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1.
J Med Chem ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665631

RESUMO

Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

2.
Bioorg Chem ; 116: 105384, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601294

RESUMO

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

3.
J Med Chem ; 64(19): 14647-14663, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477384

RESUMO

CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.

4.
Br J Nutr ; : 1-32, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34526160

RESUMO

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential for maternal and fetal health, but epidemiological data is sparse in China. We examined the trends of EPA alone and a combination of EPA plus DHA in pregnant and lactating women in three distinct geographic regions in China, and explored their potential influencing factors. A total of 1015 healthy women during mid-pregnancy, late pregnancy, or lactation were recruited from Weihai (coastland), Yueyang (lakeland), and Baotou (inland) cities of China between May and July of 2014. Maternal EPA and DHA concentrations (percentage of total fatty acids) in plasma and erythrocytes were measured by capillary gas chromatography. Adjusted EPA plus DHA concentrations in both plasma and erythrocytes significantly declined from mid-pregnancy (2.92%,6.95%), to late pregnancy (2.20%,6.42%) and lactation (2.40%,6.29%) (Ptrend<0.001); and both concentrations were highest in coastland, followed by lakeland, and lowest in inland (P<0.001). Regarding EPA alone, the concentrations were higher in women during lactation or late pregnancy and in women in coastland and inland areas. Moreover, concentrations of EPA or EPA plus DHA were higher in women with older age, higher education, higher annual family income per capita, and higher dietary intake of marine aquatic product and mutton. In lactating women, erythrocyte EPA concentration was higher in those having breastfeeding partially versus exclusively. In conclusion, maternal plasma and erythrocyte concentrations of EPA plus DHA or EPA alone differed with geographic regions, physiological periods and maternal characteristics, indicating a need of population-specific health strategies to improve fatty acids status in pregnant and lactating women.

5.
J Med Chem ; 64(19): 14822-14847, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34538051

RESUMO

Triple-negative breast cancer (TNBC) is highly aggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting transcription-associated cyclin-dependent kinases to remodel transcriptional regulation shows great promise in cancer therapy. Herein, we report the synthesis, optimization, and evaluation of new series of heterobifunctional molecules as highly selective and efficacious CDK9 degraders, enabling potent inhibition of TNBC cell growth and rapidly targeted degradation of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell apoptosis in vitro and inhibits tumor growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry assays demonstrate that the CDK9 degrader downregulates the downstream targets, such as MYC, at the transcriptional level, resulting apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting transcription regulation, which represents an effective strategy and great potential as a new targeted therapy for TNBC.

6.
Acta Pharmacol Sin ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341512

RESUMO

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

7.
Fitoterapia ; 153: 104959, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34111550

RESUMO

Three new polyprenylated acylphloroglucinol meroterpenoids, hyperiforins A-C (1-3), were isolated from Hypericum forrestii (Chittenden) N. Robson, together with twelve known analogues (4-15). Their structures were established by extensive physical and spectroscopic data analysis. Compounds 1, 2, 5, 7, and 13-15 showed potent inhibitory effects on protein tyrosine phosphatase 1B with IC50 values from 6.63 ± 2.40 to 14.21 ± 3.51 µM.


Assuntos
Hypericum/química , Floroglucinol/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Terpenos/farmacologia , China , Estrutura Molecular , Floroglucinol/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Terpenos/isolamento & purificação
8.
Eur J Med Chem ; 222: 113592, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34147909

RESUMO

Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 µM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Naftalenos/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Estrutura Molecular , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Naftalenos/síntese química , Naftalenos/química , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Immunity ; 54(6): 1123-1136.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107271

RESUMO

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.


Assuntos
Apoptose/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Lisofosfolipídeos/imunologia , Neutrófilos/imunologia , Receptores de Lisofosfolipídeos/imunologia , Animais , Células Cultivadas , Colite/imunologia , Colo/imunologia , Homeostase/imunologia , Humanos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/imunologia
10.
Eur J Med Chem ; 221: 113556, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087498

RESUMO

A series of epoxyketone analogues with varying N-caps and P3-configurations were designed, synthesized and evaluated. We found that D-Ala in P3 was crucial for ß5i selectivity over ß5c. Notably, compounds 20j (ß5i IC50 = 26.0 nM, 25-fold selectivity) and 20l (ß5i IC50 = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of ß5i alone is not sufficient to exert anticancer effects and may rely on the complementary inhibition of ß1i, ß5c and ß5i. These data further increase our understanding of immunoproteasome inhibitors in hematologic malignancies.


Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Compostos de Epóxi/farmacologia , Cetonas/farmacologia , Peptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Humanos , Cetonas/síntese química , Cetonas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Cell Res ; 31(8): 847-860, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34112954

RESUMO

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Assuntos
Antivirais/metabolismo , COVID-19/patologia , Proteínas do Envelope de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , Antivirais/uso terapêutico , Apoptose , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas do Envelope de Coronavírus/antagonistas & inibidores , Proteínas do Envelope de Coronavírus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Baço/metabolismo , Baço/patologia , Carga Viral , Virulência
12.
Nat Commun ; 12(1): 3205, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050160

RESUMO

Interactions between climate change and anthropogenic activities result in increasing numbers of open fires, which have been shown to harm maternal health. However, few studies have examined the association between open fire and pregnancy loss. We conduct a self-comparison case-control study including 24,876 mothers from South Asia, the region with the heaviest pregnancy-loss burden in the world. Exposure is assessed using a chemical transport model as the concentrations of fire-sourced PM2.5 (i.e., fire PM2.5). The adjusted odds ratio (OR) of pregnancy loss for a 1-µg/m3 increment in averaged concentration of fire PM2.5 during pregnancy is estimated as 1.051 (95% confidence intervals [CI]: 1.035, 1.067). Because fire PM2.5 is more strongly linked with pregnancy loss than non-fire PM2.5 (OR: 1.014; 95% CI: 1.011, 1.016), it contributes to a non-neglectable fraction (13%) of PM2.5-associated pregnancy loss. Here, we show maternal health is threaten by gestational exposure to fire smoke in South Asia.


Assuntos
Aborto Espontâneo/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Incêndios , Exposição Materna/efeitos adversos , Fumaça/efeitos adversos , Aborto Espontâneo/etiologia , Adulto , Poluição do Ar/efeitos adversos , Poluição do Ar/estatística & dados numéricos , Ásia/epidemiologia , Estudos de Casos e Controles , Monitoramento Ambiental/estatística & dados numéricos , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Exposição Materna/estatística & dados numéricos , Saúde Materna/estatística & dados numéricos , Gravidez , Fatores de Risco , Imagens de Satélites/estatística & dados numéricos , Adulto Jovem
13.
Phytochemistry ; 187: 112705, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957541

RESUMO

Phytochemical study on the ethanolic extract of the dried roots of Ferula samarkandica Korovin led to the isolation of nine undiscribed sesquiterpene coumarins, samarcandicins A-I, along with thirteen known sesquiterpene coumarins. Their structures were characterized by detailed spectroscopic analysis including NMR and HR-ESI-MS. Mogoltacin and nevskin exhibited high inhibitory activity against MV-4-11 cell with IC50 values of 3.94 ±â€¯0.06 µM and 3.87 ±â€¯0.10 µM, respectively, and nevskin and feshurin showed high inhibitory activity against mino cell with IC50 values of 1.48 ±â€¯0.06 µM and 7.88 ±â€¯0.60 µM, respectively.


Assuntos
Ferula , Sesquiterpenos , Cumarínicos/farmacologia , Estrutura Molecular , Raízes de Plantas , Sesquiterpenos/farmacologia
14.
Sci Rep ; 11(1): 8694, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888748

RESUMO

Social and mental stressors associated with the pandemic of a novel infectious disease, e.g., COVID-19 or SARS may promote long-term effects on child development. However, reports aimed at identifying the relationship between pandemics and child health are limited. A retrospective study was conducted to associate the SARS pandemic in 2003 with development milestones or physical examinations among longitudinal measurements of 14,647 children. Experiencing SARS during childhood was associated with delayed milestones, with hazard ratios of 3.17 (95% confidence intervals CI: 2.71, 3.70), 3.98 (3.50, 4.53), 4.96 (4.48, 5.49), or 5.57 (5.00, 6.20) for walking independently, saying a complete sentence, counting 0-10, and undressing him/herself for urination, respectively. These results suggest relevant impacts from COVID-19 on child development should be investigated.


Assuntos
COVID-19/psicologia , Desenvolvimento Infantil , Síndrome Respiratória Aguda Grave/psicologia , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
15.
Zhongguo Gu Shang ; 34(4): 337-40, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33896132

RESUMO

OBJECTIVE: To explore the clinical effect of modified interlaminar approach for the treatment of single-segment lumbar spinal stenosis. METHODS: From February 2015 to August 2017, 80 patients with single-segment lumbar spinal stenosis planned to undergo endoscopic surgery were selected, including 38 males and 42 females;aged 33 to 69 (47.6±9.5) years old. Using random number table method, the patients were divided into study group and traditional group, 40 cases in each group, and underwent surgical treatment through modified translaminar approach and traditional approach respectively. The operation time, intraoperative blood loss, and hospital stay were recorded;visual analogue scale (VAS) and Oswestry Disability Index (ODI) before and after operation were compared between two groups;spinal canal arca, spinal canal diameter, disc yellow space and surgical complications were observed. RESULTS: All 80 patients were followed up for at least 3 months. Two patients had incision infection, both of them were in traditional group;there was no significant difference in operation time between two groups(P>0.05). Intraoperative blood loss and hospital stay in study group were lower than those in traditional group(P<0.05). At 1 week and 3 months after operation, VAS and ODI of all patients were significantly lower than before operation (P<0.05), but the difference between two groups was not statistically significant (P>0.05). At 3 months after surgery, measured values of spinal canal area and spinal canal diameter were larger in study group than in traditional group (P<0.05). The operative complication rate of the study group was 5.00% compared with 12.50% of the traditional group, and the difference was not statistically significant (P>0.05). CONCLUSION: Compared with the traditional approach, the modified interlaminar approach has advantages of less trauma, faster recovery and better postoperative spinal space recovery in the treatment of single-segment lumbar spinal stenosis.


Assuntos
Fusão Vertebral , Estenose Espinal , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estenose Espinal/cirurgia , Resultado do Tratamento
16.
Eur J Med Chem ; 218: 113341, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33780898

RESUMO

SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Talidomida/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Talidomida/síntese química , Talidomida/química , Células Tumorais Cultivadas
17.
J Pharm Biomed Anal ; 198: 113993, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33677280

RESUMO

Three maytansinoids with strong cytotoxicities, dehydrotrewiasine, maytanbutine, and trewiasine, were isolated and identified from Trewia nudiflora, and maytanbutine was obtained from this plant for the first time. A quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction combined with high-performance liquid chromatography (HPLC) was established to determine the three maytansinoids in T. nudiflora. The effects of major factors on the extraction efficiency of the QuEChERS method were evaluated and the optimal conditions using acetonitrile-ethyl acetate (1:1, v/v) as the extraction solvent and PestiCarb as the clean-up sorbents were established. Compared with Soxhlet extraction (SE) and ultrasonic-assisted extraction (UAE), the QuEChERS method was easy-to-operate and afforded a cleaner extract. A phenomenex HyperClone BDS C18 column was used for HPLC analysis. Methanol-acetonitrile-water was chosen as mobile phase for gradient elution. Method validation showed that all analytes showed good linearity (r > 0.999) over the investigated ranges and satisfactory recoveries ranging from 95.0% to 105.0%. The developed QuEChERS-HPLC method was simple, efficient, and applicable to the determination of maytansinoids in T. nudiflora.


Assuntos
Espectrometria de Massas em Tandem , Água , Cromatografia Líquida de Alta Pressão , Extração em Fase Sólida , Solventes
18.
Acta Pharmacol Sin ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782542

RESUMO

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

19.
Nutrients ; 13(2)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669610

RESUMO

Maternal status of essential and toxic elements affects the health of the mother, developing fetus, or breastfeeding infant. However, few studies have examined the patterns of these elements and their determinants in pregnant or lactating women. Plasma samples of 1211 healthy mid-pregnant, late pregnant, and lactating women enrolled in coastland, lakeland, and inland areas of China from May-July 2014, were analyzed for concentrations of 15 elements, using inductively coupled plasma mass spectrometry. The adjusted median concentrations of elements varied by physiologic stage and region. Lactating versus pregnant women showed higher concentrations of Zn, Cr, Mo, Ni, Sb, Cd and Pb, but lower concentrations of Cu, I, Al and Hg. In pregnant women, the concentrations of Fe, Zn, I, Mo, Ni, Al, Hg and Cd were higher in mid- versus late-pregnancy. Overall, the highest concentrations were observed in Zn, I, Mn, Al, and Pb in coastland, in Hg in lakeland, and in Fe in inland area. Element concentrations varied by maternal age, pre-pregnancy BMI, education, parity, delivery mode, feeding practice, and intakes of aquatic products and mutton. In conclusion, essential and toxic elements coexisted in pregnant and lactating women, and their concentrations varied by physiologic stages, regions, maternal socio-demographic characteristics and dietary factors.


Assuntos
Exposição Ambiental , Lactação/sangue , Metais Pesados/toxicidade , Oligoelementos/sangue , Adolescente , Adulto , Aleitamento Materno , China , Estudos Transversais , Dieta , Feminino , Idade Gestacional , Humanos , Chumbo/sangue , Carne , Mercúrio/sangue , Metais Pesados/sangue , Necessidades Nutricionais , Gravidez , Alimentos Marinhos , Fatores Socioeconômicos , Adulto Jovem
20.
Eur J Clin Nutr ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637973

RESUMO

BACKGROUND: Cesarean has been suggested to decrease neonatal iron stores at birth. However, few studies have differentiated the effect induced by cesarean operation from that related to medical indications. OBJECTIVES: We aimed to estimate the association of cesarean delivery on maternal request (CDMR), a subtype of cesarean without any medical indications, with a spectrum of indicators reflecting iron stores at birth. METHODS: This prospective cohort study involved 288 term singleton neonates born to women without any complications by CDMR or spontaneous vaginal delivery (SVD). Measured hematological iron-related indicators in cord blood included serum ferritin (SF), hemoglobin (Hb), red blood cell (RBC), and hematocrit (Hct). Blood flow volume (BFV) of cord vein when clamping was measured to reflect placental transfusion status during birth. Quantile regression was used to assess the association between delivery mode and the iron store indicators. RESULTS: CDMR (n = 154) versus SVD group (n = 134) had lower conditional median cord blood SF (-34.80; 95% CI -64.70, -4.90 µg/L; P = 0.02), Hb (-10.67; 95% CI -18.87, -2.47 g/L; P = 0.01), RBC (-0.30; 95% CI -0.48, -0.12 ×1012/L; P = 0.002), and Hct (-3.06; 95% CI -6.08, -0.04 %; P = 0.047). The BFV was higher in CDMR than SVD group at the 25th centile (0.51; 95% CI 0.19, 0.82 ml/cm3; P = 0.002), median (0.49; 95% CI 0.04, 0.95 ml/cm3; P = 0.03) and the 75th centile (0.54; 95% CI 0.06, 1.03 ml/cm3; P = 0.03). CONCLUSIONS: The cesarean operation per se likely hampered placental transfusion from mother to neonate and decreased iron stores at birth.

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