Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 196
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Orphanet J Rare Dis ; 15(1): 72, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32178705

RESUMO

OBJECTIVE: To evaluate the effects of yoga on exercise capacity and quality of life in patients with lymphangioleiomyomatosis (LAM), a rare cystic lung disease in women. PATIENTS AND METHODS: This was a nonrandomized, controlled study conducted in Beijing, China (August 27, 2017 - April 26, 2018). Twenty-six participants were allocated to the intervention (yoga) group (n = 13) or control group (n = 13). The yoga intervention involved a 24-week program of yoga class training for 90 min once a week and no fewer than 2 at-home sessions per week (at least 15 min per session). The 6-min walking distance (6MWD), lung function, serum vascular endothelial growth factor-D (VEGF-D) levels, quality of life, and symptoms of anxiety and depression were measured at baseline, 12-week and 24-week follow-up. An incremental cardiopulmonary exercise test was conducted at baseline and the 24-week follow-up. RESULTS: Eleven patients completed the yoga training program. The yoga group exhibited improvements in the following outcomes versus those of the control group: 6MWD (+ 55 ± 29 m vs + 18 ± 49 m, P = 0.04), anaerobic threshold (3.4 ± 2.4 ml/min/kg vs 1.6 ± 1.4 ml/min/kg, P = 0.035) and peak work load (11.7 ± 14.6 W vs 0.2 ± 9.1 W, P = 0.027). There was no significant difference in peak oxygen consumption (VO2peak), lung function, VEGF-D level, and quality of life between the yoga and control groups. No adverse effects were found in the yoga group. CONCLUSION: Yoga is a feasible and safe intervention for pulmonary rehabilitation and potentially improves exercise capacity in patients with LAM. TRIAL REGISTRATION: (Clinical trial registration number at www.chictr.org.cn: ChiCTR-OON-1701274).

2.
Bioorg Chem ; 97: 103680, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32120078

RESUMO

The phytochemical investigation of Andrographis paniculata resulted in the isolation of a novel 15-spiro diterpenoid dimer bisandrographolide G (1). Its structure was determined by 1D and 2D NMR, HRESIMS, electronic circular dichroism (ECD), and TD DFT calculations of ECD spectra. It showed potent inhibitory activity against human carboxylesterase 2 (CES 2) with an IC50 value of 4.61 ± 0.23 µM, and it was defined as a mixed-competitive type inhibitor with a Ki value of 8.88 µM based on the inhibition kinetics result. This finding gave us a hit to develop new generation of human CES 2 inhibitors.

3.
Bioorg Chem ; 97: 103714, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146181

RESUMO

Six new triterpenoids (1-6) and 22 known analogues (7-28), were separated from the aerial parts of Anchusa italica Retz., a traditional Uygur medicine for treating cardiovascular and cerebrovascular diseases in the Xinjiang region, China. The possible effects of compounds 1-28 on hypoxia/reoxygenation (H/R) induced cardiomyocytes injury were assayed, and compounds 4, 6-17, 21-22 and 26-28 showed significant protective effects. Further, the representative new compound 6 significantly suppressed the levels of H/R-induced apoptosis and autophagy in neonatal rat cardiomyocytes, with the reversing of the downregulated expression of Bcl-2 and upregulated expression of Bax and Beclin-1 by compound 6 treatment in neonatal rat cardiomyocytes following H/R injury. In addition, compound 6 protected cardiomyocyte from H/R injury, and pretreatment with 6 could decrease CK and LDH levels. Compound 6 also alleviated H/R-induced phosphorylation of p38 MAPK in neonatal rat cardiomyocytes. Therefore, tripterpenoid 6 and its analogues may be the pharmacodyamic material of A. italica, and offer a promising therapeutic approach for treating cardiomyocyte injury induced by H/R.

4.
Fitoterapia ; 142: 104490, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017968

RESUMO

Privileged structures are widely used in the process of drug design, and provide an effective template in medicinal chemistry. Diarylheptanoids are a class of structurally distinctive compounds with a wide variety of bioactivity, raising keenly interest in the past decades. Turmeric is a golden spice from the rhizome of the plant Curcuma longa, used for food preparations and giving color since ancient times. Curcumin, obtained from turmeric, has showed widely biological abilities with low toxicity in recent studied. Thus, a spice originally common in the kitchen has recently broadened its application to the clinic. This review aims to highlight diarylheptanoid as a privileged scaffold in drug discovery. In this review, we summarized diverse biological and pharmacological effects of diarylheptanoids and explored the therapeutic application and development of diet based on their structure.

5.
Clin Lab ; 66(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32013359

RESUMO

BACKGROUND: To compare the diagnostic values of leukocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in distinguishing between acute appendicitis (AA) and right ureterolithiasis (RU). METHODS: In this retrospective study, 106 patients diagnosed with AA (Appendicitis group) and 33 cases with RU (Ureterolithiasis group) were enrolled due to acute right lower abdominal pain. The levels of peripheral blood leukocyte counts (leukocytes), neutrophil counts (neutrophils), lymphocyte counts (lymphocytes), platelet counts (platelets), NLR and PLR were recorded and compared between the two groups. Student's t-test for independent samples was adopted for comparing the mean between the two groups. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Comparison of AUC was performed using the Z-test. RESULTS: The levels of leukocytes, neutrophils, NLR, and PLR were significantly increased in AA compared with RU (all p < 0.01), while there were no significant statistical differences of lymphocytes and platelets (all p > 0.05); moreover, AUC in distinguishing AA from RU was 0.797 (95% confidence interval (CI), 0.721 to 0.861) for leukocytes, 0.814 (95% CI, 0.740 to 0.875) for neutrophils, 0.770 (95% CI, 0.691 to 0.837) for NLR, and 0.608 (95% CI, 0.522 to 0.690) for PLR, and significant differences were observed between PLR and any of the three other parameters (all p < 0.01), while there were no significant statistical differences after pairwise comparison between leukocytes, neutrophils and NLR (all p > 0.05). Finally, the cutoff values were 13.1 × 109/L in distinguishing between AA and RU (specificity 87.88%, sensitivity 63.21%, and Youden index 0.511) for leukocytes, 7.4 x 109/L (specificity 69.70%, sensitivity 83.02%, and Youden index 0.527) for neutrophils, 5.57 (specificity 81.82%, sensitivity 68.87%, and Youden index 0.507) for NLR, and 182.5 (specificity 84.85%, sensitivity 37.74%, and Youden index 0.226) for PLR. CONCLUSIONS: Leukocytes, neutrophils, and NLR can demonstrate more accurate and reliable diagnostic values than PLR, suggesting that they are useful and potential biomarkers in distinguishing between AA and RU.

6.
Bioorg Chem ; 96: 103609, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007722

RESUMO

Hexokinase 2 (HK2) is over-expressed in most of human cancers and has been proved to be a promising target for cancer therapy. In this study, based on the structure of HK2, we screened over 6 millions of compounds to obtain the lead. A total of 26 (E)-N'-(2,3,4-trihydroxybenzylidene) arylhydrazide derivatives were then designed, synthesized, and evaluated for their HK2 enzyme activity and IC50 values against two cancer cell lines. Most of the 26 target compounds showed excellently in vitro activity. Among them, compound 3j showed the strongest inhibitory effects on HK2 enzyme activity with an IC50 of 0.53 ± 0.13 µM and exhibited the most potent growth inhibition against SW480 cells with an IC50 of 7.13 ± 1.12 µM, which deserves further studies.

7.
EMBO J ; 39(1): e101259, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31538360

RESUMO

Psychiatric diseases are often accompanied by circadian disruptions, but the molecular underpinnings remain largely unclear. To address this, we screened genes that have been previously reported to be associated with psychiatric diseases and found that TRRAP, a gene associated with schizophrenia, is involved in circadian rhythm regulation. Knocking down Nipped-A, the Drosophila homolog of human TRRAP, leads to lengthened period of locomotor rhythms in flies. Molecular analysis demonstrates that NIPPED-A sets the pace of the clock by increasing the mRNA and protein levels of core clock genes timeless (tim) and Par domain protein 1ε (Pdp1ε). Furthermore, we found that NIPPED-A promotes the transcription of tim and Pdp1ε possibly by facilitating deubiquitination of histone H2B via the deubiquitination module of the transcription co-activator Spt-Ada-Gcn5 acetyltransferase complex. Taken together, these findings reveal a novel role for NIPPED-A in epigenetic regulation of the clock.

8.
Chem Biodivers ; 17(2): e1900531, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31825561

RESUMO

Euphorbia factor L3 , a lathyrane diterpenoid extracted from Euphorbia lathyris, was found to display good anti-inflammatory activity with very low cytotoxicity. To find more potent anti-inflammatory drugs, two series of Euphorbia factor L3 derivatives with fatty and aromatic acids were designed and synthesized. Among them, lathyrane derivative 5n exhibited most potent inhibition on LPS-induced NO production in RAW264.7 cells with no obvious cytotoxicity. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to anti-inflammatory activity, we conducted a structure-activity relationship study of these compounds.

9.
Pharmacol Res ; 151: 104547, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734345

RESUMO

B-cell lymphoma-extra large (Bcl-XL) is one of the anti-apoptotic proteins of the Bcl-2 family that is localized in the mitochondria. Bcl-XL is one of the key regulators of apoptosis that can also regulate other important cellular functions. Bcl-XL is overexpressed in many cancers, and its inhibitors have shown good therapeutic effects. Bcl-XL interacts with Beclin 1, a key factor regulating autophagy. Bcl-XL is essential for the survival of neurons and plays protective roles in neuronal injuries. It can promote the growth of neurons and the correct formation of neural networks, enhance synaptic plasticity, and control neurotoxicity. Bcl-XL can also promote the transport of Ca2+ to mitochondria, increase the production of ATP, and improve metabolic efficiency. In addition, targeting Bcl-XL has shown potential value in autoimmune diseases and aging. In this review, we summarize the functions of Bcl-XL in cancer, autophagy, Ca2+ signaling, neuroprotection, neuronal growth and synaptic plasticity, energy metabolism, immunity, and senescence as revealed by investigations conducted in the past 10 years. Moreover, we list some inhibitors that have been developed based on the functions of Bcl-XL.

10.
Chem Biol Interact ; 316: 108913, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838052

RESUMO

Protein kinases play an indispensable role in signaling pathways that regulate tumor cell functions, which represent potent therapeutic targets in cancers. Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) as a serine/threonine kinase has recently been reported to be upregulated in pancreatic ductal adenocarcinoma (PDAC) and show protumorigenic effect. By activity-guided phytochemical investigation of the extracts from Glycyrrhiza uralensis Fisch, we expect to find the effective constituents that can suppress pancreatic cancer cell proliferation and/or induce cells apoptotic by inhibiting DYRK1A. Eight isopentenyl-substituted compounds (1-8), including four coumarins (1-4), one benzofuran (5), and three flavonoids (6-8), were isolated and identified from G. uralensis Fisch. Among them, licocoumarone (LC, 5) showed effective inhibitory activity against DYRK1A with an IC50 value of 12.56 µM. Molecular docking analysis suggested that LC completely occupied the whole pocket of DYRK1A and formed obvious hydrophobic interactions and hydrogen bonds with DYRK1A residues. Further in vitro validation, including Microscale Thermophoresis (MST) and drug affinity responsive target stability (DARTS) techniques, demonstrated the specific combining capacity of LC to DYRK1A. Meanwhile, LC induced significant cytotoxicity against DYRK1A-overexpressing BxPC-3 cells with an IC50 value of 50.77 µM. Mechanism studies revealed that LC reduced c-MET protein level by inhibiting DYRK1A. These findings provide preliminary evidences that LC as a natural DYRK1A inhibitor suppresses human pancreatic adenocarcinoma BxPC-3 cell proliferation and induces cell apoptotic, which might present new options and possibilities for targeted therapies in pancreatic cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Resorcinóis/farmacologia , Benzofuranos/química , Benzofuranos/metabolismo , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Glycyrrhiza/química , Glycyrrhiza/metabolismo , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Resorcinóis/química , Resorcinóis/metabolismo
11.
Biosens Bioelectron ; 151: 111971, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31868610

RESUMO

For D-amino acid (DAA) electrochemical biosensors, it is necessary to achieve chiral recognition in racemic solutions or mixtures. However, common chiral recognition is only performed in a single isomer solution. Here, D-amino acid oxidase (DAAO) was used as a chiral selector, and carbon nanotubes (CNTs) as a signal amplifier to construct a non-mediator-style DAA biosensor. The biosensor showed high performance against enantiomer interference: in alanine (Ala) enantiomer mixtures, accurate quantification of D-Ala was achieved when the concentration ratio of L-Ala to D-Ala was 100. In Ala racemic solutions, the linear equation slope was almost consistent with that of standard D-Ala. This high performance was due to the combination of stereoselectivity (enzyme protein) and a catalytic reaction (redox center). The mechanism for the electrical signal change of the biosensor was explored and verified by cyclic voltammetry (CV). The results showed that (i) flavin adenine dinucleotide (FAD, redox center of DAAO) was a direct electroactive substance that produced a reduction peak current; in the presence of O2, the amount of FAD increased leading to an increase of the reduction peak current. (ii) In the presence of DAA, the chemical reaction FAD+DAA â†’ imino acids+ FADH2 occurred and consumed FAD, which resulted in its decrease; thus, the reduction peak current also decreased. Under the same oxygen concentration, the linear decrease of the reduction peak current in the presence of DAA was due to FAD consumption. The biosensor was used for practical analyses in milk and urine samples with satisfactory results.


Assuntos
Alanina/análise , D-Aminoácido Oxidase/química , Enzimas Imobilizadas/química , Técnicas Biossensoriais , Catálise , Técnicas Eletroquímicas , Eletrodos , Flavina-Adenina Dinucleotídeo/química , Nanotubos de Carbono/química , Oxirredução , Estereoisomerismo , Propriedades de Superfície
13.
Curr Med Sci ; 39(6): 863-873, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845216

RESUMO

Voltage-gated sodium (Nav) channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization. Mutations in Nav channels are associated with a variety of channelopathies, which makes them relevant targets for pharmaceutical intervention. So far, the cryoelectron microscopic structure of the human Nav1.2, Nav1.4, and Nav1.7 has been reported, which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery. In this review, we focus on the recent advances in the structure, molecular mechanism and modulation of Nav channels, and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future.

14.
Chem Commun (Camb) ; 55(95): 14271-14274, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31714545

RESUMO

Q[8]-based honeycomb-like frameworks can be obtained in [AuCl4]--free aqueous HNO3 solution and aqueous HCl and HNO3 solutions that contain [AuCl4]-. The outer surface interaction of Q[8] with planar inorganic anions [AuCl4]- and NO3- is the main driving force. These frameworks exhibit a high selectivity for imprisoning [AuCl4]- that could establish a process for gold recovery.

15.
Anal Chem ; 91(21): 13803-13809, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31591882

RESUMO

Identification and quantitation of enantiomers is a critical and challenging step in the process of chiral capillary electrophoresis (CE) analysis, especially when the optically pure enantiomers are expensive or commercially unavailable. Herein, a method of CE in combination with circular dichroism (CD) spectroscopy for the identification of enantiomeric peak independent of single enantiomer standard was proposed. By comparing the theoretical CD spectrum of the single enantiomer calculated by time-dependent density functional theory (TDDFT) with the experimental CD spectrum of the enantiomeric mixture, the configuration of the dominant enantiomer in the nonracemic mixture was determined. Considering that the dominant enantiomer showed bigger peak area on the CE electrophoretogram, the enantiomeric peak was easily identified. Three kinds of enantiomers including seven chiral compounds (i.e., tryptophan, tyrosine, phenylalanine, Boc-valine, Boc-leucine, ibuprofen, and naproxen) were used to evaluate the reliability of the method. The concentration of the single enantiomer in the mixture can be further accurately quantified based on the total concentration of the mixture and the peak area ratio of a couple of enantiomers, and the accuracy was assessed by taking ibuprofen as an example. The developed CE-CD method provides an alternative tool for the analysis of nonracemic mixture with good ECD signals.

16.
Bioorg Chem ; 93: 103315, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31605927

RESUMO

Glutamic-oxaloacetic transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements for sustained proliferation. As such, the GOT1 inhibitor may provide a new strategy for the treatment of various cancers. Adapalene has been approved by FDA for the treatment of acne, pimples and pustules, and it may also contribute to the adjunctive therapy for advanced stages of liver and colorectal cancers. In this work, we first examined the enzyme inhibition of over 500 compounds against GOT1 in vitro. As a result, Adapalene effectively inhibited GOT1 enzyme in a non-competitive manner. MST and DARTS assay further confirmed the high affinity between Adapalene and GOT1. Furthermore, the growth and migration of ovarian cancer ES-2 cells were obviously inhibited by the treatment of Adapalene. And it induced the apoptosis of ES-2 cells according to Western blot and Hoechst 33258 straining. In addition, molecular docking demonstrated that Adapalene coordinated in an allosteric site of GOT1 with low binding energy. Furthermore, knockdown of GOT1 in ES-2 cells decreased their anti-proliferative sensitivity to Adapalene. Together, our data strongly suggest Adapalene, as a GOT1 inhibitor, could be regarded as a potential drug candidate for ovarian cancer therapy.

17.
J Org Chem ; 84(21): 13595-13603, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31549831

RESUMO

Five unusual dimers of ent-labdane diterpenoids (1-5) were isolated and identified from Andrographis paniculata, a famous medicinal plant. Bisandrographolide E (1) represents the first example of a labdane dimer possessing an unprecedent tricyclic system that comprised a spiroketal moiety fused with a ketal-γ-lactone unit in its skeleton. Its biosynthetically related intermediates, all four stereoisomers at C-12 and C-15', bisandrographolides F (2, a new compound) and A-C (3-5), were obtained at the same time. The steric configurations of the newly formed asymmetric carbons in 1-5 were first solved by single-crystal X-ray diffraction of the diacetone derivatives of 2-4 and ECD and NMR calculations of 1. More importantly, bisandrographolides 1-5, with different chemical structures or absolute configurations at C-12 and C-15', selectively activated different TRPV1-4 channels and protected cardiomyocytes from hypoxia-reoxygenation injury. Among them, 5 with 12R/15'S configuration activated TRPV1 most effectively and displayed the best cardiomyocyte protection.

18.
Lasers Med Sci ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31485783

RESUMO

miR-548-3p is one of the members of miR-548 family, a large primate-specific miRNA gene family. The role of miR-548-3p in lung cancer was less studied. In this study, we found the expression of miR-548-3p was lower both in clinical tumor specimens and lung cancer cells compared with normal controls. In vitro, miR-548-3p inhibited lung cancer cell growth and promoted cell apoptosis at the S stage of cell cycle. The underlying mechanism of miR-548b-3p-induced cell proliferation inhibition and apoptosis may be associated with the inhibition of PI3K/AKT signaling pathway. In vivo, miR-548b-3p also suppressed tumor growth in xenografts model of lung cancer cells. Our results indicated that miR-548b-3p might be an anti-tumor target of lung cancer in the future.

19.
Spine (Phila Pa 1976) ; 44(20): 1441-1448, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31365514

RESUMO

STUDY DESIGN: A prospective study of cardiopulmonary function in patients with congenital scoliosis (CS). OBJECTIVE: To investigate the relationship of thoracic cage deformity and exercise tolerance in CS patients. SUMMARY OF BACKGROUND DATA: Congenital thoracic scoliosis and chest deformity lead to restrictive pulmonary dysfunction and in some severe cases cause cardiopulmonary failure. However, it is still unknown the relationship between thoracic deformity and exercise performance. METHODS: Patients with congenital thoracic spinal deformity were included and had radiological assessment of thoracic cage, pulmonary function testing, and cardiopulmonary exercise testing. Thoracic dimension including height, width, and depth were measured and geometry parameters were calculated. Two-tailed Pearson and Spearman correlation test and linear regression analysis were performed to investigate correlation of radiographic parameters, pulmonary function, and physical capacity. RESULTS: Sixty patients (41 females and 19 males) were included, with an average age of 18.9 years. Patients with smaller thoracic height (P < 0.001) and width (P < 0.01) and larger depth (P < 0.05) had significantly worse static pulmonary function. In exercise testing, these patients showed significant tendency of ventilation insufficiency, including lower minute ventilation (P < 0.05), faster breathing frequency (P < 0.05), and smaller tidal volume (P < 0.01). Thoracic depth was negatively correlated to exercise capacity, reflected by work rate (P < 0.001), peak oxygen intake (P < 0.001), and heart rate (P = 0.043). Patients with abnormal thoracic geometry, especially a lower ratio of height to depth and a lower ratio of width to depth, have significantly worse static pulmonary function and exercise capacity (all P < 0.05). CONCLUSION: Decreasing thoracic height and width results in restrictive pulmonary dysfunction. Distortion and asymmetry of the thoracic cage are associated with abnormal breathing pattern and reduction of exercise capacity. LEVEL OF EVIDENCE: 3.


Assuntos
Teste de Esforço/métodos , Pulmão/diagnóstico por imagem , Caixa Torácica/anormalidades , Caixa Torácica/diagnóstico por imagem , Escoliose/diagnóstico por imagem , Adolescente , Adulto , Exercício/fisiologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Estudos Prospectivos , Testes de Função Respiratória/métodos , Caixa Torácica/fisiologia , Escoliose/fisiopatologia , Adulto Jovem
20.
Bioorg Chem ; 92: 103186, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465967

RESUMO

Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herb Physalis pubescens L., commonly named as "husk tomato or hairy groundcherry", and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA