromatic hydrocarbons (PAHs) found in fine particulate matter (PM2.5) in a typical industrial city in northern China. We also evaluated the incremental lifetime cancer risk (ILCR) from the inhalation of these PAHs. Atmospheric PM2.5 samples were collected for 7 consecutive days each month from 2014 to 2019, and the 16 PAHs were measured using multiplex gas chromatography-tandem mass spectrometry. The carcinogenic risk of PAH exposure was assessed using the inhalation unit risk (IUR) and cancer slope factor (CSF) methods. The annual average concentrations of PM2.5 for each year from 2014 to 2019 were 102.87±55.25, 86.92±60.43, 69.17±37.74, 58.20±59.15, 56.01±34.52, and 52.54±58.15 µg m-3, and the annual average ΣPAH concentrations were 56.03±81.09, 47.99±79.30, 40.41±57.31, 33.57±51.79, 43.23±74.80, and 25.20±50.91 ng m-3, respectively. Source identification, using diagnostic ratio analysis, indicated that the major PAH sources were coal/biomass combustion, fuel combustion, and traffic emissions. A health risk assessment showed that the ILCR from PAH inhalation decreased throughout the study period and varied with age. The IUR and CSF methods both showed that the adult ILCR exceeded 1.0×10-6. These findings demonstrate the importance of addressing the carcinogenic risk of PM2.5-bound PAHs, particularly in adults.

19.
Food Funct ; 13(9): 5050-5060, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35403637

RESUMO

Due to the rapid evolution of antibiotic resistance in Staphylococcus aureus, antivirulence therapy may be a promising alternative for the effective control of the spread of resistant pathogens. The Chinese Materia Medica has been widely used for the treatment of diseases and production of health foods, and it remains a valuable resource for the discovery of compounds possessing antivirulence activity. Through a Caenorhabditis elegans infection model, an EtOAc-soluble fraction of 80% EtOH extract of Salvia miltiorrhiza Bunge (SMEA) was found to possess potential anti-infective activity against S. aureus. Then, several in vitro assays indicated that SMEA had robust antivirulence activity at the dose of 400 µg mL-1, reducing hemolytic activity and α-hemolysin expression in S. aureus. Furthermore, at 100 mg kg-1, SMEA reduced abscess formation in the main organs of mice challenged with S. aureus. In order to identify the bioactive components of SMEA and investigate the mechanisms underlying the antivirulence activity, SMEA was separated using bioassay-guided fractionation. As a result, eight compounds were identified in SMEA. Among them, tanshinone IIB (TNB) showed strong antivirulence activity both in vitro and in vivo. Furthermore, at 24 µg mL-1, TNB significantly reduced the expression of RNAIII and psmα, indicating that the mechanism underlying TNB activity was related to the accessory gene regulator quorum sensing system. In conclusion, TNB's antivirulence properties make it a promising candidate for drug development against S. aureus infections.


Assuntos
Anti-Infecciosos , Salvia miltiorrhiza , Infecções Estafilocócicas , Animais , Antibacterianos/metabolismo , Anti-Infecciosos/farmacologia , Camundongos , Percepção de Quorum , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Virulência
20.
Artigo em Inglês | MEDLINE | ID: mdl-35410587

RESUMO

In this paper, the interacting characteristics of febuxostat (FBST), an inhibitor of xanthine oxidase for treating gout patients with hyperuricemia with calf thymus DNA (ctDNA) was investigated through multi-spectroscopic methodologies combined with theoretical calculation for understanding the interacting mode on ctDNA, affinity with ctDNA, interacting forces, as well as the alteration in the conformation of ctDNA after interacting FBST The experimental results demonstrated that interacting FBST with ctDNA formed 1:1 complex, the association constant was 913 M-1 at 298 K, suggesting the affinity of FBST on ctDNA was very weak, the interacting mode of FBST on ctDNA was groove binding, and it inserted into the minor groove with rich A-T region of ctDNA. Based on the results of the thermodynamic analysis and theoretical calculation, it can be inferred that the dominated interacting forces between FBST and ctDNA were van der Waals forces and hydrogen bond. And, interacting FBST with ctDNA was a spontaneous, enthalpy-driven, and exothermic process because of ΔG0 < 0, ΔH0 < 0, and |ΔH0| > T|ΔS0|. The results of the circular dichroism (CD) measurements indicated the conformation of ctDNA was weakly disturbed after interacting with FBST but still maintained B-conform. The studied results offer significant insight into further clarifying whether it has genotoxicity.

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