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1.
Anal Chim Acta ; 1184: 339016, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34625243

RESUMO

Sulfur-containing metabolites are related to several physiologic disorders and metabolic diseases. In this study, a simultaneous identification and quantification strategy in one batch for determination of sulfhydryl-containing metabolites was developed using stable isotope labeling combined with liquid chromatography-tandem mass spectrometry (SIL-LC-MS). In the proposed method, a pair of isotope labeling reagents, D0/D5-N-ethylmaleimide (D0/D5-NEM), was used to derivatize sulfhydryl-containing metabolites in blood and plasma of normal- and high-fat-diet (NFD and HFD) hamsters for reduced (-SH) and total (-SH, -S-S-, S-glutathionylated proteins) analysis. Quality control (QC) samples and test samples were prepared for LC-MS analysis. First, both QC samples and stable isotope labeled internal standards were used to monitor the status of the instrument and ensure the reliability of the analysis. Subsequently, an inhouse database containing 45 sulfhydryl-containing metabolites was established by MS1 based on QC samples. Then, qualitatively differential sulfhydryl-containing metabolites were found by MS2 between the NFD and HFD hamsters of the test samples, including 3 in reduced and 8 in total analysis of blood samples, and 2 in reduced and 2 in total analysis of plasma samples. Next, in quantitative analysis, satisfied linearities for 6 sulfhydryl-containing metabolites were obtained with the correlation coefficient (R2) > 0.99 and absolute quantification was carried out. The results showed that glutathione and cysteine have different concentrations in blood and plasma of hamsters. Finally, the correlation of sulfhydryl-containing metabolites with blood lipid and oxidative stress levels was determined, which provided insight into the hyperlipidemia-related oxidative stress. Taken together, the developed method of simultaneous identification with the inhouse database and MS2 and quantification with standards in one batch provides a promising strategy for the analysis of sulfhydryl-containing metabolites in biological samples, which may promote the in-depth investigation on sulfhydryl-containing metabolites and related diseases.


Assuntos
Dieta Hiperlipídica , Espectrometria de Massas em Tandem , Cromatografia Líquida , Cricetinae , Marcação por Isótopo , Reprodutibilidade dos Testes
3.
J Med Chem ; 64(18): 13676-13692, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34491054

RESUMO

A series of pyrazole-fused betulinic acid (BA) derivatives were designed and synthesized by replacing the carboxyl group at C-17 with aliphatic amine, amide, and urea groups. The suppressive effects of the compounds on osteoclast (OC) formation and inflammatory cytokine production were evaluated on murine macrophages, RAW264.7 cells, conditioned with receptor activator for nuclear factor-κB ligand (RANKL)/macrophage colony stimulating factor (M-CSF) or lipopolysaccharide (LPS), respectively. Results showed that, compared with betulinic acid, most of these compounds exhibited significant improvements in inhibitory potency. Compound 25 exhibited distinguished activities on inhibiting OC differentiation with an IC50 value of 1.86 µM. Meanwhile, compound 25, displaying the most promising suppression on IL-1ß secretion from RAW264.7 cells, was further found to possess therapeutic effects in the sodium monoiodoacetate (MIA)-induced osteoarthritis rat model. Dose-dependent benefits were observed in MIA-elicited rats with ameliorated joint pain as well as decreased cartilage damage and bone changes after compound 25 treatment.

4.
J Med Chem ; 64(18): 13704-13718, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34491761

RESUMO

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

5.
Reprod Toxicol ; 105: 91-100, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34478853

RESUMO

Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O2 from gestational day 4-21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETAR/ETBR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETBR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETBR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETBR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETBR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETBR/Nox1/4-derived ROS pathway.

6.
Cell Res ; 31(10): 1047-1060, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34465913

RESUMO

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~103 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 106 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.

7.
Phytochemistry ; 192: 112955, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34555775

RESUMO

Sesquiterpene lactones supply a variety of scaffolds for the development of anti-inflammatory drugs. In this study, eight undescribed guaianolides, i.e., lavandolides A‒H, were isolated from the whole plants of Artemisia codonocephala, together with five known analogues. Their planar structures and relative configurations were elucidated by spectroscopic measurements, and their absolute configurations were determined by electronic circulardichroism spectra and single crystal X-ray diffraction experiments. The nitric oxide inhibitory effect of all the isolates was assessed on lipopolysaccharide stimulated THP-1 macrophages. Lavandolide D showed a potent inhibitory effect on NO production, with IC50 values of 3.31 ± 0.74 µM. Furthermore, lavandolide D inhibited NOD-, LRR- and pyrin domain-containing protein 3 inflammasome-mediated interleukin-1ß production through activating autophagy.

8.
Food Res Int ; 148: 110613, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34507757

RESUMO

Oxygen involved fermentation is generally recognized as the critical process for the formation of quality of black tea. However, the specific role of oxygen plays in taste-related metabolites' alteration has not been illustrated clearly. In the present work, a series of fermentation systems with different oxygen concentrations were used to investigate the mechanism of the effects of oxygen on the quality and nonvolatile metabolites in black tea. The results showed that oxygen-enriched fermentation significantly improved the taste of black tea. And sixty-six metabolites, including catechins, theaflavins (TFs), proanthocyanidins, amino acids, flavonoid glycosides, and phenolic acids, were significantly different in the black teas fermented by three oxygen concentrations. Meanwhile, a 10-30% decrease in catechins, flavonoid glycosides and phenolic acids and a 5% increase in TFs, glutamate and glutamine in oxygen-enriched group, when compared to the control group, reduced astringency and bitterness and enhanced umami intensity. Furthermore, increased oxygen concentrations promoted the oxidation of catechins, flavonoid glycosides and some phenolic acids. And catechins oxidation in turn could accelerate the degradation of amino acids to form volatile aldehydes and also promote phenolic acids oxidation. Our results reveal the potential role of oxygen plays in the metabolites' alteration in black tea during fermentation, which gives a new insight into understanding the quality formation of black tea.

9.
J Pharmacol Exp Ther ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465632

RESUMO

Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration (RCTR1) is an endogenous lipid mediator derived from DHA, exerting pro-resolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in Lipopolysaccharide-induced ARDS/ALI rat model. Rats were injected with RCTR1 (5 µg/kg) via caudal veins 8h after LPS (14 mg/kg) treatment, then AFC was estimated after 1h of ventilation. Primary type II alveolar epithelial cells (AEC II) were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 h. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase, and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased Nedd4-2 level via up-regulating P-Akt expression. Besides, inhibitors of ALX, cAMP, and PI3K (BOC-2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase, and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI. Significance Statement 1.RCTR1, an endogenous lipid mediator, enhanced the rate of AFC to accelerate the resolution of inflammation in the LPS-induced murine lung injury model. 2. RCTR1 up-regulates the expression of ENaC and Na, K-ATPase in vivo and in vitro to accelerate the AFC. 3. The efficacy of RCTR1 on the ENaC and Na, K-ATPase level was in an ALX/cAMP/PI3K/Nedd4-2-dependent.

10.
J Hazard Mater ; 421: 126841, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34388915

RESUMO

The reaction parameters including catalyst dosage, oxidant amount, initial contaminant concentration and pH etc. play the crucial roles in the heterogeneous persulfate oxidation processes, while the synergistic interactions among these reaction parameters are still obscure. We herein took an efficient heterogeneous persulfate oxidation system "bimetallic MnxCo3-xO4 solid solution (MnCo) activated peroxymonosulfate (PMS)" for carbamazepine (CBZ) removal from water. MnCo/PMS system exhibited outstanding performance that CBZ was completely removed within 10 min. The CBZ degradation performance was ascribed to the radical oxidation of SO4·- and O2·-, the nonradical oxidation of 1O2, the redox cycles between Mn and Co species and synergistic interactions among MnCo, PMS and CBZ. By monotonously or synchronously adjusting the MnCo dosage, PMS amount and initial CBZ concentration, the inherent connections of different reaction parameters were established. Strong and different synergistic interactions between MnCo and PMS, and among MnCo, PMS and CBZ, were existed due to the formation of three different reaction modes when reaction parameters met certain conditions. The features of the modes were "two-stage, the following auto-deceleration", "one-stage, constant velocity" and "two-stage, the following auto-acceleration". This discovery may provide new insights into the synergistic interactions of reaction parameters in advanced oxidation processes for wastewater treatment.

11.
Pacing Clin Electrophysiol ; 44(9): 1523-1531, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34337768

RESUMO

BACKGROUND: His bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique. OBJECTIVE: To evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF). METHODS: Consecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation. RESULTS: Both HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5  vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3  vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2  vs. 3.1 ± 12.7 ms, p < .01; Ts-LV-RV, 37.9 ± 10.7  vs. 18.5 ± 10.8 ms, p < .001). CONCLUSIONS: Although LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.

12.
J Sci Food Agric ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34420207

RESUMO

BACKGROUND: Red light withering significantly improves the sensory flavor qualities of tea, although changes in metabolites during this process have not been systematically studied until now. The present study comprehensively analyzes metabolites in withered tea leaves at 2-h intervals up to 12 h under red light (630 nm) and dark conditions using ultra performance liquid chromatography-high resolution mass spectrometry (untargeted metabolomics). RESULTS: Ninety-four non-volatile compounds are identified and relatively quantified, including amino acids, catechins, dimeric catechins, flavonol glycosides, glycosidically-bound volatiles, phenolic acids and nucleosides. The results show that amino acids, catechins and dimeric catechins are most affected by red light treatment. Ten free amino acids, theaflavins and theasinensin A increase after red light irradiation, whereas epigallocatechin gallate and catechin fall. CONCLUSION: The present study provides a comprehensive and systematic profile of the dynamic effects of red light on withering tea and a rationale for its use in tea processing quality control. © 2021 Society of Chemical Industry.

13.
Acta Pharmacol Sin ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349236

RESUMO

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.

14.
Mol Med ; 27(1): 89, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407760

RESUMO

BACKGROUND: Renin-angiotensin-aldosterone system activation is the critical factor in renal remodeling and dysfunction. Our previous study suggested that miR-29b may attenuate AngII-induced renal intestinal fibrosis in vitro. In the present study, we aimed to determine whether recombinant rAAV9-mediated miR-29b delivery protects against AngII-induced renal fibrosis and dysfunction. METHOD: Mice were treated with AngII via osmotic mini-pumps, or phosphate-buffered saline. rAAV9 vectors were produced using the rBac-based system in SF9 cells. rAAV9-miR-29b or rAAV9-control-miR was injected into the kidneys of mice subjected to the model of AngII infusion. The role of miR-29b in renal fibrosis was assessed using quantitative polymerase chain reaction, western blot, and histology. RESULTS: In AngII-induced fibrotic kidney tissue, miR-29b expression was downregulated. rAAV9-miR-29b delivery significantly reversed renal injury as indicated by decreased serum creatinine and injury related gene expression in AngII-infused mice. Regarding organ remodeling, tubulointerstitial fibrosis and deposition of extracellular matrix components such as collagen type I and type III were significantly decreased in renal tissue from mice delivered rAAV9-miR-29b. CONCLUSION: Our results demonstrate great potential for use of rAAV9 as an applicable vector for delivery of miR-29b as an antifibrogenic factor for treatment of tubulointerstitial fibrosis-induced renal injury.

15.
Chin J Nat Med ; 19(8): 632-640, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34419263

RESUMO

A phytochemical investigation was carried out on the extract of a medicinal plant Callicarpa nudiflora, resulting in the characterization of five new 3, 4-seco-isopimarane (1-5) and one new 3, 4-seco-pimarane diterpenoid (6), together with four known compounds. The structures of the new compounds were fully elucidated by extensive analysis of MS, 1D and 2D NMR spectroscopic data, and time-dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra, and DFT calculations for NMR chemical shifts and optical rotations.

17.
Chin J Nat Med ; 19(7): 481-490, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247771

RESUMO

Honokiol is the dominant biphenolic compound isolated from the Magnolia tree, and has long been considered as the active constituent of the traditional Chinese herb, 'Houpo', which is widely used to treat symptoms due to 'stagnation of qi'. Pharmacological studies have shown that honokiol possesses a wide range of bioactivities without obvious toxicity. Honokiol protects the liver, kidneys, nervous system, and cardiovascular system through reducing oxidative stress and relieving inflammation. Moreover, honokiol shows anti-diabetic property through enhancing insulin sensitivity, and anti-obese property through promoting browning of adipocytes. In vivo and in vitro studies indicated that honokiol functions as an anti-cancer agent through multiple mechanisms: inhibiting angiogenesis, promoting cell apoptosis, and regulating cell cycle. A variety of therapeutic effects of honokiol may be associated with its physiochemical properties, which make honokiol readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier, with high bioavailability. In the future, more clinical researches on honokiol are needed to fully authenticate its therapeutic values.

18.
Biomed Chromatogr ; : e5219, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34327712

RESUMO

Ginsenosides Rb1, Rb2, Rb3 and Rc, four major protopanaxadiol (PPD)-type ginsenosides, can be metabolized by gut microbiota. The composition of gut microbiota varies in different species. Existing publications have reported the metabolite fates of ginsenosides by gut microbiota from single species. However, their microbiota-related metabolic species differences have not been evaluated yet. In current study, in vitro anaerobic incubations of PPD-type ginsenosides with gut microbiota from humans, rabbits and rats were conducted. The metabolites of each ginsenoside were then identified by LC-MS. A total of 15 metabolites from the four ginsenosides were identified. The major metabolic pathways were stepwise removals of the C-20 and C-3 sugar moieties to obtain aglycone PPD. The results showed that the hydrolysis rate of C-20 terminal ß-D-glucopyranosyl was significantly higher than those of α-L-arabinopyranosyl, ß-D-xylopyranosyl and α-L-arabinofuranosyl in different species. The activity of ß-glucosidase, the metabolic rates of parent compounds and the formation rates of their metabolites were significantly higher in gut microbiota from rabbits than from humans and rats. Our research draws researchers' attention to the species differences of microbiota-related drug metabolism.

19.
Fitoterapia ; 153: 104961, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34129923

RESUMO

Ten undescribed noreudesmane-type sesquiterpenoids, including eight 12,13-dinoreudesmanes and a pair of 11,12,13-trinoreudesmane epimers were isolated from the whole plant of Artemisia hedinii. Their structures were elucidated by extensive analysis of spectroscopic data, including MS, 1D and 2D NMR, and their absolute configurations were confirmed by X-ray diffraction experiments and DFT calculations. Compounds 1-5, 7-10 were evaluated for their anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells, and all of them could significantly inhibit the LPS induced CCL2 mRNA expression in a dose-dependent manner.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisia/química , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Quimiocina CCL2 , China , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Células RAW 264.7 , Sesquiterpenos/isolamento & purificação
20.
J Anal Toxicol ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34086913

RESUMO

A sensitive, fast and robust liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of usaramine (USM) and usaramine N-oxide (UNO) in rat plasma. The separation was conducted on an ACQUITY UPLC BEH C18 Column (50 × 2.1 mm, 1.7 µm), and gradient eluted with mobile phase A (0.1% formic acid with 5 mM ammonium acetate in water) and B (0.1% formic acid in acetonitrile/methanol, 9/1, v/v). The method was linear over the range of 1-2000 ng/mL for both analytes. The validated method was applied to investigate the pharmacokinetic behaviors and sex differences of USM and its N-oxide metabolite in rats. After intravenous administration of USM at 1 mg/kg, the AUC0-t values for USM and UNO were 363 ± 65 and 172 ± 32 ng/mL*h in male rats, respectively, while 744 ± 122 and 30.7 ± 7.4 ng/mL*h in females, respectively. The clearance of USM was significantly higher in male rats than in females (2.77 ± 0.50 vs 1.35 ± 0.19 L/h/kg, p < 0.05). After oral administration of USM at 10 mg/kg, the AUC0-t values of USM and UNO were 1960 ± 208 and 1637 ± 246 ng/mL*h in male rats, respectively, while 6073 ± 488 and 300 ± 62 ng/mL*h in females, respectively. The oral bioavailability of USM in female rats (81.7%) was much higher than in males (54.0%). In conclusion, sex-based differences were observed in the pharmacokinetics, N-oxide metabolism and oral bioavailability of USM.

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