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1.
Biomed Res Int ; 2021: 9140602, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869773

RESUMO

Background: T-helper 17 (Th17) and CD4+CD25+ T-regulatory (Treg) cells play important roles in the pathogenesis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This study is aimed at investigating shifts in Treg/Th17 balance in the peripheral blood of HBV-ACLF patients at different disease stages. Methods: Sixty HBV-ACLF patients, admitted to the First Hospital of Hunan University of Chinese Medicine, China, including early-stage (n = 20), middle-stage (n = 20), and late-stage patients (n = 20), were enrolled in the study. In addition, 20 patients with chronic hepatitis B and 20 healthy volunteers were also included in the study as controls. Flow cytometry, cytometric bead array, and quantitative real-time PCR protocols were used to evaluate the expression of Treg and Th17 cells as well as of related cytokines. Results: The levels of Th17 cells and their effectors interleukin- (IL-) 17A, IL-23, and tumor necrosis factor-α increased with disease progression. Similarly, Treg cells and their effector cytokines transforming growth factor-ß and IL-10 also increased. Although Treg and Th17 levels were positively correlated, the latter were always at higher numbers. Noteworthy, the Treg/Th17 ratio gradually decreased and was negatively correlated with ACLF severity. FoxP3 levels in the peripheral blood gradually decreased with ACLF progression, whereas ROR-γt gradually increased. Serum c-reactive protein, procalcitonin, and lipopolysaccharide were also upregulated with disease progression and positively correlated with Th17 abundance. Further, Th17, IL-17A, and IL-23 were independent risk factors for ACLF. A prognostic model for HBV-ACLF was established, with a correct prediction rate of 90.00% (54/60). Conclusion: Treg/Th17 imbalance occurs throughout the pathogenic course of HBV-ACLF, with an imbalance shift toward Th17. Hence, the Th17-mediated inflammatory response drives HBV-ACLF-associated inflammation and supports the pathological mechanisms of liver failure.

2.
Front Pharmacol ; 12: 761722, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880757

RESUMO

Background: Ligustrazine injection has been widely used as adjunctive therapy in the treatment of acute cerebral infarction (ACI) during the past decades in China, but its clinical efficacy is not yet well confirmed. This study aims to evaluate the efficacy of ligustrazine injection as adjunctive therapy for ACI. Methods: Databases including China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), PubMed, Medline, Google Scholar, Chinese Biomedical Literature Database, Cochrane Library, Embase, Sino-Med, Wanfang Database, and Chinese Science Citation Database were systematically searched for the published randomized controlled trials (RCTs) on ligustrazine injection in the treatment of ACI until November 2020. Meta-analysis was performed on the primary outcome measure (i.e., clinical effective rate) and the secondary outcome measure [i.e., neurological deficit score (NDS), fibrinogen, low shear blood viscosity (LBV), and high shear blood viscosity (HBV)]. The quality of the included RCTs was assessed according to the M scoring system (the refined Jadad scale). Sensitivity analysis and subgroup analysis were conducted according to the methodological quality, years of publication, and sample size. Results: Nineteen RCTs, containing 2022 patients, were included in this study. Meta-analysis indicated that ligustrazine injection combined with Western medicine could achieve a better effect in the treatment of ACI than using Western medicine alone in terms of clinical effective rate (RR = 1.24; 95% CI, 1.19-1.29), NDS (MD = -3.88; 95%CI, -4.51 to -3.61), fibrinogen (MD = -0.59; 95% CI, -0.76 to -0.42), LBV (MD = -2.11; 95% CI, -3.16 to -1.06), and HBV (MD = -0.88; 95% CI, -1.20 to -0.55). Conclusions: This research indicated that ligustrazine injection as adjunctive therapy seemed to be more effective than using western medicine alone in treating ACI. However, more evidence is required to confirm the efficacy of ligustrazine injection due to the low methodological quality of the included RCTs.

3.
J Biophotonics ; : e202100242, 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34775685

RESUMO

Mueller matrix (MM) polarimetry can provide comprehensive information about the polarization properties that are closely related to the microstructural features and has demonstrated its potential in biomedical studies and clinical practices, and bright-field microscopy is widely used in pathological diagnosis as the golden standard. In this work, we improve the throughput of MM microscopy by learning a statistical transformation between these two imaging systems based on deep learning. Using this approach, the MM microscope can generate an image that is equivalent to a bright-field microscope image of the matching field of view. We add new transformative capability to the existing MM imaging system without requiring extra hardware. The translation model is based on conditional generative adversarial network with customized loss functions. We demonstrated the effectiveness of our approach on liver and breast tissues and evaluated the performance by four quantitative similarity assessment methods in pixel, image and distribution levels, respectively.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34650611

RESUMO

Background: In view of the global efforts to develop effective treatments for the current worldwide coronavirus 2019 (COVID-19) pandemic, Qingfei Paidu decoction (QPD), a novel traditional Chinese medicine (TCM) prescription, was formulated as an optimized combination of constituents of classic prescriptions used to treat numerous febrile and respiratory-related diseases. This prescription has been used to treat patients with COVID-19 pneumonia in Wuhan, China. Hypothesis/Purpose. We hypothesized that QPD would have beneficial effects on patients with COVID-19. We aimed to prove this hypothesis by evaluating the efficacy of QPD in patients with COVID-19 pneumonia. Methods: In this single-center, retrospective, observational study, we identified eligible participants who received a laboratory diagnosis of COVID-19 between January 15 and March 15, 2020, in the west campus of Union Hospital in Wuhan, China. QPD was supplied as an oral liquid packaged in 200-mL containers, and patients were orally administered one package twice daily 40 minutes after a meal. The primary outcome was death, which was compared between patients who did and did not receive QPD (QPD and NoQPD groups, respectively). Propensity score matching (PSM) was used to identify cohorts. Results: In total, 239 and 522 participants were enrolled in the QPD and NoQPD groups, respectively. After PSM at a 1 : 1 ratio, 446 patients meeting the criteria were included in the analysis with 223 in each arm. In the QPD and NoQPD groups, 7 (3.2%) and 29 (13.0%) patients died, and those in the QPD group had a significantly lower risk of death (hazard ratio (HR) 0.29, 95% CI: 0.13-0.67) than those in the NoQPD group (p = 0.004). Furthermore, the survival time was significantly longer in the QPD group than in the NoQPD group (p < 0.001). Conclusion: The use of QPD may reduce the risk of death in patients with COVID-19 pneumonia.

5.
Front Pharmacol ; 12: 726229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34658865

RESUMO

A study on 70 acute lymphoblastic leukemia (ALL) children (age ≤16 years) treated with high-dose methotrexate (HD-MTX) in Sichuan Provincial People's Hospital was conducted. The aim of the study was to establish a risk-scoring model to predict HD-MTX-induced liver injury, considering gene polymorphisms' effects. Data screening was performed through t-test, chi-square test, and ridge regression, and six predictors were identified: age, MTRR_AA, MTRR_AG, SLCO1B1_11045879_CC, albumin_1 day before MTX administration, and IBIL_1 day before MTX administration (p < 0.1). Then, the risk-scoring model was established by ridge regression and evaluated the prediction performance. In a training cohort (n = 49), the area under the curve (AUC) was 0.76, and metrics including accuracy, precision, sensitivity, specificity, positive predictive value, and negative predictive value were promising (0.86, 0.81, 0.76, 0.91, 0.81, 0.88, respectively). In a test cohort (n = 21), the AUC was 0.62 and negative predictive value was 0.80; other evaluation metrics were not satisfactory, possibly due to the limited sample size. Ultimately, the risk scores were stratified into three groups based on their distributions: low- (≤48), medium- (49-89), and high-risk (>89) groups. This study could provide knowledge for the prediction of HD-MTX-induced liver injury and reference for the clinical medication.

6.
Glycoconj J ; 38(5): 551-560, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34515908

RESUMO

Methylene blue (MB) is one of the most common cationic dyes to detect heparin. As the sulfate residue presented in heparin was the main contributor to bind with MB, the UV performance of the MB with selectively desulfated heparin derivatives was investigated. It was found that the sulfate residue in different heparin analogues did not show the equal ability to attract MB binding. The stoichiometry of sulfate with MB among the heparin and derivatives was verified as a non-constant number. For the two selectively desulfated heparin derivatives: sulfate elimination at 6-O (6-OdeS) and N-acetylated heparin (N-deS-Acetyl), the MB to sulfate ratios were significantly higher than for heparin. For the not fully diminished sulfate at 2-O heparin derivative (2-OdeS), the MB-SO3- ratio of 2-OdeS was between 6-OdeS, N-deS-Acetlyl and heparin. Although in a distinct sulfation position, the MB-SO3- ratio of 6-OdeS and N-deS-Acetyl was almost equal, which agreed with the comparable total desulfation degree between 6-OdeS and N-deS-Acetyl. In addition, compared to heparin groups, the non-desulfated gs-HP showed no significantly different MB-SO3- ratio with heparin. The above results demonstrated that compared with the sulfate location and glycan composition of heparin, the content of sulfate was the most essential factor for the MB binding.

7.
J Pept Sci ; : e3368, 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34514664

RESUMO

Coupling reagents play crucial roles in the iterative construction of amide bonds for the synthesis of peptides and peptide-based derivatives. The novel DIC/Oxyma condensation system featured with the low risk of explosion displayed remarkable abilities to inhibit racemization, along with efficient coupling efficiency in both manual and automated syntheses. Nevertheless, an ideal reaction molar ratio in DIC/Oxyma condensation system and the moderate reaction temperature by manual synthesis remain to be further investigated. Herein, the synthetic efficiencies of different reaction ratios between DIC and Oxyma under moderate reaction temperature were systematically evaluated. The robustness and efficiency of DIC/Oxyma condensation system are validated by the rapid synthesis of linear centipede toxin RhTx. Different folding strategies were applied for the construction of disulfide bridges in RhTx, which was further confirmed in assays of circular dichroism and patch-clamp electrophysiology evaluation. This work establishes the DIC/Oxyma-based accelerated synthesis of peptides under moderate condensation conditions, which is especially useful for the manual synthesis of peptides. Besides, the strategy presented here provides robust technical supports for the large-scale synthesis and oxidative folding of RhTx.

8.
Artif Cells Nanomed Biotechnol ; 49(1): 483-492, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34151664

RESUMO

Oxidative stress has been proven to play a critical role in the pathogenesis of neuronal injury. As a novel adipocytokine, omentin is produced by visceral adipose with insulin sensitizing effects and has been revealed to possess anti-inflammatory effects. However, the possible effect of omentin on oxidative stress remains unknown. The present study aimed to detect the potential protective effect of omentin against hydrogen peroxide (H2O2)-induced cytotoxicity of PC12 cells. The results showed that no cytotoxic effect was shown in PC12 cells co-cultured with omentin alone at a concentration of 50-1000 ng/mL. The CCK8 and TUNEL assays suggested that omentin could remarkably attenuate apoptosis induced by 100 µM H2O2. The PCR and western blotting showed that the expression levels of Bax was significantly inhibited by omentin via the upregulation of miR-128-3p at its 3'-UTR. Taken together, these results indicated that omentin protects PC12 cells against H2O2-induced apoptosis, and further studies need to be conducted before utilization in the clinic for the treatment of neurodegenerative diseases.

9.
Dalton Trans ; 50(20): 6778-6783, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33972985

RESUMO

Herein, we reported two didysprosium single-molecule magnets constructed with {Dy(bbpen)(MeOH)} subunits and a π-conjugated tpb or non-conjugated tpcb bridging ligand. The former exhibits extremely weak luminescence that makes it difficult to simulate its emission spectra. However, the later shows obviously enhanced and well-resolved luminescence, which helps us to gain knowledge about the magneto-optical correlation and the relevant magnetic energy levels.

10.
Comput Biol Chem ; 92: 107481, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33838390

RESUMO

In this study, firstly, the pharmacophore model was established based on LAR inhibitors. ZINC database and drug-like database were screened by Hypo-1-LAR model, and the embryonic compound ZINC71414996 was obtained. Based on this compound, we designed 9 compounds. Secondly, the synthetic route of the compound was determined by consulting Reaxys and Scifinder databases, and 9 compounds (1a-1i) were synthesized by nucleophilic substitution, Suzuki reaction and so on. Meanwhile, their structures were confirmed by 1H NMR and 13C NMR. Thirdly, the Enzymatic assays was carried out, the biological evaluation of compounds 1a-1i led to the identification of a novel PTP-LAR inhibitor 1c, which displayed an IC50 value of 4.8 µM. At last, molecular dynamics simulation showed that compounds could interact strongly with the key amino acids LYS1350, LYS1352, ARG1354, TYR1355, LYS1433, ASP1435, TRP1488, ASP1490, VAL1493, SER1523, ARG1528, ARG1561, GLN1570, LYS1681, thereby inhibiting the protein activity. This study constructed the pharmacophore model of LAR protein, designed small-molecule inhibitors, conducted compound synthesis and enzyme activity screening, so as to provide a basis for searching for drug-capable lead compounds.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
11.
Mol Divers ; 25(3): 1873-1887, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33392964

RESUMO

The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33044923

RESUMO

Acoustic pyrometer is expected to be a useful noninvasive method for monitoring gas temperature distribution inside a steel-making furnace. On the superficial layer above the burden of a blast furnace, most of the high-temperature gas is concentrated near the center, and tracking the position of the hotspot is critical for productivity. However, most of the existing acoustic temperature distribution reconstruction algorithms are developed with relatively uniform temperature distribution environments. Besides, their capabilities of tracking the pinnacle of temperature distribution in the region of interest (ROI) are rarely discussed. In this research, a reconstruction method of acoustic temperature tomography dedicated for highly centralized gas temperature distribution is proposed and demonstrated. The key metrics include the reproducibility of 2-D temperature distribution, the sensitivity of hotspot shift, and the accuracy of point-to-point (P2P)/peak temperature. To optimize the result of each metric, previous approaches of acoustic temperature tomography have been first evaluated. Then, the investigation of effects from the shape and size of meshes is proceeded to improve the performance. After that, a novel method to address convergence issues while using the iterative method is introduced. Consequently, the reconstruction method proposed in this article could effectively visualize the temperature map while hotspot moves to different locations. It could also sense the occurrence of a hotspot (2.56% of ROI) traveled from center to 1% of ROI's diameter. Moreover, a competitive accuracy with 5.89% and 1.46% error at P2P root-mean-square (rms) and peak temperature is achieved, respectively. Finally, a practical acoustic 2-D pyrometer consisted of 12 ultrasonic transducers arranged in a circular pattern with a 1-m width of ROI successfully detected the shift of a hotspot when the displacement of a heater reaches 5 cm.

13.
J Mol Graph Model ; 103: 107807, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33338846

RESUMO

Abnormal activation of Ras/MAPK signaling pathway could trigger excessive cell division. Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2) could promote Ras/MAPK activation by integrating growth factor signals. Thus, SHP2 inhibitors had become a hot topic in the treatment of cancer. SHP2F285S, mutation in SHP2, was detected in leukemia variants. The compound 2 (3-benzyl-8-chloro-2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one) had been reported that it was a potent allosteric inhibitor of both SHP2 wild type (SHP2WT) and the F285S mutant (SHP2F285S). However, the mechanism of inhibition remained to be further discovered. Herein, molecular docking and molecular dynamic (MD) simulation were performed to explain the inhibition mechanism of compound 2 on SHP2WT and SHP2F285S. Overall, the molecular docking analysis revealed that compound 2 maintained the "close" structure of SHP2 protein probably by locking the C-SH2 and PTP domain. Next, post-analysis demonstrated that compound 2 might make TYR66-GLU76 of D'E-loop in N-SH2 and GLU258-LYS266 of B'C-loop, HIS458-ARG465 of P-loop, VAL497-THR507 of Q-loop in PTP domain regions tightly connect and much easier maintain "self-inhibited" conformation of SHP2F285S-compound2 than that of SHP2WT-compound2. Importantly, GLU76 of D'E-loop could play a vital role in inhibition of SHP2WT-compound2 and SHP2F285S-compound2. This work provided a reliable clue to develop novel inhibitors for leukemia related to SHP2F285S.


Assuntos
Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Conformação Molecular , Simulação de Acoplamento Molecular , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
14.
Bioorg Chem ; 105: 104391, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33113413

RESUMO

PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value. Here, based on the compound PubChem CID 8,478,960 (IC50 = 45.01 µM), a series of thiophene [2,3-d] pyrimidine derivatives (IC50 = 0.4-37.87 µM) were discovered as novel and efficient inhibitors of SHP2 through powerful "core hopping" and CDOCKER technology. Furthermore, the SHP2-PTP phosphatase activity assay indicated that Comp#5 (IC50 = 0.4 µM) was the most active SHP2 inhibitor. Subsequently, the effects of Comp#5 on the structure and function of SHP2 were investigated through molecular dynamics (MD) simulation and post-kinetic analysis. The result indicated that Comp#5 enhanced the interaction of residues THR357, ARG362, LYS366, PRO424, CYS459, SER460, ALA461, ILE463, ARG465, THR507 and GLN510 with the surrounding residues, improving the stability of the catalytic active region and the entrance of catalytic active region. In particular, the Comp#5 conjugated with residue ARG362, elevating the efficient and selectivity of SHP2 protein. The study here may pave the way for discovering the novel SHP2 inhibitors for suffering cancer patients.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Análise de Componente Principal , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
15.
BMC Pregnancy Childbirth ; 20(1): 654, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121473

RESUMO

BACKGROUND: Ectopic pregnancy is a major life- and fertility-threatening women's health concern. As a result of advances in examination technology, an increasing number of ectopic pregnancies can be diagnosed early and treated with medical methods instead of surgery. The aim of this study was to summarize the clinical features and identify the predictors of success of methotrexate (MTX) treatment of ectopic pregnancy. METHODS: This was a retrospective study of 238 ectopic pregnancies treated with MTX in the Department of Gynecology of Shaanxi Provincial People's Hospital from January 2017 to December 2017. RESULTS: Patients were divided into two groups: the successful treatment group (n = 166) and the failed treatment group (n = 72). The overall success rate of MTX therapy for ectopic pregnancy was 69.75%. The mean initial beta-human chorionic gonadotropin (ß-hCG) level was significantly lower in the successful treatment group than in the failed treatment group (2538.08 IU/L versus 3533.17 IU/L, P = 0.000). The treatment success rate of the group with an initial ß-hCG concentration less than 4000 IU/L was significantly higher than that of the group with an initial ß-hCG concentration greater than 4000 IU/L. However, the success rate of the group with an initial ß-hCG concentration greater than 4000 IU/L was still relatively high (54.55%). ß-hCG levels were significantly increased on the 4th day in the failed treatment group (P = 0.000). Compared to the initial ß-hCG level, the day-4 ß-hCG level increased by more than 8.21%, indicating that the treatment was effective. The diagnostic sensitivity was 88.6%, the specificity was 74.5%, and the area under the receiver operating characteristic (ROC) curve was 0.863 (95% confidence interval (CI): 0.805-0.920). CONCLUSIONS: MTX therapy as a treatment option is safe and effective for asymptomatic, hemodynamically stable patients with ectopic pregnancies who are interested in conservative treatment, regardless of the serum ß-hCG level or adnexal mass size. The change in the ß-hCG level between the initial day and the 4th day is an effective and early predictive tool for the success of MTX therapy for ectopic pregnancy.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Tratamento Conservador/métodos , Monitoramento de Medicamentos/métodos , Metotrexato/administração & dosagem , Gravidez Ectópica/tratamento farmacológico , Adulto , Doenças Assintomáticas/terapia , Feminino , Humanos , Metotrexato/efeitos adversos , Gravidez , Gravidez Ectópica/sangue , Gravidez Ectópica/diagnóstico , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto Jovem
16.
Nat Commun ; 11(1): 3236, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591543

RESUMO

The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A's phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A's canonical function. We demonstrate that PDE3A's H840, Q975, Q1001, and F1004 residues-as well as I105 in SLFN12-are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Naftiridinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cilostazol/farmacologia , Feminino , Humanos , Indóis/química , Camundongos Nus , Naftiridinas/química , Inibidores da Fosfodiesterase 3/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Chem ; 100: 103875, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380342

RESUMO

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC50 value of 1.36 µM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F3 cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Molecular docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small molecule SHP2 inhibitors.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Modelos Biológicos , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Piridinas/síntese química , Piridinas/farmacocinética
18.
Biochem Biophys Res Commun ; 526(1): 273-280, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32209254

RESUMO

Protein tyrosine phosphatase 1B (PTP1B) is a widely expressed 50 kDa enzyme and the first intracellular PTP to be purified from human placental tissue. It has been proved that protein tyrosine phosphatase 1B played a significant role in the negative regulation of insulin signaling pathway and overexpression of PTP1B could lead to the decrease of insulin resistance. Therefore PTP1B has emerged as a novel promising therapeutic target for the treatment of type-2 diabetes mellitus. Computer aided drug design (CADD), chemical synthesis and biological activity assay resulted in the identification of a novel potent PTP1B inhibitor, compound 1a, which shared an IC50 value of 4.46 µM. Finally, the analysis of molecular dynamics simulation provided the theoretical basis for favorable activity of compound 1a.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Concentração Inibidora 50 , Análise de Componente Principal , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
19.
J Biomol Struct Dyn ; 38(14): 4232-4245, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31588870

RESUMO

Owing to its negative regulatory role in insulin signaling, protein tyrosine phosphatase of leukocyte antigen-related protein (PTP-LAR) was widely thought as a potential drug target for diabetes. Now, it was urgent to search for potential LAR inhibitors targeting diabetes. Initially, the pharmacophore models of LAR inhibitors were established with the application of the HypoGen module. The cost analysis, test set validation, as well as Fischer's test was used to verify the efficiency of pharmacophore model. Then, the best pharmacophore model (Hypo-1-LAR) was applied for the virtual screening of the ZINC database. And 30 compounds met the Lipinski's rule of five. Among them, 10 compounds with better binding affinity than the known LAR inhibitor (BDBM50296375) were discovered by docking studies. Finally, molecular dynamics simulations and post-analysis experiments (RMSD, RMSF, PCA, DCCM and RIN) were conducted to explore the effect of ligands (ZINC97018474 and Compound 1) on LAR and preliminary understand why ZINC97018474 had better inhibitory activity than Compound 1 (BDBM50296375). Communicated by Ramaswamy H. Sarma.


Assuntos
Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Leucócitos , Ligantes , Simulação de Acoplamento Molecular
20.
Int J Ophthalmol ; 12(12): 1898-1907, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31850176

RESUMO

AIM: To evaluate the relative efficacy and safety of besifloxacin for treatment of acute bacterial conjunctivitis. METHODS: A comprehensive search in PubMed, EMBASE Web of Science, Cochrane Central Database and CNKI was undertaken for randomized controlled trials (RCTs) comparing besifloxacin with other treatments or placebo. The primary outcome measures were clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, and bacterial eradication rates of different kinds of pathogens. Safety outcomes were the number of adverse effects (AEs). The final search was performed on August 2018. RESULTS: Six RCTs were included. Four studies compared the efficacy and safety of besifloxacin with placebo, 1 study compared besifloxacin with moxifloxacin, and 1 study compared besifloxacin with gatifloxacin. A total of 2780 patients met the inclusion criteria. Besifloxacin presented higher efficacy and safety than did placebo in clinical resolution, rates of bacterial eradication, individual clinical outcomes, cure rates, bacterial eradication rates of different kinds of pathogens and the number of AEs. There was no significant difference between besifloxacin and moxifloxacin or gatifloxacin in the comparison items mentioned above. CONCLUSION: Besifloxacin is highly effective and safe for treatment of acute bacterial conjunctivitis. Further comparative trials regarding the effect of besifloxacin for treatment of acute bacterial conjunctivitis will aid in treatment decisions.

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