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1.
Front Microbiol ; 14: 1160631, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37125154

RESUMO

Interactions between plants and arbuscular mycorrhizal fungi (AMF) are strongly affected by soil phosphorus (P) availability. However, how P forms impact rhizosphere AMF diversity, community composition, and the co-occurrence network associated with native and invasive plants, and whether these changes in turn influence the invasiveness of alien species remain unclear. In this work, we performed a greenhouse experiment with the invasive species Solidago canadensis and its native congener S. decurrens to investigate how different forms of P altered the AMF community and evaluate how these changes were linked with the growth advantage of S. canadensis relative to S. decurrens. Plants were subjected to five different P treatments: no P addition (control), simple inorganic P (sodium dihydrogen phosphate, NaP), complex inorganic P (hydroxyapatite, CaP), simple organic P (adenosine monophosphate, AMP) and complex organic P (myo-inositol hexakisphosphate, PA). Overall, invasive S. canadensis grew larger than native S. decurrens across all P treatments, and this growth advantage was strengthened when these species were grown in CaP and AMP treatments. The two Solidago species harbored divergent AMF communities, and soil P treatments significantly shifted AMF community composition. In particular, the differences in AMF diversity, community composition, topological features and keystone taxa of the co-occurrence networks between S. canadensis and S. decurrens were amplified when the dominant form of soil P was altered. Despite significant correlations between AMF alpha diversity, community structure, co-occurrence network composition and plant performance, we found that alpha diversity and keystone taxa of the AMF co-occurrence networks were the primary factors influencing plant growth and the growth advantage of invasive S. canadensis between soil P treatments. These results suggest that AMF could confer invasive plants with greater advantages over native congeners, depending on the forms of P in the soil, and emphasize the important roles of multiple AMF traits in plant invasion.

2.
Cell Rep ; 42(5): 112469, 2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37141094

RESUMO

Recent studies have highlighted the importance of understanding the architecture and function of microvasculature, and dysfunction of these microvessels may underlie neurodegenerative disease. Here, we utilize a high-precision ultrafast laser-induced photothrombosis (PLP) method to occlude single capillaries and then quantitatively study the effects on vasodynamics and surrounding neurons. Analysis of the microvascular architecture and hemodynamics after single-capillary occlusion reveals distinct changes upstream vs. downstream branches, which shows rapid regional flow redistribution and local downstream blood-brain barrier (BBB) leakage. Focal ischemia via capillary occlusions surrounding labeled target neurons induces dramatic and rapid lamina-specific changes in neuronal dendritic architecture. Further, we find that micro-occlusion at two different depths within the same vascular arbor results in distinct effects on flow profiles in layers 2/3 vs layer 4. The current results reveal laminar-scale regulation distinctions in microinfarct response and raise the possibility that relatively greater impacts on microvascular function contribute to cognitive decline in neurodegenerative disease.

3.
Infect Drug Resist ; 16: 2311-2320, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37155474

RESUMO

Purpose: We attempted to establish a model for predicting the mortality risk of sepsis patients during hospitalization. Patients and Methods: Data on patients with sepsis were collected from a clinical record mining database, who were hospitalized at the Affiliated Dongyang Hospital of Wenzhou Medical University between January 2013 and August 2022. These included patients were divided into modeling and validation groups. In the modeling group, the independent risk factors of death during hospitalization were determined using univariate and multi-variate regression analyses. After stepwise regression analysis (both directions), a nomogram was drawn. The discrimination ability of the model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and the GiViTI calibration chart assessed the model calibration. The Decline Curve Analysis (DCA) was performed to evaluate the clinical effectiveness of the prediction model. Among the validation group, the logistic regression model was compared to the models established by the SOFA scoring system, random forest method, and stacking method. Results: A total of 1740 subjects were included in this study, 1218 in the modeling population and 522 in the validation population. The results revealed that serum cholinesterase, total bilirubin, respiratory failure, lactic acid, creatinine, and pro-brain natriuretic peptide were the independent risk factors of death. The AUC values in the modeling group and validation group were 0.847 and 0.826. The P values of calibration charts in the two population sets were 0.838 and 0.771. The DCA curves were above the two extreme curves. Moreover, the AUC values of the models established by the SOFA scoring system, random forest method, and stacking method in the validation group were 0.777, 0.827, and 0.832, respectively. Conclusion: The nomogram model established by combining multiple risk factors could effectively predict the mortality risk of sepsis patients during hospitalization.

4.
Sci Total Environ ; 885: 163854, 2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37142009

RESUMO

Uncovering the mechanisms driving patterns of diversity across space and through time is of critical importance in microbial community ecology. Previous studies suggest that microorganisms also follow the same spatial scaling patterns as macro-organisms. However, it remains unclear whether different microbial functional groups differ in spatial scaling and how different ecological processes may contribute to such differences. In this study, two typical spatial scaling patterns, taxa-area (TAR) and distance-decay relationships (DDR), were investigated for the whole prokaryotic community and seven microbial functional groups using marker genes, including amoA (AOA), amoA (AOB), aprA, dsrB, mcrA, nifH and nirS. Different microbial functional groups harbored different spatial scaling patterns. Microbial functional groups had weaker TAR slope coefficients than the whole prokaryotic community. The archaeal ammonia-oxidizing group, however, displayed a stronger DDR pattern than the bacterial ammonia-oxidizing group. For both TAR and DDR, rare subcommunities were mainly responsible for the observed microbial spatial scaling patterns. Significant associations between environmental heterogeneity and spatial scaling metrics were observed for multiple microbial functional groups. Dispersal limitation, which positively correlated with phylogenetic breadth, was also strongly associated with the strength of microbial spatial scaling. The results demonstrated that environmental heterogeneity and dispersal limitation simultaneously contributed to microbial spatial scaling patterns. This study links microbial spatial scaling patterns with ecological processes, providing mechanistic insights into the typical diversity patterns followed by microbes.

5.
J Colloid Interface Sci ; 646: 597-605, 2023 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-37210907

RESUMO

Herein, selenium (Se)-doped MoS1.5Se0.5@VS2 nanosheets aggregated nano-roses were successfully prepared from a simple hydrothermal process and the subsequent selenium doping process. The hetero-interfaces between MoS1.5Se0.5 and VS2 phase can effectively promote the charge transfer. Meanwhile, the different redox potentials of MoS1.5Se0.5 and VS2 alleviate volume expansion during the repeated sodiation/desodiation processes, which improves the electrochemical reaction kinetics and structural stability of electrode material. Besides, Se doping can induce charge reconstruction and improve the conductivity of electrode materials, resulting in improved diffusion reaction kinetics by expanding interlayer spacing and exposing more active sites. When used as anode material for sodium ion batteries (SIBs), the MoS1.5Se0.5@VS2 heterostructure exhibits excellent rate capability and long-term cycling stability with the capacity of 533.9 mAh g-1 at 0.5 A g-1 and a reversible capacity of 424.5 mAh g-1 after 1000 cycles at 5 A g-1, demonstrating potential application as anode material for SIBs.

6.
Chem Commun (Camb) ; 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37183637

RESUMO

An efficient approach for the direct synthesis of alkylated 4-hydroxycoumarin derivatives via a Cu-catalyzed cascade dehydrogenation/conjugate addition sequence starting from simple saturated ketones and 4-hydroxycoumarins has been developed. This protocol features excellent functional-group tolerance, easy scale-up, and a broad substrate scope including bioactive molecules. More importantly, a series of marketed drugs, such as warfarin, acenocoumarol, coumachlor, and coumafuryl, can be obtained by this method.

7.
Chronobiol Int ; : 1-7, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37183834

RESUMO

The effects of the moon on mental activities remain contentious. Few studies have investigated associations between lunar phases and different types of bipolar disorder (BD) episodes. In the current study, 7,452 patients with BD from three hospitals were enrolled. Patients were divided into two groups on the basis of episode types, and the effects of lunar phase were examined for each type. The cosinor analysis revealed moon-related rhythmicity in admissions for BD in a period of 14.75 days. There were fewer admissions around the new moon and the full moon. There was no significant difference between different groups in acrophase. There was possibly a temporal lag between the onset of BD and hospitalization. Thus, it is too early to draw firm conclusions about the impact of lunar phases on BD. Sleep might be a middle way from moon effect to admissions of BD. These results have implications for future disease prevention strategies and research.

8.
Spectrochim Acta A Mol Biomol Spectrosc ; 298: 122759, 2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37119635

RESUMO

In this work, we investigated the potential UV protection mechanism of the natural compounds hydroxy resveratrol and pterostilbene by combining theoretical calculations and femtosecond transient absorption spectra (FTAS). The UV absorption spectra showed that the two compounds exhibited strong absorption properties and high photostability. We found two molecules will reach the S1 state or an even higher excited state after UV exposure and molecules in S1 will cross a lower energy barrier to reach the conical intersection. The adiabatic trans-cis isomerization process happened and finally return to the ground. Meanwhile, FTAS clarified the time scale of trans-cis isomerization of two molecules was âˆ¼ 10 ps, which also met the requirement of fast energy relaxation. This work also provides theoretical guidance for developing new sunscreen molecules from natural stilbene.

9.
Life (Basel) ; 13(4)2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37109514

RESUMO

DSPAα1 is a potent rude thrombolytic protein with high medicative value. DSPAα1 has two natural N-glycan sites (N153Q-S154-S155, N398Q-K399-T400) that may lead to immune responses when administered in vivo. We aimed to study the effect of its N-glycosylation sites on DSPAα1 in vitro and in vivo by mutating these N-glycosylation sites. In this experiment, four single mutants and one double mutant were predicted and expressed in Pichia pastoris. When the N398Q-K399-T400 site was mutated, the fibrinolytic activity of the mutant was reduced by 75%. When the N153Q-S154-S155 sites were inactivated as described above, the plasminogen activating activity of its mutant was reduced by 40%, and fibrin selectivity was significantly reduced by 21-fold. The introduction of N-glycosylation on N184-G185-A186T and K368N-S369-S370 also considerably reduced the activity and fibrin selectivity of DSPAα1. The pH tolerance and thermotolerance of all mutants did not change significantly. In vivo experiments also confirmed that N-glycosylation mutations can reduce the safety of DSPAα1, lead to prolonged bleeding time, non-physiological reduction of coagulation factor (α2-AP, PAI) concentration, and increase the risk of irregular bleeding. This study ultimately demonstrated the effect of N-glycosylation mutations on the activity and safety of DSPAα1.

10.
J Am Chem Soc ; 145(16): 9334-9342, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37068218

RESUMO

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas/patologia , Genes myc
11.
Artigo em Inglês | MEDLINE | ID: mdl-37032411

RESUMO

Evaluating efficacy of probiotics combined with prebiotics in small intestinal bacterial overgrowth (SIBO) in subclinical hypothyroidism (SCH) in the second trimester. We collected data from 78 pregnant women with SCH (SCH group) and 74 normal pregnant women (control group) in second trimester, compare the differences in high sensitivity C-reactive protein (hsCRP), result of lactulose methane-hydrogen breath test and gastrointestinal symptoms assessed by GSRS scale between two groups. In SCH group, 32 patients with SIBO were selected as intervention group. Treatment with probiotics + prebiotics for 21 days; The differences of lipid metabolism, hsCRP, thyroid function level, methane-hydrogen breath test results and GSRS scores before and after treatment were compared to evaluate the therapeutic effect. (1) The positive rate of SIBO and methane, hsCRP levels in SCH group were higher than those in control group (P < 0.05), the total score of GSRS scale, mean score of indigestion syndrome, and constipation syndrome in SCH group were higher (P < 0.05). (2) The mean abundance of hydrogen and methane were higher in SCH group. (3) After treatment, serum levels of thyrotropin(TSH), total cholesterol(TC), triglyceride(TG), low-density lipoprotein (LDL), and hsCRP in intervention group were decreased, and high-density lipoprotein (HDL) was increased compared with before treatment (P < 0.05). (4) After treatment, methane positive rate, total score of GSRS scale, mean score of diarrhea syndrome, dyspepsia syndrome, and constipation syndrome were decreased (P < 0.05). (5) The average abundance of methane and hydrogen were lower. Probiotics combined with prebiotics are effective in the treatment of SIBO in pregnant SCH patients.Clinical Trial Registration Number: ChiCTR1900026326.

12.
Acta Biochim Biophys Sin (Shanghai) ; 55(4): 683-690, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37097058

RESUMO

MgtE is a Mg 2+-selective channel regulated by the intracellular Mg 2+ concentration. MgtE family proteins are highly conserved in all domains of life and contribute to cellular Mg 2+ homeostasis. In humans, mutations in the SLC41 proteins, the eukaryotic counterparts of the bacterial MgtE, are known to be associated with various diseases. The first MgtE structure from a thermophilic bacterium, Thermus thermophilus, revealed that MgtE forms a homodimer consisting of transmembrane and cytoplasmic domains with a plug helix connecting the two and that the cytoplasmic domain possesses multiple Mg 2+ binding sites. Structural and electrophysiological analyses revealed that the dissociation of Mg 2+ ions from the cytoplasmic domain induces structural changes in the cytoplasmic domain, leading to channel opening. Thus, previous works showed the importance of MgtE cytoplasmic Mg 2+ binding sites. Nevertheless, due to the limited structural information on MgtE from different species, the conservation and diversity of the cytoplasmic Mg 2+ binding site in MgtE family proteins remain unclear. Here, we report crystal structures of the Mg 2+-bound MgtE cytoplasmic domains from two different bacterial species, Chryseobacterium hispalense and Clostridiales bacterium, and identify multiple Mg 2+ binding sites, including ones that were not observed in the previous MgtE structure. These structures reveal the conservation and diversity of the cytoplasmic Mg 2+ binding site in the MgtE family proteins.


Assuntos
Antiporters , Proteínas de Bactérias , Humanos , Antiporters/química , Antiporters/genética , Antiporters/metabolismo , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Modelos Moleculares , Raios X , Thermus thermophilus
13.
Bioorg Chem ; 135: 106505, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37027950

RESUMO

In this study, a series of novel oxazol-5-one derivatives containing a chiral trifluoromethyl and isoxazole moiety were synthesized and evaluated for cytotoxic activities. Among them, 5t was the most effective compound against HepG2 liver cancer cells with an IC50 of 1.8 µM. 5t inhibited cell proliferation, migration, invasion, and induced cell cycle arrest and apoptosis in vitro. Nevertheless, the potential anti-hepatocellular carcinoma (HCC) target and mechanism of 5t were unclear. This work aimed to seek the molecular target of 5t against HCC and investigate its mechanism. Liquid chromatography tandem-mass spectrometry was used to identify peroxiredoxin 1(PRDX1) as a possible target of 5t. Cellular thermal shift assay, drug affinity responsive target stability, and molecular docking provided conclusive evidence that 5t targeted PRDX1 and inhibited its enzymatic activity. 5t augmented the level of reactive oxygen species (ROS) and led to ROS-dependent DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in HepG2 cells. Silencing PRDX1 also resulted in ROS-mediated apoptosis in HepG2 cells. In vivo, 5t inhibited mouse tumor growth by increasing oxidative stress. Briefly, our studies revealed that compound 5t targeted PRDX1 through a ROS-dependent mechanism, highlighting the future development of compound 5t as a novel therapeutic drug for HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Simulação de Acoplamento Molecular , Antineoplásicos/química , Apoptose , Proliferação de Células , Linhagem Celular Tumoral
14.
Curr Drug Targets ; 2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-36998143

RESUMO

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint inhibitors have been on the front line of clinical revolution in which, the targeted PD-L1 therapy has obtained some success in patients with solid tumors. A large number of clinical trials revealed that both monotherapy and combination therapy of PD-L1 antibody significantly suppress some tumor growth and promote the survival of patients. At present, anti-PD-L1 treatment has been used as a portion of standard treatment for lung cancer, breast cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. Although much evidence has demonstrated that PD-L1 antibody is safe in most patients, there are still some adverse reactions, such as pneumonitis, hepatitis, colitis, neurologic events and myocarditis. In this review, the clinical information, including the efficacy and safety of durvalumab in solid tumors, was enumerated and summarized at this stage to grasp the current application of targeted PD-L1 therapy and provide guidance for clinical application.

15.
Front Vet Sci ; 10: 1140655, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36968469

RESUMO

Edwardsiella tarda is a Gram-negative, facultative anaerobic rod-shaped bacterium and the causative agent of the systemic disease "Edwardsiellosis". It is commonly prevalent in aquatic organisms with subsequent economic loss and hence has attracted increasing attention from researchers. In this study, we investigated the complete genome sequence of a highly virulent isolate Edwardsiella tarda SC002 isolated from hatchlings of the Siamese crocodile. The genome of SC002 consisted of one circular chromosome of length 3,662,469 bp with a 57.29% G+C content and four novel plasmids. A total of 3,734 protein-coding genes, 12 genomic islands (GIs), 7 prophages, 48 interspersed repeat sequences, 248 tandem repeat sequences, a CRISPR component with a total length of 175 bp, and 171 ncRNAs (tRNA = 106, sRNA = 37, and rRNA = 28) were predicted. In addition, the coding genes of assembled genome were successfully annotated against eight general databases (NR = 3,618/3,734, COG = 2,947/3,734, KEGG = 3,485/3,734, SWISS-PROT = 2,787/3,734, GO = 2,648/3,734, Pfam = 2,648/3,734, CAZy = 130/3,734, and TCDB = 637/3,734) and four pathogenicity-related databases (ARDB = 11/3,734, CARD = 142/3,734, PHI = 538/3,734, and VFDB = 315/3,734). Pan-genome and comparative genome analyses of the complete sequenced genomes confirmed their evolutionary relationships. The present study confirmed that E. tarda SC002 is a potential pathogen bearing a bulk amount of antibiotic resistance, virulence, and pathogenic genes and its open pan-genome may enhance its host range in the future.

16.
J Immunother Cancer ; 11(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36918219

RESUMO

BACKGROUND: Immunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored. METHODS: The efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl /SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging. RESULTS: We report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo. CONCLUSION: This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now.


Assuntos
Mieloma Múltiplo , Receptores do Ácido Retinoico , Camundongos , Animais , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Imunoterapia Adotiva , Camundongos Endogâmicos NOD , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Tretinoína/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo
17.
J Hazard Mater ; 451: 131154, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-36889068

RESUMO

A novel Bi2WO6-g-C3N4/polyvinylidene fluoride (PVDF) composite ultrafiltration (UF) membrane (BWO-CN/PVDF) was prepared by microwave hydrothermal and immersion precipitation phase transformation method. The BWO-CN/PVDF-0.10 exhibited an outstanding photocatalytic removal rate of atrazine (ATZ) (97.65 %) under the simulated sunlight and enhanced permeate flux (1356.09 L·m-2·h-1). The multiple optical and electrochemical detection confirmed that combining ultrathin g-C3N4 and Bi2WO6 can increase carrier separation rate and prolong its lifetime. The quenching test revealed that h+ and 1O2 were the prominent reactive species. Additionally, after a 10-cycle photocatalytic process, the BWO-CN/PVDF membrane presented remarkable reusability and durability. And it showed excellent anti-fouling performance by filtering BSA, HA, SA, and Songhua River under simulated solar irradiation. The molecular dynamic (MD) simulation showed that the combination of g-C3N4 and Bi2WO6 can enhance the interaction between BWO-CN and PVDF. This work opens up a new idea for designing and constructing a highly efficient photocatalytic membrane for water treatment.

18.
Nat Commun ; 14(1): 1290, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36894562

RESUMO

Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.


Assuntos
Antineoplásicos , Mieloma Múltiplo , Humanos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Inibidores de Proteassoma/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Fatores de Transcrição/farmacologia , Antineoplásicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo
19.
Exp Gerontol ; 175: 112138, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36893949

RESUMO

Diabetic retinopathy (DR) is a leading cause of blindness worldwide and a costly complication of diabetes mellitus (DM). DR severity is associated with DM duration; thus, DR has become more devastating to individuals and healthcare systems owing to the aging population and the significantly increased human lifespan. Aging is an irreversible cellular state characterized by long-term stagnation of the cell cycle from excessive stress or damage. Furthermore, aging plays a critical role in developing age-related diseases, but its effects (direct or indirect) on DR development remain considerably understudied. Nonetheless, some studies have demonstrated that aging-related degeneration and DR development share common risk factors, which helps explain the increased prevalence of DR and visual impairment in the elderly population. This review aims to provide some conceptual insight into aging and DR development, two intertwined pathophysiological processes, and discusses potential therapeutic strategies for DR, including prevention and treatment, during this era of longevity.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Humanos , Idoso , Retinopatia Diabética/complicações , Retinopatia Diabética/epidemiologia , Fatores de Risco , Longevidade , Prevalência
20.
Ecotoxicol Environ Saf ; 253: 114691, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36868036

RESUMO

There is evidence that the triazine herbicide atrazine, which is used extensively, is present in both surface water and groundwater, and its interfering effect on immune systems, endocrine systems, and tumours has been reported by laboratory and epidemiological studies. This study explored how atrazine affected 4T1 breast cancer cell development in vitro and in vivo. The obtained results showed that after exposure to atrazine, the cell proliferation and tumour volume were significantly increased and the expression of MMP2, MMP7, and MMP9 was upregulated. The thymus and spleen indices, the CD4 + and CD3 + lymphocyte percentages which from the spleen and inguinal lymph nodes, and the CD4 + /CD8 + ratio were noticeably lower than they were in the control group. Importantly, tumour-infiltrating lymphocytes such as CD4 + , CD8 + , and NK cells were decreased while Treg cells were increased. Moreover, IL-4 was increased and IFN-γ and TNF-α were decreased in the serum and tumour microenvironment. These results suggested that atrazine can suppress systemic as well as local tumour immune function and upregulate MMPs to promote breast tumour development.


Assuntos
Atrazina , Neoplasias da Mama , Herbicidas , Humanos , Feminino , Atrazina/toxicidade , Neoplasias da Mama/induzido quimicamente , Linfócitos T Reguladores , Herbicidas/toxicidade , Imunidade , Microambiente Tumoral
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