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1.
Chemosphere ; : 132907, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34780744

RESUMO

The aggregation of anaerobic ammonium oxidation (anammox) bacteria is important for the start-up and biomass retention of anammox processes. However, it is unclear whether it is beneficial to the activity, growth and reproduction of anammox bacteria. In this study, four reactor systems were developed to explore the effects of aggregation on anammox activity, growth and reproduction, after excluding the contribution of aggregation to sludge settling and retention. Results demonstrated that (i) compared with free-living planktonic bacteria, the aggregated bacteria had a higher volumetric nitrogen removal rate (0.75 kg-N/(m³·d)) and specific nitrogen removal activity (1.097 kg-N/VSS/d). And after 67 days cultivation, it had the higher sludge concentration and relative abundance (92.4%); (ii) compared with acidic polysaccharides and α-d-glucopyranose polysaccharides, ß-d-glucopyranose polysaccharide play more essential roles of anammox aggregation; (iii) norspermidine triggered the secretion of α-d-glucopyranose polysaccharides to combat the toxicity, and inhibited biomass growth rate; (iv) immobilization in polyvinyl alcohol (10%) or sodium alginate (2%) gel beads was better than sodium alginate-chitosan gel beads and norspermidine (biofilm inhibitor) for the cultivation of free-living planktonic anammox bacteria. This is the first comparative study of three methods for cultivating free-living anammox bacteria. In conclusion, we found that the aggregation of anammox sludge not only facilitates biomass retention but also enhances the bioactivity, relative abundance, growth, and reproduction rate of anammox bacteria. The work is helpful to understand the formation of anammox granular sludge and contribute to the fast start-up and stable operation in anammox application.

2.
Eur J Med Chem ; : 113986, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34802839

RESUMO

Biased agonism refers to the ability of compounds to drive preferred signaling pathways and avoid adverse signaling pathways in a ligand-dependent manner for some G-protein-coupled receptors. It is thought that the separation of therapeutic efficacy (e.g., analgesia) from adverse effects (e.g., respiration depression) can be achieved through the design of biased MOR agonists and one example is the recently approved MOR biased agonist oliceridine (TRV130). However, oliceridine only demonstrates modest beneficial effects as compared to other opioids in terms of therapeutic/adverse effect balance. One possibility attributable to the modest success of oliceridine is its limited bias, and as such developing MOR ligands with a more biased agonism profile could in theory further improve the beneficial effects of the ligands. Here, we rationally designed and synthesized a series of derivatives as potent highly biased MOR agonists (19a-v) through the modification and structure-activity relationship study of TRV130. This novel synthetic molecule, LPM3480392 (19m), demonstrated improved in vitro biased agonism (EC50 = 0.35 nM, Emax = 91.4%) with no measured ß-arrestin recruitment (EC50 > 30000 nM, Emax = 1.6%), good brain penetration (B/P ratio = 4.61, 0.25 h post-IV dosing 2.0 mg/kg), a favorable pharmacokinetic profile (distribution volume = 10766 mL/kg, t1/2 = 1.9 h) and produced potent antinociceptive effect with reduced respiratory suppression (sO2(%) = 92.17, 0.32 mg/kg, SC) as compared to TRV130. LPM3480392 has completed preclinical studies and is currently under clinical development (CTR20210370) as an analgesic for the treatment of moderate to severe pain.

3.
Physiol Plant ; : e13596, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34761393

RESUMO

Sugars are essential regulatory molecules involved in plant growth and development and defense response. Although the relationship between sugars and disease resistance has been widely discussed, the underlying molecular mechanisms remain unexplored. Ring rot caused by Botryosphaeria dothidea (B. dothidea), which severely affects fruit quality and yield, is a destructive disease of apples (Malus domestica Borkh.). The present study found that the degree of disease resistance in apple fruit was closely related to glucose content. Therefore, the gene encoding a hexokinase, MdHXK1, was isolated from the apple cultivar 'Gala', and characterized during the defense response. Overexpression of MdHXK1 enhanced disease resistance in apple calli, leaves and fruits by increasing the expression levels of genes related to salicylate (SA) synthesis (PHYTOALEXIN DEFICIENT 4, PAD4; PHENYLALANINE AMMONIA-LYASE, PAL; and ENHANCED DISEASE SUSCEPTIBILITY 1, EDS1) and signaling (PR1; PR5; and NONEXPRESSER OF PR GENES 1, NPR1) as well as increasing the superoxide (O2- ) production rate and the hydrogen peroxide (H2 O2 ) content. Overall, the study provides new insights into the MdHXK1-mediated molecular mechanisms by which glucose signaling regulates apple ring rot resistance.

4.
J Agric Food Chem ; 69(45): 13373-13385, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34735146

RESUMO

Succinate dehydrogenase (SDH) is known as an ideal target for the investigations of fungicides. To develop novel SDH inhibitors, 30 novel thiophene/furan-1,3,4-oxadiazole carboxamide derivatives were designed and synthesized. In the in vitro antifungal assay, a majority of the target compounds demonstrated fair to potent antifungal activity against seven tested phytopathogenic fungi. Compounds 4b, 4g, 4h, 4i, and 5j showed remarkable antifungal activity against Sclerotinia sclerotiorum, affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound 4i displayed the most potent activity against S. sclerotiorum (EC50 = 0.140 ± 0.034 mg/L), which was superior to that of boscalid (EC50 = 0.645 ± 0.023 mg/L). A further morphological investigation revealed the abnormal mycelia and damaged cell structures of compound 4i-treated S. sclerotiorum by scanning electron microscopy. Furthermore, the in vivo antifungal assay against S. sclerotiorum revealed that compounds 4g and 4i were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds 4g and 4i also presented significant inhibitory activity with IC50 values of 1.01 ± 0.21 and 4.53 ± 0.19 µM, respectively, which were superior or equivalent to that of boscalid (3.51 ± 2.02 µM). Molecular docking and molecular dynamics simulation of compound 4g with SDH revealed that compound 4g could form strong interactions with the key residues of the SDH. These results indicated that this class of derivatives could be a promising scaffold for the discovery and development of novel SDH inhibitors.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Antifúngicos/farmacologia , Ascomicetos , Inibidores Enzimáticos/farmacologia , Fungicidas Industriais/farmacologia , Furanos/farmacologia , Simulação de Acoplamento Molecular , Oxidiazóis , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo , Ácido Succínico , Tiofenos/farmacologia
5.
Front Cell Dev Biol ; 9: 736298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616742

RESUMO

Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as "cold tumors," have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

6.
Front Pharmacol ; 12: 741794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594228

RESUMO

Toludesvenlafaxine hydrochloride dihydrate is a novel chemical entity and a potential triple monoamine reuptake inhibitor. This study characterized the in vitro triple reuptake inhibition activity, antidepressant-like activity in animals, and pharmacokinetic profiles in rats of toludesvenlafaxine. Binding affinity was determined using human serotonin transporter (SERT) protein, norepinephrine transporter (NET) protein and dopamine transporter (DAT) protein, and the reuptake inhibition was determined using Chinese hamster ovary cells expressing human SERT, NET and DAT. The antidepressant-like activity was examined in rat chronic unpredictable mild stress model and olfactory bulbectomized model. In rats, the tissue distribution and pharmacokinetic parameters were determined. Toludesvenlafaxine had high binding affinity on SERT, NET and DAT, and significantly inhibited the reuptake of serotonin (IC50 = 31.4 ± 0.4 nM), norepinephrine (IC50 = 586.7 ± 83.6 nM) and dopamine (IC50 = 733.2 ± 10.3 nM) in vitro. Toludesvenlafaxine demonstrated significant antidepressant-like effects in rat models at 8-16 mg/kg. In addition, toludesvenlafaxine significantly reduced serum corticosterone and significantly increased testosterone levels in rats. Toludesvenlafaxine was quickly absorbed and converted to O-desvenlafaxine (ODV) after oral administration, both of which were selectively distributed into the hypothalamus with high concentration. Plasma ODV exposure was proportionally related to the doses after oral dosing. These results suggest that toludesvenlafaxine is a triple reuptake inhibitor with relatively fast-acting antidepressant-like activity and good therapeutic profile including improvement of anhedonia and sexual function.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34705656

RESUMO

The computational methods of protein-protein interaction sites prediction can effectively avoid the shortcomings of high cost and time in traditional experimental approaches. However, the serious class imbalance between interface and non-interface residues on the protein sequences limits the prediction performance of these methods. This work therefore proposed a new strategy, NearMiss-based under-sampling for unbalancing datasets and Random Forest classification (NM-RF), to predict protein interaction sites. Herein, the residues on protein sequences were represented by the PSSM-derived features, hydropathy index (HI) and relative solvent accessibility (RSA). In order to resolve the class imbalance problem, an under-sampling method based on NearMiss algorithm is adopted to remove some non-interface residues, and then the random forest algorithm is used to perform binary classification on the balanced feature datasets. Experiments show that the accuracy of NM-RF model reaches 87.6% and 84.3% on Dtestset72 and PDBtestset164 respectively, which demonstrate the effectiveness of the proposed NM-RF method in differentiating the interface or non-interface residues.

8.
Front Oncol ; 11: 698278, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631528

RESUMO

Background: Glioma is the most frequent brain malignancy presenting very poor prognosis and high recurrence rate. Focal adhesion complexes play pivotal roles in cell migration and act as hubs of several signaling pathways. Methods: We used bioinformatic databases (CGGA, TCGA, and GEO) and identified a focal adhesion-related differential gene expression (FADG) signature by uniCox and LASSO regression analysis. We calculated the risk score of every patient using the regression coefficient value and expression of each gene. Survival analysis, receiver operating characteristic curve (ROC), principal component analysis (PCA), and stratified analysis were used to validate the FADG signature. Then, we conducted GSEA to identify the signaling pathways related to the FADG signature. Correlation analysis of risk scores between the immune checkpoint was performed. In addition, the correlation of risk scores and genes related with DNA repair was performed. CIBERSORT and ssGSEA were used to explore the tumor microenvironment (TME). A nomogram that involved our FADG signature was also constructed. Results: In total, 1,726 (528 patients diagnosed with WHO II, 591 WHO III, and 603 WHO IV) cases and 23 normal samples were included in our study. We identified 29 prognosis-related genes in the LASSO analysis and constructed an eight FADG signature. The results from the survival analysis, stratified analysis, ROC curve, and univariate and multivariate regression analysis revealed that the prognosis of the high-risk group was significantly worse than the low-risk group. Correlation analysis between risk score and genes that related with DNA repair showed that the risk score was positively related with BRCA1, BRCA2, RAD51, TGFB1, and TP53. Besides, we found that the signature could predict the prognosis of patients who received radiation therapy. SsGSEA indicated that the high-risk score was positively correlated with the ESTIMATE, immune, and stromal scores but negatively correlated with tumor purity. Notably, patients in the high-risk group had a high infiltration of immunocytes. The correlation analysis revealed that the risk score was positively correlated with B7-H3, CTLA4, LAG3, PD-L1, and TIM3 but inversely correlated with PD-1. Conclusion: The FADG signature we constructed could provide a sensitive prognostic model for patients with glioma and contribute to improve immunotherapy management guidelines.

9.
Environ Technol ; : 1-11, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34661510

RESUMO

Ni-EDTA is widely present in electroplating effluents. It cannot be effectively removed by traditional wastewater treatment methods due to its chemical stability. In this study, copper sulphide/cuprous sulphide doped zero-valent iron@carbon (ZVI@C/CuS/Cu2S) was prepared to active peroxymonsulphate (PMS) to decomposition Ni-EDTA. The ZVI@C/CuS/Cu2S + PMS process shows excellent performance under neutral or even alkaline conditions. This is due to the acceleration of ZVI electron transport by CuS/Cu2S, the autocatalysis of CuS/Cu2S itself, and the synergistic effect of CuS/Cu2S and Ni-EDTA. The removal efficiency of 50 ppm Ni-EDTA electroplating effluents reached 99.53% at 10 min, and the discharge water can meet the Chinese emission standard. The influences of the main parameters such as initial pH value, catalyst, PMS and initial Ni-EDTA concentration on removal efficiency was systematically investigated.

10.
Macromol Rapid Commun ; : e2100510, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643989

RESUMO

To solve the issue of polymeric materials recycling, developing intrinsic self-healing materials containing dynamic bonds has attracted many researchers' highly concerning. However, the tradeoff between their mechanical strength and stretchability always does not avoid. Herein, to surmount the above tradeoff, metal-ligand (Cu2+ -S) interactions are introduced into the cross-linking polythiourethane covalent adaptable networks (PTU CANs) with three kinds of dynamic motifs (thiourethane, disulfide, and hydrogen bonds). When the molar ratio of Cu2+ to S is 6.37%, the break strength (9.41 ± 0.34 MPa) and Young's modulus (26.02 ± 0.55 MPa) of the metal-ligand coordination complex PTU (Cu2+ -PTU-3) dramatically increase, whereas the peak strain almost does not decline (454.44 ± 3.95%). To conduct the repairing, Cu2+ -PTU-3 is further confirmed excellent repairing capability. Therefore, these new PTU CANs have significant potential for the new self-healing materials.

11.
Cancer Cell Int ; 21(1): 512, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563200

RESUMO

BACKGROUND: Unilateral breast cancer (UBC) patients with germline pathogenic BRCA1/2 variants have a higher risk of developing contralateral breast cancer (CBC) and need contralateral risk-reducing local treatments, including contralateral risk-reducing mastectomy (CRRM) and prophylactic irradiation (CPI). The aim of our study was to systematically explore the efficacy of CRRM and CPI in reducing CBC risk and increasing survival. METHODS: A search was done, and eligible randomized trials and cohort studies should include and compare UBC patients with germline pathogenic BRCA1/2 variants who have and have not received contralateral risk-reducing local treatment. Random-effects meta-analysis was used in this study. Primary outcomes of the studies included overall survival (OS) and the incidence of contralateral breast cancer (CBC), and secondary outcomes included breast cancer-specific survival (BCSS). RESULTS: A total of five studies with 1769 UBC patients with germline pathogenic BRCA1/2 variants were enrolled in our meta-analysis. CRRM was correlated with a lower risk of CBC in UBC patients with germline pathogenic BRCA1/2 variants (summary RR = 0.07; 95%CI 0.03-0.13, I2 = 3%), a significantly increased OS (summary RR, 1.15; 95%CI 1.04-1.26, I2 = 26%) and a significantly increased BCSS (summary RR, 1.18; 95%CI 1.07-1.31, I2 = 64%) compared with surveillance. CPI also decreased the risk of CBC (RR 0.02; 95%CI 0.05-0.88) but did not significantly improve OS (RR 0.97; 95%CI 0.90-1.05) and BCSS (RR 0.97; 95%CI 0.90-1.05) compared with surveillance. CONCLUSIONS: CRRM reduces CBC risk and increases OS and BCSS in UBC patients with germline pathogenic BRCA1/2 variants, and could be offered as a risk-reducing local treatment. For those who oppose CRRM, CPI could be offered for CBC-risk reduction, while its survival benefit is still uncertain.

12.
Front Oncol ; 11: 710156, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336698

RESUMO

A proportion of up to 10% of breast cancer resulted from hereditary germline pathogenic variants (GPVs) in cancer predisposition genes (CPGs), which been demonstrated distinct clinical features and imaging manifestations. However, the performance of imaging modalities for breast cancer surveillance in CPG mutation-carriers is still unclear, especially in Asian women. A population of 3002 breast cancer patients who received germline genetic testing of CPGs was enrolled from three hospitals in China. In total, 343 (11.6%) patients were found to harbor GPVs in CPGs, including 137 (4.6%) in BRCA1 and 135 (4.6%) in BRCA2. We compared the performances of ultrasound, mammograms, MRI, and the combining strategies in CPG mutation carriers and non-carriers. As a result, the ultrasound showed a higher detection rate compared with mammograms regardless of the mutation status. However, its detection rate was lower in CPG mutation carriers than in non-carriers (93.2% vs 98.0%, P=2.1×10-4), especially in the BRCA1 mutation carriers (90.9% vs 98.0%, P=2.0×10-4). MRI presented the highest sensitivity (98.5%) and the lowest underestimation rate (14.5%) in CPG mutation carriers among ultrasound, mammograms, and their combination. Supplemental ultrasound or mammograms would add no significant value to MRI for detecting breast cancer (P>0.05). In multivariate logistic regression analysis, the family or personal cancer history could not replace the mutation status as the impact factor for the false-negative result and underestimation. In summary, clinicians and radiologists should be aware of the atypical imaging presentation of breast cancer in patients with GPVs in CPGs.

13.
Invest Ophthalmol Vis Sci ; 62(10): 28, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34427623

RESUMO

Purpose: Decreased trabecular meshwork (TM) cellularity has been implicated as a major reason for TM dysfunction and aqueous humor (AH) outflow abnormalities in primary open angle glaucoma. We previously found that transplantation of induced pluripotent stem cell (iPSC)-derived TM cells can restore TM function and stimulate endogenous TM cell division. The goal of the present study is to investigate whether signaling via gap junctions is involved in this process. Methods: Differentiated iPSCs were characterized morphologically, transcriptionally, and immunohistochemically. After purification, iPSC-TM were co-cultured with mouse TM (MTM) cells to mimic the transplantation procedure. Through the pharmacological antagonists and short hairpin RNA (shRNA) technique, the gap junction function in iPSC-based therapy was determined. Results: In the co-culture system, iPSC-TM increase MTM cell division as well as transfer of Ca2+ to MTM. This effect was blocked by treatment with the gap junction inhibitors carbenoxolone (CBX) or flufenamic acid (FFA). The shRNA mediated knock down of connexin 43 (Cx43) expression in iPSC-TM also results in decreased Ca2+ transfer and lower MTM proliferation rates. In vivo, Cx43 downregulation in transplanted iPSC-TM weakened their regenerative role in an Ad5.myocilinY437H mouse model of glaucoma. Mice receiving these cells exhibited lower TM cellularity and higher intraocular pressure (IOP) than those receiving unmodified iPSC-TM. Conclusions: Our findings reveal a crucial role of gap junction, especially Cx43, in iPSC-based TM regeneration, and provides insights to enhance the regenerative effect of iPSCs in glaucoma therapy.


Assuntos
Humor Aquoso/metabolismo , Glaucoma de Ângulo Aberto/patologia , Células-Tronco Pluripotentes Induzidas/citologia , Pressão Intraocular/fisiologia , Malha Trabecular/patologia , Animais , Diferenciação Celular , Divisão Celular , Células Cultivadas , Modelos Animais de Doenças , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma de Ângulo Aberto/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Malha Trabecular/metabolismo
14.
Cancer Lett ; 520: 422-433, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389434

RESUMO

As the highest incidence of female malignancy, breast cancer is likewise the leading cause of cancer-related deaths. The development of cancer relies on neo-vascularization, which provides sufficient nutrition and oxygen, and supplies a pathway for distant metastasis. Angiogenesis represents the formation of new blood vessels, and is a principal pathogenetic action in breast cancer. Vascular endothelial growth factor (VEGF) is a major angiogenesis regulator that modulates the maintenance and function of mature vascular networks. Therefore, the VEGF pathway is a promising oncotherapeutic target. This review elaborates an update on the prognostic value of VEGF in breast cancer, summarizes clinical experience and lessons of anti-VEGF therapeutics, meanwhile, provides an overview of biomarkers that predict the effectiveness of anti-angiogenic treatment.

15.
Biomed Chromatogr ; 35(12): e5226, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34388261

RESUMO

S-epacadostat (S-EPA) is an efficient and selective small-molecule inhibitor of indoleamine 2,3-dioxygenase 1. It is an EPA analog with a sulfur atom instead of a nitrogen atom at the furazan C3 position. This study documents the pharmacokinetics of S-EPA in dogs and its metabolic pathway. After an oral administration of 15 mg/kg of S-EPA in dogs, the time to peak concentration was 0.80 h, the mean elimination half-life was 7.3 h, and the absolute bioavailability was 55.8%. Furthermore, we identified S-EPA metabolites in dog plasma and dog liver microsomes by UPLC-Q Exactive Orbitrap HRMS. In dog plasma, we found five metabolites, which came from glucuronidation (M1 and M2), deoxygenation (the amidine M4), glucuronidation of M4 (M3), and desulfonamidation and oxidation of M4 (the carboxylic acid M5). In dog liver microsomes, we identified three major metabolites, namely, the glucuronide conjugate (M6), a mono-oxidation product (M7), and a desulfonamidation and oxidation product (M8). Gut microbiota may cause the differences between in vivo and in vitro oxidation metabolisms. Contrary to EPA, S-EPA did not undergo dealkylation, suggesting that substituting the nitrogen with sulfur affects the metabolism of the adjacent alkyl side chain.

16.
Yonsei Med J ; 62(8): 691-701, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34296546

RESUMO

PURPOSE: Resveratrol (REV), a natural compound found in red wine, exhibits antitumor activity in various cancers, including ovarian cancer (OC). However, its potential anti-tumor mechanisms in OC are not well characterized. Here, we tried to elucidate the underlying mechanisms of REV in OC cells. MATERIALS AND METHODS: The anti-proliferative effects of REV against OC cells were measured using CCK-8 assay. Apoptosis was measured using an Annexin V-FITC/PI apoptosis detection kit. The anti-metastasis effects of REV were evaluated by invasion assay and wound healing assay. The miRNA profiles in REV-treated cells were determined by microarray assay. RESULTS: Our results showed that REV treatment suppresses the proliferation, induces the apoptosis, and inhibits the invasion and migration of OV-90 and SKOV-3 cells. miR-34a was selected for further study due to its tumor suppressive roles in various human cancers. We found miR-34a overexpression enhanced the inhibitory effects of REV on OC cells, whereas miR-34a inhibition had the opposite effect in OC cells. In addition, we verified that BCL2, an anti-apoptotic gene, was found directly targeted by miR-34a. We also found that REV reduced the expression of Bcl-2 in OC cells. Further investigations revealed that overexpression of Bcl-2 significantly abolished the anti-tumor effects of REV on OC cells. CONCLUSION: Overall, these results demonstrated that REV exerts anti-cancer effects on OC cells through an miR-34a/Bcl-2 axis, highlighting the therapeutic potential of REV for treatment of OC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Resveratrol/farmacologia , Regulação para Cima
17.
Eur J Med Chem ; 224: 113718, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329999

RESUMO

Vesicular monoamine transporter 2 (VMAT2) is essential for synaptic transmission of all biogenic amines in the brain including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system, VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD). Here, a novel series of dihydrotetrabenazine derivative analogs were designed and synthesized to evaluate their effects on [3H]dihydrotetrabenazine (DTBZ) binding and [3H]DA uptake at VMAT2. Of these analogs, compound 13e showed a high binding affinity for VMAT2 (IC50 = 5.13 ± 0.16 nM) with excellent inhibition of [3H]DA uptake (IC50 = 6.04 ± 0.03 nM) in striatal synaptosomes. In human liver microsomes, 13e was more stable (T1/2 = 161.2 min) than other reported VMAT2 inhibitors such as DTBZ (T1/2 = 119.5 min). In addition, 13e effectively inhibited the spontaneous locomotor activity (percent inhibition at 3 µmol/kg = 64.7%) in Sprague-Dawley rats. Taken together, our results indicate that 13e might be a promising lead compound for the development of novel treatments of TD.

18.
J Med Chem ; 64(14): 10286-10296, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34253025

RESUMO

The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.


Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Descoberta de Drogas , Compostos Macrocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inibidores , Receptor trkC/metabolismo , Relação Estrutura-Atividade
19.
Zhongguo Zhen Jiu ; 41(6): 615-20, 2021 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-34085477

RESUMO

OBJECTIVE: To observe the effect of five-element acupuncture on the cognitive function repair of migraine patients with depression/anxiety disorder. METHODS: The migraine patients with depression/anxiety disorder (19 cases, 5 cases dropped off) were taken as the observation group, and received five-element acupuncture twice a week for 8 weeks. Healthy subjects (19 cases) were selected by demographic data matching as the control group. The cognitive function was evaluated with the event related potential (ERP) technique, and the latency and amplitude of visual evoked potential P300 were adopted as the observation indexes. The headache days (every 4 weeks), headache intensity [visual analogue scale(VAS) score], and headache impact test-6 (HIT-6) score, Hamilton depression scale (HAMD) score and Hamilton anxiety scale (HAMA) score were used as the observation indexes for curative effect. RESULTS: Before the treatment, latency of target stimulus at Fz [ (417.5±34.3) ms] in the observation group was extended compared with the healthy subjects of the control group [(388.6±42.1) ms, P<0.05]. In the observation group, the latency of each point target stimulus [Fz: (376.1±36.2) ms, F3: (374.8±37.6) ms, F4: (372.0±37.6) ms] after treatment were shorter than those [Fz: (417.5±34.3) ms, F3: (417.4±33.8) ms, F4: (416.0±36.6) ms] before treatment (P<0.05). Before and after treatment, there was no significant difference in the amplitude of each point between the observation group and the control group (P>0.05). In the observation group, the headache days was shorter than that before treatment (P<0.01), and the VAS score, HIT-6 score, HAMD score and HAMA score were all lower than before treatment (P<0.01). CONCLUSION: There are some cognitive impairments in migraine patients with depression/anxiety disorder. Five-element acupuncture not only relieves headache, anxiety and depression effectively, but also improves the activation level of the frontal lobe. It significantly repairs the impaired cognitive function.


Assuntos
Terapia por Acupuntura , Transtornos de Enxaqueca , Pontos de Acupuntura , Transtornos de Ansiedade , Cognição , Depressão/terapia , Potenciais Evocados Visuais , Humanos , Transtornos de Enxaqueca/terapia , Resultado do Tratamento
20.
Behav Sci (Basel) ; 11(5)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063082

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic worsened financial stress for higher education students in the U.S. Financial stress is associated with poor dietary behaviors; however, factors that might influence this relationship are not well characterized. The present cross-sectional study investigated the associations between financial stress and dietary intake and dietary risk scores among higher education students (undergraduate and graduate students) in the U.S. and examined whether poor sleep quality and short sleep duration mediated the relationship between financial stress and dietary risk score. Validated tools were used to assess financial stress, sleep quality, sleep duration, dietary intake, and dietary risk. A total of 1280 students from three large U.S. universities completed the study. Results indicated that higher financial stress was associated with lower vegetable, fruit, fiber, and calcium intake, higher added sugar intake from sugar sweetened beverages, and higher dietary risk score. Further, the positive relationship between financial stress and dietary risk score was completely mediated by poor sleep quality among students who reported poor sleep quality and by short sleep duration among students who slept less than 7 h per night. These findings suggest that students might benefit from both financial management training and sleep education services to reduce undesirable dietary behaviors.

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