RESUMO
The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses the anti-HIV triterpenoids and analogs reported during the period of 2009-2019. The article includes not only a comprehensive review of the recent anti-HIV agent development from the perspective of medicinal chemistry, but also discusses structure-activity relationship analyses of the described triterpenoids.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Triterpenos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Extratos Vegetais , Relação Estrutura-Atividade , Triterpenos/farmacologiaRESUMO
A new furostan type steroidal saponin, kingianoside Z (1), along with four known compounds (2-5), was isolated from the ethanolic extract of Polygonatum sibiricum Delar. ex Redoute. Their structures were determined by spectroscopical method and by comparison with previously reported spectroscopic data. Compounds 3-5 showed significant cytotoxicity against HepG2 cell lines with IC50 values of 14.2, 12.1 and 8.5 µM, respectively.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Polygonatum/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Isoflavonas/isolamento & purificação , Estrutura Molecular , Rizoma/química , Saponinas/química , Saponinas/isolamento & purificaçãoRESUMO
A new cyclolanostane triterpenoid glycoside, soulieoside O (1), together with 25-O-acetylcimigenol-3-O-ß-d-xylopyranoside (2) and cimigenol-3-O-ß-d-xylopyranoside (3), was isolated from the rhizomes of Souliea vaginata. Their structures were characterized by spectroscopic analysis and chemical methods. The new compound showed moderate inhibitory activity against three human cancer cell lines with IC50 values of 9.3-22.5 µM.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Glicosídeos/isolamento & purificação , Ranunculaceae/química , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Rizoma/química , Estereoisomerismo , Triterpenos/química , Triterpenos/farmacologiaRESUMO
One new cassane diterpene possessing an unusual N bridge between C-19 and C-20 named caesalsappanin R (1), as well as another new diterpene caesalsappanin S (2), were isolated from the seeds of Caesalpinia sappanwith methanol extract. Their structures were determined by spectroscopic analysis and examined alongside existing data from prior studies. Their biological activities were profiled by their antiplasmodial activity.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Caesalpinia/química , Diterpenos/química , Diterpenos/farmacologia , Antimaláricos/isolamento & purificação , Diterpenos/isolamento & purificação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Testes de Sensibilidade Parasitária , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Twenty-eight compounds were isolated and purified from Clinopodium chinense by Sephedax LH-20, ODS, MCI and preparative HPLC. Their structures were identified as apigenin (1), apigenin-7-O-ß-D-glucopyranoside (2), apigenin-7-O-ß-D-glucuronopyranoside (3), thellungianol (4), apigenin-7-O-ß-D-rutinoside (5), luteolin (6), luteolin-4'-O-ß-D-glucopyranoside (7), apigenin-7-O-ß-D-pyranglycuronate butyl ester (8), luteolin-7-O-ß-D-rutinoside (9), luteolin-7-O-ß-D-noehesperidoside (10), acacetin (11), acacetin-7-O-ß-D-glucuronopyranoside (12), buddleoside (13), naringenin (14), pruning (15), nairutin (16), isosakuranetin (17), isosakuranin (18), didymin (19), hesperidin (20), kaempferol (21), quercetin (22), kaempferol-3-O-α-L-rahmnoside (23), p-hydroxycinnamic acid (24), caffeic acid (25), cis-3-[2-[1-(3,4-dihydroxy-phenyl)-1 -hydroxymethyl]-1,3-ben-zodioxol-5-yl]-(E)-2-propenoic acid (26), mesaconic acid (27), gentisic acid 5-O-ß-D-(6'-salicylyl)-glucopyranoside (28). Among them, compounds 7, 9-10, 12, 23, 26-28 were isolated from the Clinopodium for the first time. The protective effects of compounds 1-6, 8-17 and 19 against H2O2-induced H9c2 cardiomyocyte injury were tested, compounds 15 exhibited significantly protective effects. Compared with the cell viability of (62.12±6.18)% in the model, pruning exhibited viabilities of (84.25±7.36)% at 25.0 mgâ¢L⻹, respectively, using quercetin as a positive control [cell viability of (84.55±8.26)%, 20 mgâ¢L⻹].
Assuntos
Lamiaceae/química , Compostos Fitoquímicos/isolamento & purificação , Animais , Apigenina/isolamento & purificação , Linhagem Celular , Sobrevivência Celular , Miócitos Cardíacos/efeitos dos fármacos , RatosRESUMO
We used Smo siRNA to inhibit hedgehog signaling pathway in embryonic day (E) 13 palatal shelves in organ culture. SiRNA 4 was chosen as the most efficient from four synthesized Smo siRNAs. Palatal shelf fusion rate of 4 µg/mL cyclopamine group was the lowest and significantly lower than that of blank control group (P<0.05), and that of siRNA 4 group was also lower than that of blank control group (P=0.183). At 48 h after transfection, Smo protein level of siRNA 4 group was 64.8% lower than that of blank control group (P<0.05), and Gli1 protein level of 4 µg/mL cyclopamine group was 68.9% lower than that of blank control group (P<0.05). Hedgehog signaling pathway inhibition decreased palatal fusion in organ culture, probably owing to downregulation of Smo and Gli1 proteins.
Assuntos
Proteínas Hedgehog/metabolismo , Palato/embriologia , RNA Interferente Pequeno/genética , Transdução de Sinais , Animais , Proteínas Hedgehog/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Palato/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína Gli2 com Dedos de Zinco , Proteína Gli3 com Dedos de ZincoRESUMO
A new phenylethanoid glycoside, 3'''-O-methylcampneoside I (1), was isolated from the 90% ethanolic extract of the roots of Incarvillea compacta, together with three known compounds, campneoside I (2), ilicifolioside A (3), and campneoside II (4). Their structures were determined spectroscopically and compared with previously reported spectral data. Compound 1 existed as epimers and displayed better 1,1-diphenyl-2-picrylhydrazyl (DPPH)-free radical scavenging activity using di-tert-butyl-4-methylphenol (BHT) as the positive control. In addition, pretreatment of human HepG2 cells with compound 1 significantly increased the viability on CCl4-induced cell death.
Assuntos
Bignoniaceae/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Hidroxitolueno Butilado , Tetracloreto de Carbono/farmacologia , Cresóis , Glicosídeos/química , Humanos , Estrutura Molecular , Fenóis , Picratos/farmacologia , Raízes de Plantas/químicaRESUMO
Altered expression of TROP2 is observed in various types of human cancers. However, the clinical significance and pathological role of TROP2 in gallbladder cancer (GBC) remains unclear. The main objective of this investigation was to clarify the relationships between TROP2 expression and the clinicopathological features of patients with GBC. Immunohistochemistry was performed to investigate the expression of TROP2 and epithelial-mesenchymal transition (EMT) indicator proteins in 93 patients with GBC. Immunohistochemistry showed that the protein expression level of TROP2 was significantly higher in GBC tissues than in adjacent noncancerous tissues. In addition, immunohistochemistry analysis showed that TROP2 expression was significantly correlated with histologic grade (P=0.038), tumor stage (P=0.015), and lymph node metastasis (P=0.007). Furthermore, high TROP2 expression was significantly associated with a loss of the epithelial marker E-cadherin (P=0.013) and acquisition of expression of the mesenchymal marker vimentin (P=0.031). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between TROP2 expression and prognosis of GBC patients. Kaplan-Meier analysis indicated that patients with high TROP2 expression had poor overall survival (P<0.001). Multivariate analysis showed that high TROP2 expression was an independent predictor of overall survival. In conclusion, our data suggest for the first time that the increased expression of TROP2 in GBC is associated significantly with aggressive progression and poor prognosis. In conclusion, this study confirmed that TROP2 might be involved in regulating the EMT and malignant progression in GBC. It also provided the first evidence that TROP2 expression in GBC was an independent prognostic factor of patients, which might be a potential diagnostic and therapeutic target of GBC.
Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias da Vesícula Biliar/metabolismo , Caderinas/metabolismo , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Vimentina/metabolismoRESUMO
Test question has already become an important factor to restrict the development of integrated circuit industry. A new test data compression scheme, namely irrational numbers stored (INS), is presented. To achieve the goal of compress test data efficiently, test data is converted into floating-point numbers, stored in the form of irrational numbers. The algorithm of converting floating-point number to irrational number precisely is given. Experimental results for some ISCAS 89 benchmarks show that the compression effect of proposed scheme is better than the coding methods such as FDR, AARLC, INDC, FAVLC, and VRL.
Assuntos
Algoritmos , Compressão de Dados/métodos , Armazenamento e Recuperação da Informação/métodos , Modelos Teóricos , Reprodutibilidade dos TestesRESUMO
Cassane-type diterpenes are main bioactive constituents of Caesalpinia minax HANCE. As a part of our ongoing chemical investigation of C. minax, two new degradative cassane-type diterpenes, named caesalpins I (1) and J (2), were isolated from the EtOAc extract of the seeds of C. minax. The structures were elucidated by means of spectroscopic analysis.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Caesalpinia/química , Diterpenos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Hidrocarbonetos Aromáticos com Pontes/química , Diterpenos/química , Medicamentos de Ervas Chinesas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sementes/químicaRESUMO
A new ursane-type triterpene, cymosic acid (1) together with two known compounds, 3ß,19α-dihydroxy-2-oxo-12-ursen-28-oic acid (2) and 2α,19α-dihydroxy-3-oxo-12-ursen-28-oic acid (3), were isolated from Rosa cymosa Tratt. The structure of compound 1 was elucidated by analyzing its ¹H and ¹³C NMR, ¹H-¹H COSY, HSQC, HMBC, NOESY, and HR-ESI-MS values. The three compounds were found to display moderate inhibitory activities against nitric oxide production in lipopolysaccharide-activated macrophage cell lines, RAW 264.7 cells.
Assuntos
Medicamentos de Ervas Chinesas/isolamento & purificação , Rosa/química , Triterpenos/isolamento & purificação , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Triterpenos/química , Triterpenos/farmacologiaRESUMO
The constituents in 95% ethanol extract of the root of Rosa cymosa Tratt were purified by column chromatography techniques, leading to isolation of eleven triterpenes. Their structures were elucidated by spectroscopic data as pomolic acid (1), fupenzic acid (2), ursolic acid (3), euscaphic acid (4), arjunic acid (5), tomentic acid (6), 3ß-E-feruloyl corosolic acid (7), 1ß-hydroxyeuscaphic acid (8), myrianthic acid (9), cecropiacic acid (10), and ilexoside B (11). Among them, compounds 3, 6-8, 10 and 11 were obtained from this plant for the first time, and compounds 7 and 10 were obtained from this genus for the first time.
Assuntos
Medicamentos de Ervas Chinesas/química , Rosa/química , Triterpenos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
OBJECTIVE: To determine the correlation between differential leukocyte counts and hyperglycemic emergencies. METHODS: Fifty patients with diabetic ketoacidosis (DKA), 50 patients with diabetic ketosis (DK), 50 non-DK diabetic patients with stable glycemic control, and 50 normal controls were enrolled. Their total and differential leukocyte counts were measured and evaluated at admission and after treatment. RESULTS: The patients with DKA and DK had higher plasma glucose levels (20.84±6.73 mmol/L, 15.55±2.6 mmol/L, respectively) and more median leukocytes (13325/mm(3) and 6595/mm(3), respectively) and median neutrophils (11124 /mm(3) and 4125/mm(3), respectively) but fewer median eosinophils (28/mm(3) and 72/mm(3), respectively) compared to non-DK and control groups (all p < 0.05). Acute infection increased the elevating extent. The median leukocyte counts in DK and non-DK patients (6595/mm(3) and 6008/mm(3), respectively) were within the normal range. The counts of total leukocytes and neutrophils were significantly higher but eosinophils lower in severe DKA cases than in mild/moderate cases (p < 0.05). When the DKA and DK and infection resolved, total leukocytes and neutrophils fell, but eosinophils increased. The counts of total leukocytes, neutrophils, and monocytes were negatively correlated with arterial pH levels (r = -0.515, r = -0.510, r = -0.517, all p < 0.001, respectively) and positively correlated with plasma glucose levels (r = 0.722, r = 0.733, r = 0.632, all p < 0.05, respectively) in DKA patients. The arterial pH level was the most significant factor affecting total leukocytes in DKA (ß = 0.467, p = 0.003). The diagnosis analysis showed that higher total leukocyte and neutrophil counts and lower eosinophil counts had a significant ability to reflect the presence of hyperglycemic emergencies. CONCLUSION: More total leukocytes and neutrophils but fewer eosinophils was significantly correlated with DKA and DK. Leukocyte counts can add valuable information to reflect the presence of hyperglycemic crisis and acute infection.
Assuntos
Cetoacidose Diabética/terapia , Emergências , Hiperglicemia/terapia , Contagem de Leucócitos , Adulto , Glicemia , Cetoacidose Diabética/sangue , Cetoacidose Diabética/patologia , Eosinófilos/citologia , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Neutrófilos/citologiaRESUMO
The mol-ecular conformation of the title compound, C(14)H(24)NO(4)PS(3), the selective herbicide bensulide, is stabilized by a weak intra-molecular C-Hâ¯S inter-action. In the crystal, chains are formed through inter-molecular N-Hâ¯S hydrogen bonds.
RESUMO
OBJECTIVE: To explore the correlation of males'age with sperm apoptosis, sperm DNA integrity and other seminal parameters. METHODS: We collected 104 semen samples and divided them into three groups according to the males' age: <35 yr (n = 43), 35 -39 yr (n = 31), and > or = 40 yr (n = 30). Based on the WHO Laboratory Manual (4th ed), we detected the seminal parameters, calculated the percentage of apoptotic sperm by flow cytometry (FCM), determined sperm DNA integrity by Acridine orange staining, and compared the results among the three groups. RESULTS: There were no statistically significant differences among the < 35 yr, 35 -39 yr and > or = 40 yr groups in semen volume ([2.87 +/- 0.89] ml vs [2.98 +/- 1.09] ml vs [2.65 +/- 0.95] ml), sperm concentration ([60.40 +/- 25.43] x 10(6)/ml vs [69.74 +/- 28.33] x 10(6)/ml vs [55.97 +/- 27.22] x 10(6)/ml) (P>0.05). The percentage of progressively motile sperm was significantly lower in the > or = 40 yr ([39.00 +/- 8.35 %) than in the <35 and 35 -39 yr groups ([48.73 +/- 9.89]% and [45.65 +/- 10.55]%) (P<.0.1), and so was the percentage of morphologically normal sperm in the > or = 40 yr than in the < 35 yr group ([11.11 +/- 8.26]% vs [16.43 +/- 8.75 ]%, P<0.01). The percentage of apoptotic sperm was markedly higher in the > or = 40 yr than in the <35 yr group ([11.82 +/- 5.77]% vs [7.04 +/- 3.50]%, P<0.01), while the sperm DNA integrity significantly reduced in the > or = 40 yr group ([75.52 +/- 10.60]%) as compared with the <35 yr ([86.55 +/- 5.60])% and 35 -39 yr group ( [81.39 +/- 8.94]%) (P<0.01). The males' age was correlated positively with the rate of sperm apoptosis (P<0.01), and negatively with sperm DNA integrity and the percentage of progressively motile sperm (P<0.01). CONCLUSION: The advance in males' age increases sperm apoptosis and reduces sperm progressive motility, normal morphology and DNA integrity.
Assuntos
Apoptose/genética , DNA , Espermatozoides/citologia , Adulto , Fatores Etários , Citometria de Fluxo , Humanos , Infertilidade Masculina/genética , Masculino , Contagem de Espermatozoides , Motilidade dos EspermatozoidesRESUMO
OBJECTIVE: To study the influence of male age on the outcome of conventional IVF-ET. METHODS: Based on male age, 170 couples undergoing conventional IVF-ET were divided into three groups: <35 yr (n = 60), 35 -39 yr (n = 77) and > or = 40 yr (n = 33). We observed the rates of fertilization, cleavage, good quality embryo, implantation, clinical pregnancy and abortion in different groups. RESULTS: There were no significant differences among the three groups in semen volume ([3.10 +/- 1.22] ml vs [2.84 +/- 1.05] ml vs [2.80 +/- 0.79] ml), sperm concentration ([54.23 +/- 26.07] x 10(6)/ml vs [60.27 +/- 24.80] x 10(6)/ml vs [60.21 +/- 27.42] x 10(6)/ml) and sperm viability ([53.93 +/- 13.25]% vs [56.10 +/- 16.58]% vs [51.82 +/- 15.45]%) (P>0.05). The men of the > or = 40 yr group showed a significantly lower percentage of grade a + b sperm ([40.97 +/- 11.91]%) than those of the <35 and 35 - 39 yr groups ([48.47 +/- 11.78]% and [46.84 +/- 13.51]%) (P<0.05), and morphologically normal sperm ([11.76 +/- 5.97]%) than those of the <35 yr group ([15.25 +/- 6.94]% (P<0.05). The rates of fertilization, cleavage, good quality embryo, implantation, clinical pregnancy were 81.52%, 82.61%, 52.33%, 18.06% and 33.33% in the > or = 40 yr group, with no significant differences from those of the <35 yr group (83.18%, 82.68%, 56.99%, 22.40% and 40.00%) and the 35 - 39 yr group (78.78%, 80.66%, 55.01%, 21.74% and 38.96%) (P>0.05), while the abortion rate was markedly increased in the > or = 40 yr group as compared with the <35 yr group (36.36% vs 8.33%, P>0.05). CONCLUSION: Increasing male age is related with decreasing percentages of progressively motile sperm and morphologically normal sperm, but not obviously with the rates of fertilization, good quality embryo, implantation, pregnancy and abortion.
Assuntos
Fertilização in vitro , Idade Paterna , Resultado da Gravidez , Adulto , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , GravidezRESUMO
Terpenes possess a wide range of structural features and pharmaceutical activities and are promising for drug candidates. With the aim to find bioactive terpene molecules, eight new compounds were isolated from the medicinal plant Nepeta bracteata Benth., including seven new abietane-type diterpenoids (1-7), along with a new ursane-type triterpenoid (8). The structures of compounds 1-8 were elucidated through the detailed spectroscopic analyses of their 1D and 2D NMR and MS data, and the absolute configurations of compounds 1-7 were determined by comparing their experimental and calculated ECD spectra. Compound 1 was a novel degraded carbon diterpene with the disappearing of methyl signal at C-19, while compound 7 possessed a new norabietane-type diterpenoid carbon skeleton with the presence of five-membered lactone arising from ring rearrangement. The anti-inflammatory of all obtained isolates were evaluated on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the results of anti-inflammatory activity screening showed that compared with the LPS model group, all compounds were significantly down-regulation the TNF-α inflammatory factor at the specific concentration, except for compound 6.
RESUMO
Two new flavone C-glycosides, trollisin A (1) and trollisin B (2), along with seven known flavonoids, isoswertisin (3), isoswertiajaponin (4), orientin (5), 2â³-O-ß-L-galactopyranosylvitexin (6), 2â³-O-ß-L-galactopyranosylorientin (7), neodiosmin (8) and acacetin-7-O-neohesperidoside (9) were isolated from the flowers of Trollius ledebourii REICHB. The structures of the new compounds were elucidated based on spectral analysis, including MS, 1D- and 2D-NMR experimentation.
Assuntos
Flavonas/química , Glicosídeos/química , Ranunculaceae/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Flores/química , Glicosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação MolecularRESUMO
OBJECTIVE: To study the effect of Qianyang Recipe (QYR) on the Gan-yang hyperactivity syndrome (GYHS), the blood pressure, and correlated vascular regulatory factors of hypertension rat. METHODS: Thirty SD rats were randomly divided into the normal control group, the model group, and the QYR group, ten in each. Hypertension rat model of GYHS was prepared using Aconiti Praeparata Decoction plus ephedrine plus salt water. Rats in the QYR group orally took QYR physic liquor, while distilled water was given to rats in the normal control group and the model group. They were medicated for 28 successive days. The facial temperature, the grip strength, and the systolic pressure were determined once every 7 days. Rats' irritable degree and feather color were observed and recorded once every 14 days. After the last administration the plasma renin (PR), angiotensin II (Ang II), aldosterone (ALD), atrial natriuretic peptide (ANP), calcitonin gene-related peptide (cGRP) were determined. RESULTS: Compared with the model group of the same phase, the facial temperature of rats in the QYR group significantly decreased on the 14th, 21th and 28th day after administration. The systolic pressure obviously decreased on the 21st day after administration. On the 28th day after administration symptoms such as irritability, dry hair were improved, and the Ang II level decreased. There was significant difference in all these changes (P<0.05, P<0.01). CONCLUSIONS: QYR could relieve GYHS rats' symptoms such as facial hotness, irritability, dry hair, and so on, and decrease the systolic pressure. Decreased Ang II level might be one of its mechanisms.