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1.
J Oncol ; 2022: 9999343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35518784

RESUMO

Background: Emerging studies have revealed long noncoding RNAs (lncRNAs) were key regulators of cancer progression. In this research, the expression and roles of MBNL1-AS1 were explored in breast cancer (BC). Methods: In this study, the MBNL1-AS1 expression in breast cancer tissue, as well as in cell line, was studied by qRT-PCR assays. The effects of MBNL1-AS1 on proliferation and stemness were evaluated by MTT assays, colony formation assays, orthotopic breast tumor mice models, extreme limiting dilution analysis (ELDA), fluorescence in situ hybridization (FISH), flow cytometry assays, and sphere formation assays. Flexmap 3D assays were performed to show that MBNL1-AS1 downregulated the centromere protein A (CENPA) secretion in BC cells. Western blot, RNA pull-down assays, RNA immunoprecipitation (RIP) assays, and FISH were conducted to detect the mechanism. Results: The results showed that the expression levels of MBNL1-AS1 were downregulated in breast cancer tissues and cell lines. In vitro and in vivo studies demonstrated that overexpression of MBNL1-AS1 markedly inhibited BC cells proliferation and stemness. RNA pull-down assay, RIP assay, western blot assay, and qRT-PCR assay showed that MBNL1-AS1 downregulated CENPA mRNA via directly interacting with Zinc Finger Protein 36 (ZFP36) and subsequently decreased the stability of CENPA mRNA. Restoration assays also confirmed that MBNL1-AS1 suppressed the CENPA-mediated proliferation and stemness in breast cancer cells. Conclusions: The new mechanism of how MBNL1-AS1 regulates BC phenotype is elucidated, and the MBNL1-AS1/ZFP36/CENPA axis may be served as a therapeutic target for BC patients.

2.
Small ; : e2200885, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396794

RESUMO

Solar-driven production of hydrogen peroxide (H2 O2 ), as an important industrial chemical oxidant with an extensive range of applications, from oxygen reduction is a sustainable alternative to mainstream anthraquinone oxidation and direct hydrogenation of dioxygen methods. The efficiency of solar to hydrogen peroxide over semiconductor-based photocatalysts is still largely limited by the narrow light absorption to visible light. Here, the authors proposed and demonstrate the proof-of-concept application of light-generated hot electrons in a graphene/semiconductor (exemplified with widely used TiO2 ) dyad to largely extend visible light spectra up to 800 nm for efficient H2 O2 production. The well-designed graphene/semiconductor heterojunction has a rectifying interface with a zero barrier for the hot electron injection, largely boosting excited hot electrons with an average lifetime of ≈0.5 ps into charge carriers with a long fluorescent lifetime (4.0 ns) for subsequent H2 O2 production. The optimized dyadic photocatalyst can provide an H2 O2 yield of 0.67 mm g-1  h-1 under visible light irradiation (λ ≥ 400 nm), which is 20 times of the state-of-the-art noble-metal-free titanium oxide-based photocatalyst, and even achieves an H2 O2 yield of 0.14 mm g-1  h-1 upon photoexcitation by near-infrared-region light (≈800 nm).

3.
J Chem Phys ; 156(14): 144304, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35428391

RESUMO

The characterization and identification of the dynamics of cluster catalysis are crucial to unraveling the origin of catalytic activity. However, the dynamical catalytic effects during the reaction process remain unclear. Herein, we investigate the dynamic coupling effect of elementary reactions with the structural fluctuations of sub-nanometer Au clusters with different sizes using ab initio molecular dynamics and the free energy calculation method. It was found that the adsorption-induced solid-to-liquid phase transitions of the cluster catalysts give rise to abnormal entropy increase, facilitating the proceeding of reaction, and this phase transition catalysis exists in a range of clusters with different sizes. Moreover, clusters with different sizes show different transition temperatures, resulting in a non-trivial size effect. These results unveil the dynamic effect of catalysts and help understand cluster catalysis to design better catalysts rationally.

4.
Phys Chem Chem Phys ; 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35482304

RESUMO

The dynamic evolution of catalyst structures greatly influences the reactivity, especially sub-nanometer clusters, exhibiting complex configurational fluctuation. In the present work, we study the structural dynamics of a Ru19 cluster during the dissociation of N2 and calculate the reaction free energies using ab initio molecular dynamics (AIMD). Our AIMD calculation predicts a peak-shaped reaction entropy curve due to the adsorption-induced phase transition of the Ru19 cluster. The low melting points of sub-nanometer clusters make it possible to activate N2 at low temperatures. This work demonstrates that the dynamic changes of cluster structures have a non-negligible effect on reaction free energy and offer an opportunity for achieving ammonia synthesis under mild conditions.

5.
J Am Chem Soc ; 144(12): 5418-5423, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35230846

RESUMO

Merging existing catalysts together as a cascade catalyst may achieve "one-pot" synthesis of complex but functional molecules by simplifying multistep reactions, which is the blueprint of sustainable chemistry with low pollutant emission and consumption of energy and materials only when the smooth mass exchange between different catalysts is ensured. Effective strategies to facilitate the mass exchange between different active centers, which may dominate the final activity of various cascade catalysts, have not been reached until now, even though charged interfaces due to work function driven electron exchange have been widely observed. Here, we successfully constructed mass (reactants and intermediates) exchange paths between Pd/N-doped carbon and MoC/N-doped carbon induced by interfacial electron exchange to trigger the mild and cascade methylation of amines using CO2 and H2. Theoretical and experimental results have demonstrated that the mass exchange between electron-rich MoC and electron-deficient Pd could prominently improve the production of N,N-dimethyl tertiary amine, which results in a remarkably high turnover frequency value under mild conditions, outperforming the state-of-the-art catalysts in the literature by a factor of 5.9.


Assuntos
Dióxido de Carbono , Elétrons , Aminas/química , Carbono/química , Dióxido de Carbono/química , Catálise
6.
Int J Biol Macromol ; 206: 148-158, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35227703

RESUMO

This study evaluated quality attributes and in vivo antioxidant activity of Auricularia cornea var. Li polysaccharide (ACP)-fortified set yogurt during 21 days of storage (4 °C). Set yogurt was manufactured using a commercial yogurt culture, and 3% (w/v) ACP was added. Physicochemical (pH, titratable acidity, and water-holding capacity), textural, rheological, microstructural, flavor, and antioxidant properties of set yogurt were investigated. The results showed that the addition of ACP significantly enhanced WHC, viscosity, firmness, and cohesiveness, while inhibiting post-acidification of set yogurt during storage. The yogurt supplemented with ACP showed a larger hysteresis area and higher G' and G″ values, formed a porous, dense, mesh-like structure and exhibited a unique mushroom flavor. Antioxidant results showed that administration of ACP-fortified yogurt significantly decreased serum alanine aminotransferase and aspartate aminotransferase enzyme activities and malondialdehyde levels, while increasing superoxide dismutase, catalase, phospholipid hydroperoxide glutathione peroxidase, and total antioxidant capacity in the liver and hippocampus of the mice. ACP-fortified yogurt might alleviate hepatic damage and hippocampal neuroinflammation induced by d-galactose. Additionally, ACP-fortified yogurt downregulated the expression of Keap1 and upregulated the expression of Nrf2 and HO-1 in the liver. In conclusion, ACP may be used as an ingredient to produce yogurt with desired properties.


Assuntos
Antioxidantes , Iogurte , Animais , Antioxidantes/farmacologia , Auricularia , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Fator 2 Relacionado a NF-E2 , Polissacarídeos/química , Polissacarídeos/farmacologia
7.
Ren Fail ; 44(1): 461-472, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35272573

RESUMO

OBJECTIVES: IgA Nephropathy (IgAN) is common chronic kidney disease with a high incidence. This study aims to analyze comprehensively therapeutic clinical trials for IgAN registered on ClinicalTrials.gov. METHODS: Therapeutic trials for IgAN registered on ClinicalTrials.gov. up to 15 August 2021 were obtained. The general characteristics, features of experimental design, treatment strategies, and some main inclusion criteria and outcome measures were accessed. RESULTS: A total of 104 therapeutic clinical trials for IgAN were extracted on ClinicalTrials.gov up to 15 August 2021. Most of these trials explored the treatment for primary IgAN confirmed by renal biopsy in adults. Only 9% of all selected trials had results. Forty-five percent of trials recruited 50 or fewer participants, and 73% were adults or older adults. 99% of trials were interventional studies, and of all the interventional trials, 70% of trials were randomized, and 68% exercised a parallel assignment of intervention model. Immunosuppression was the most studied for the treatment of IgAN. Moreover, many novel agents had been increasingly studied in recent years. Furthermore, the inclusion criteria and primary outcome measures in these trials were diverse, and the level of proteinuria and change of proteinuria levels were the most used as inclusion criteria and primary outcome, respectively. CONCLUSIONS: The majority of therapeutic trials for IgAN were randomized, none masking and parallel-assignment interventional studies, primarily recruiting adult patients as research subjects. These trials had relatively small sample sizes and short observation. Thus, more large-scale, multicenter, and randomized controlled trials are still needed to improve the management for IgAN.


Assuntos
Glomerulonefrite por IGA/tratamento farmacológico , Imunossupressores/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adulto , Ensaios Clínicos como Assunto/estatística & dados numéricos , Compreensão , Humanos , Seleção de Pacientes , Resultado do Tratamento
8.
Cancer Res ; 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35320355

RESUMO

The majority of TP53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis, we generated mice harboring a novel germline Trp53R245W allele (contact mutation) and compared them to existing models with Trp53R172H (structural mutation) and Trp53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed that all three hotspot mutations exhibited similar inhibitory effects on wild-type Trp53 transcription in vivo, and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of Trp53R245W/+ and Trp53R270H/+ mice, but not Trp53R172H/+ mice, was significantly shorter than that of Trp53+/- mice, providing strong evidence for p53 mutant-specific GOF contributions to tumor development. Furthermore, Trp53R245W/+ and Trp53R270H/+ mice had more osteosarcoma metastases than Trp53R172H/+ mice, suggesting that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Transcriptomic analyses using RNA-sequencing data from Trp53R172H/+, Trp53R245W/+, and Trp53R270H/+ primary osteosarcomas in comparison to Trp53+/- indicated that GOF of the three mutants was mediated by distinct pathways. Thus, both the inhibitory effect of mutant over WT p53 and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcoma.

9.
Open Life Sci ; 17(1): 1-9, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35128064

RESUMO

The aim of this study was to explore the effects of dabigatran and rivaroxaban on the activities of various coagulation factors. To achieve that, 60 rabbits were randomly divided into experimental groups that received different doses of dabigatran or rivaroxaban. The effects of dabigatran and rivaroxaban on the activities of FII, FV, FVIII, FX, and activated protein C (APC) were analyzed. In the dabigatran groups, activated partial thromboplastin time and thromboplastin time (TT) were prolonged after drug administration, and the activities of FII, FV, FVIII, and FX were inhibited as the drug concentration increased. Low doses of dabigatran inhibited APC activity. In the rivaroxaban groups, APTT and TT were not significantly prolonged after drug administration. In contrast, the high-dose rivaroxaban group exhibited prolonged PT, and the degree of inhibition of the activities of FII, FV, FVIII, and FX increased as the drug concentration increased. Rivaroxaban had no significant effect on APC activity regardless of dosage. As the drug concentration increased, both NOACs had more significant inhibitory effects on the activities of FII, FV, FVIII, and FX. Low concentrations of dabigatran generated an inhibitory effect on APC activity, while high concentrations of dabigatran had no significant effect. Rivaroxaban had no significant effect on APC activity.

10.
Zhongguo Gu Shang ; 35(2): 108-12, 2022 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-35191259

RESUMO

OBJECTIVE: To investigate the accuracy and safety of pedicle screw placement assisted by orthopedic robot and C-arm fluoroscopy. METHODS: The clinical data of 36 patients with spinal diseases underwent surgical treatment from January 2019 to August 2020 was retrospectively analyzed. Among them, 18 cases were implanted pedicle screws assisted by orthopaedic robot(observation group), including 12 males and 6 females, aged from 16 to 61 years with an average of (38.44±3.60) years;there were 1 case of adolescent scoliosis, 1 case of spinal tuberculosis, 7 cases of lumbar spondylolisthesis, 4 cases of thoracic fracture and 5 cases of lumbar fracture. Another 18 cases were implanted pedicle screws assisted by C-arm fluoroscopy(control group), including 10 males and 8 females, aged from 18 to 58 years with an average of (43.22±2.53) years;there were 1 case of adolescent scoliosis, 6 cases of lumbar spondylolisthesis, 6 cases of thoracic fracture and 5 cases of lumbar fracture. The intraoperative fluoroscopy times, nail placement time and postoperative complications were recorded in two groups. CT scan was performed after operation. The Gertzbein-Robbins standard was used to evaluate the accuracy of pedicle screw placement which was calculated. RESULTS: The number of intraoperative fluoroscopy in observation group was(6.89±0.20) times, which was significantly higher than that in control group(14.00±0.18)times(P<0.05). The placement time of each screw in observation group was(2.56±0.12) min, which was significantly different from that in control group(4.22±0.17) min (P<0.05). One case of incision infection occurred in control group after operation, and recovered after active dressing change. During the follow-up period, no serious complications such as screw loosening and fracture occurred in two groups, and there was no significant difference in complications between two groups(P>0.05). A total of 107 screws were placed in observation group, including 101 screws in class A, 4 in class B, 2 in class C, 0 in class D and 0 in class E, the accuracy rate of pedicle screw placement=[(number of screws in class A+B) / the number of all screws placed in the group] ×100%=98.1%(105/107); and a total of 104 screws were placed in control group, including 90 screws in class A, 4 in class B, 5 in class C, 5 in class D and 0 in class E, the accuracy rate of pedicle screw implantation=[(number of screws in class A+B/the number of all screws placed in the group]×100%=90.3% (94/104); there was significant difference between two groups (P<0.05). CONCLUSION: Orthopaedic robot assisted pedicle screw placement has the advantages of less fluoroscopy times, shorter screw placement time and higher accuracy, which can further improve the surgical safety and has a broad application prospect in the orthopaedic.


Assuntos
Parafusos Pediculares , Procedimentos Cirúrgicos Robóticos , Robótica , Escoliose , Fusão Vertebral , Cirurgia Assistida por Computador , Adolescente , Adulto , Feminino , Fluoroscopia/métodos , Humanos , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Fusão Vertebral/métodos , Adulto Jovem
11.
Lasers Med Sci ; 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35028765

RESUMO

Functional near-infrared spectroscopy (fNIRS) is a non-invasive and promising method for continuously monitoring hemodynamic and metabolic changes in tissues. However, the existing fNIRS equipment uses optical fiber, which is bulky, expensive, and time-consuming. We present a miniaturized, modular, novel silicon photomultiplier (SiPM) detector and develop a fNIRS instrument aimed at investigating the cerebral hemodynamic response for patients with epilepsy. Light emitting probe is a circle with a diameter of 5 mm. Independent and modular light source and detector are more flexible in placement. The system can be expanded to high-density measurement with 16 light sources, 16 detectors, and 52 channels. The sampling rate of each channel is 25 Hz. Instrument performance was evaluated using brain tissue phantom and in vivo experiments. High signal-to-noise ratio (60 dB) in source detector separation (SDS) of 30 mm, good stability (0.1%), noise equivalent power (0.89 pW), and system drift (0.56%) were achieved in the phantom experiment. Forearm blood-flow occlusion experiments were performed on the forearm of three healthy volunteers to demonstrate the ability to track rapid hemodynamic changes. Breath holding experiments on the forehead of healthy volunteers demonstrated the system can well detect brain function activity. The computer software was developed to display the original light signal intensity and the concentration changes of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (HbR) in real time. This system paves the way for our further diagnosis of epilepsy.

12.
Dalton Trans ; 51(4): 1333-1343, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34989734

RESUMO

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/uso terapêutico , Piridinas/uso terapêutico , Compostos de Rutênio/uso terapêutico , Animais , Antineoplásicos/química , Apoptose , Benzimidazóis , Cálcio , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Dano ao DNA , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Membranas Mitocondriais/efeitos dos fármacos , Piridinas/química , Espécies Reativas de Oxigênio , Compostos de Rutênio/química , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bioengineered ; 13(2): 2371-2386, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35034538

RESUMO

Chronic heart failure (CHF) is a prevalent health concern with complex pathogenesis. This current study set out to estimate the function of the miR-129-5p/Smurf1/PTEN axis on cardiac function injury in CHF. The model of CHF in rats was established. The cardiac function indexes, myocardial tissue damage, and oxidative stress-related factors in CHF rats were evaluated after the interference of Smurf1/miR-129-5p/PTEN. The targeting relationships between miR-129-5p and Smurf1 and between PTEN and Smurf1 were verified. It was found that that after modeling, cardiac functions were impaired, heart/left ventricular/lung weight and the myocardial structure was destroyed, and the degree of fibrosis of myocardial tissue was increased. After Smurf1 knockdown, the cardiac function, myocardial structure, and oxidative stress were improved, and the fibrosis in myocardial tissue was decreased. Smurf1 was a target of miR-129-5p. miR-129-5p could annul the protective effect of Smurf1 silencing on CHF rats. Smurf1 inhibited PTEN expression by promoting PTEN ubiquitination, while miR-129-5p enhanced PTEN expression by inhibiting Smurf1. Meanwhile, overexpression of PTEN annulled the cardiac dysfunction in CHF rats induced by Smurf1. In conclusion, miR-129-5p targeted Smurf1 and repressed the ubiquitination of PTEN, and promoted PTEN expression, thus improving the cardiac function of CHF rats.


Assuntos
Regulação Enzimológica da Expressão Gênica , Insuficiência Cardíaca/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/biossíntese , Ubiquitina-Proteína Ligases/metabolismo , Animais , Doença Crônica , Insuficiência Cardíaca/genética , Masculino , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Ratos , Ratos Wistar , Ubiquitina-Proteína Ligases/genética
14.
Eur J Med Chem ; 231: 114141, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35092899

RESUMO

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC50 value of 0.5 µM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24.


Assuntos
Antineoplásicos , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Mitocôndrias , Fase S
15.
Pain ; 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35082247

RESUMO

ABSTRACT: Following surgical repair after peripheral nerve injury, neuropathic pain diminishes in most patients but can persist in a small proportion of cases, the mechanism of which remains poorly understood. Based on the spared nerve injury (SNI), we developed a rat nerve repair (NR) model, where a delayed reconstruction of the SNI-injured nerves resulted in alleviating chronic pain-like behavior only in a subpopulation of rats. Multiple behavioral measures were assayed over 11-week presurgery and postsurgery periods (tactile allodynia, pain prick responses, sucrose preference, motor coordination, and cold allodynia) in SNI (n = 10), sham (n = 8), and NR (n = 12) rats. All rats also underwent resting-state functional magnetic resonance imaging under anesthesia at multiple time points postsurgery, and at 10 weeks, histology and retrograde labeling were used to calculate peripheral reinnervation. Behavioral measures indicated that at approximately 5 weeks postsurgery, the NR group separated to pain persisting (NR persisting, n = 5) and recovering (NR recovering, n = 7) groups. Counts of afferent nerves and dorsal root ganglion cells were not different between NR groups. Therefore, NR group differences could not be explained by peripheral reorganization. By contrast, large brain functional connectivity differences were observed between NR groups, where corticolimbic reorganization paralleled with pain recovery (repeated-measures analysis of variance, false discovery rate, P < 0.05), and functional connectivity between accumbens and medial frontal cortex was related both to tactile allodynia (nociception) and to sucrose preference (anhedonia) in the NR group. Our study highlights the importance of brain circuitry in the reversal of neuropathic pain as a natural pain-relieving mechanism. Further studies regarding the therapeutic potentials of these processes are warranted.

16.
Blood Cancer J ; 12(1): 5, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017466

RESUMO

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.


Assuntos
Antineoplásicos/farmacologia , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Aminopiridinas/farmacologia , Benzimidazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Rearranjo Gênico/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Mutação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Sulfonamidas/farmacologia
17.
J Clin Neurosci ; 95: 75-80, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34929655

RESUMO

BACKGROUND: Interleukin 35 (IL-35) plays an anti-inflammatory in numerous autoimmune diseases. However, the potential roles of IL-35-producing T and B cells and serum IL-35 levels in the pathogenesis of myasthenia gravis (MG) and its association with disease activity in patients with MG remain unclear. METHODS: The percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells among peripheral blood mononuclear cells were determined in 37 patients with anti-acetylcholine receptor (AChR) antibody-positive MG and 35 healthy controls (HCs) by performing a flow cytometry analysis. Serum IL-35 levels in participants were determined using an enzyme-linked immunosorbent assay. Further, the correlations between IL35 levels and disease activity were analysed. RESULTS: The percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells were significantly lower in patients with anti-AChR antibody-positive MG than in HCs (p = 0.001 and p = 0.002, respectively). Furthermore, patients with thymoma and patients with generalized MG had lower percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells than those without thymoma and those with ocular MG (p = 0.001 and p = 0.003; p = 0.008 and p = 0.001, respectively). Interestingly, the suppression of IL-35 secretion correlated negatively with the activities of daily living scores of patients with MG (r = -0.4774, p = 0.0028) and the quantitative MG scores (r = -0.4656, p = 0.0037). The proportions of IL-35-producing T cells and B cells and serum levels of IL-35 increased after treatment. CONCLUSIONS: IL-35 may represent a potential biomarker for the clinical evaluation of MG.


Assuntos
Linfócitos B , Interleucinas , Leucócitos Mononucleares , Miastenia Gravis , Linfócitos T , Atividades Cotidianas , Autoanticorpos , Linfócitos B/imunologia , Humanos , Receptores Colinérgicos , Linfócitos T/imunologia
18.
Nat Mater ; 21(3): 284-289, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34916657

RESUMO

Nanoscale periodic moiré patterns, for example those formed at the interface of a twisted bilayer of two-dimensional materials, provide opportunities for engineering the electronic properties of van der Waals heterostructures1-11. In this work, we synthesized the epitaxial heterostructure of 1T-TiTe2/1T-TiSe2 with various twist angles using molecular beam epitaxy and investigated the moiré pattern induced/enhanced charge density wave (CDW) states with scanning tunnelling microscopy. When the twist angle is near zero degrees, 2 × 2 CDW domains are formed in 1T-TiTe2, separated by 1 × 1 normal state domains, and trapped in the moiré pattern. The formation of the moiré-trapped CDW state is ascribed to the local strain variation due to atomic reconstruction. Furthermore, this CDW state persists at room temperature, suggesting its potential for future CDW-based applications. Such moiré-trapped CDW patterns were not observed at larger twist angles. Our study paves the way for constructing metallic twist van der Waals bilayers and tuning many-body effects via moiré engineering.

19.
Int J Nurs Stud ; 125: 104110, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34736073

RESUMO

BACKGROUND: Mild cognitive impairment affects 36% of people aged ≥65 years in China, around 50% of whom will develop dementia within 3 years. Early intervention can slow disease progression and delay the onset of dementia; however, whether a multicomponent intervention can decelerate the progression of mild cognitive impairment remains unknown. OBJECTIVE: To evaluate the effects of a multicomponent intervention to slow mild cognitive impairment progression in Chinese patients. DESIGN: Randomized controlled trial. SETTING(S) AND PARTICIPANTS: This study was conducted in two large regional communities in Guangzhou, China. Patients aged ≥ 65 years diagnosed with mild cognitive impairment were included. METHODS: A total of 112 eligible participants were assigned to receive either a 6-month multicomponent intervention or usual care from September 2019 until January 2021. Data were collected at the beginning of the study and at 1, 3, and 6 months thereafter. The primary outcomes were cognitive function, comprehensive physical capacity, depression, and quality of life. Analysis followed the intention-to-treat principle. A generalized estimating equation was used to determine intervention effects. RESULTS: At baseline, clinical characteristics did not differ significantly between groups. Significant interaction effects between time and group were detected (p < 0.001), indicating that the scores of five outcomes (cognitive function, short physical performance battery, timed up and go test, quality of life, and depression) of intervention and control groups changed differently over time. Participants in the intervention group were found to have a significantly greater improvement in cognitive function, physical function, quality of life, and fewer depression symptoms compared with the control group at baseline and follow-up periods. CONCLUSIONS: This study demonstrates the beneficial effects of a multicomponent intervention on cognitive function, physical function, depression symptoms, and quality of life in people with mild cognitive impairment in the East Asia region. The effectiveness and feasibility of this intervention program suggest that its application should be promoted in community settings to delay the progression of disease in people with mild cognitive impairment. Registration number:ChiCTR1900026042 Tweetable abstract: The multicomponent intervention improves cognitive/physical function, depression, and quality of life, slowing cognitive impairment progression.

20.
Arthritis Res Ther ; 23(1): 279, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34736521

RESUMO

BACKGROUND: Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. METHODS: The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. RESULTS: A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 7.02×10-11, OR 1.19, 95%CI 1.13-1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression. CONCLUSIONS: The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.


Assuntos
Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Alelos , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fatores Reguladores de Interferon , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína EWS de Ligação a RNA
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