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The purpose of this study was to develop an assay for simultaneous determination of lapatinib and its metabolites (N-dealkylated lapatinib and O-dealkylated lapatinib) by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and to determine the interaction between shikonin and lapatinib in vitro , in vivo , in silico and its mechanism of action. A new UPLC-MS/MS method for the determination of the concentrations of lapatinib and its metabolites was developed. In vivo , Sprague-Dawley (SD) rats were given lapatinib with or without shikonin. In vitro , to study the interaction mechanism, rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4.1 were used for determining enzyme kinetics. Lastly, we used in silico molecular docking to investigate the molecular mechanism of inhibition. The selectivity, precision, accuracy, stability, matrix effect and recovery of UPLC-MS/MS all met the requirements of quantitative analysis of biological samples. Administration of lapatinib combined with shikonin resulted in significantly increased pharmacokinetic parameters (AUC (0-t) and C max) of lapatinib, indicating that shikonin increased the exposure of lapatinib in rats. Moreover, in vitro kinetic measurements indicated that shikonin was a time-independent inhibitor, which inhibited the metabolism of lapatinib through a competitive mechanism in RLMs, while noncompetitive inhibition type in both HLMs and CYP3A4.1. Molecular docking analysis further verified the non-competitive inhibition of shikonin on lapatinib in CYP3A4.1. We developed an UPLC-MS/MS assay for simultaneous determination of lapatinib and its metabolites. It could be successfully applied to the study of pharmacokinetic interaction of shikonin on the inhibition of lapatinib metabolism in vivo and in vitro. In the end, further studies are needed to determine if such interactions are indeed valid in humans and if the interaction is clinically relevant. • UPLC-MS/MS for the determination of lapatinib with metabolites was established. • The interaction between shikonin and lapatinib was determined in vitro , in vivo , in silico. • It helps in evaluating the clinical safety of lapatinib and shikonin. [ABSTRACT FROM AUTHOR]

Whether household air pollution is associated with dementia risk remains unknown. This study examined the associations between solid fuel use for cooking and heating (the main source of household air pollution) and dementia risk. This analysis included data on 11,352 participants (aged 45+ years) from the 2011 wave of China Health and Retirement Longitudinal Study, with follow-up to 2018. Dementia risk was assessed by a risk score using the Rotterdam Study Basic Dementia Risk Model (BDRM), which was subsequently standardized for analysis. Household fuel types of cooking and heating were categorized as solid (e.g., coal and crop residue) and clean (e.g., central heating and solar). Multivariable analyses were performed using generalized estimating equations. Moreover, we examined the joint associations of solid fuel use for cooking and heating with the BDRM score. After adjusting for potential confounders, we found an independent and significant association of solid (vs. clean) fuel use for cooking and heating with a higher BDRM score (e.g., β = 0.17 for solid fuel for cooking; 95% confidence interval [CI]: 0.15–0.19). Participants who used solid (vs. clean) fuel for both cooking and heating had the highest BDRM score (β = 0.32; 95% CI: 0.29–0.36). Subgroup analysis suggested stronger associations in participants living in rural areas. Solid fuel use for cooking and heating was independently associated with increased dementia risk in Chinese middle-aged and older adults, particularly among those living in rural areas. Our findings call for more efforts to facilitate universal access to clean energy for dementia prevention. • Solid fuel use for cooking and heating was independently associated with increased dementia risk. • Participants who used solid fuel for both cooking and heating had the highest dementia risk. • Stronger association of solid fuel use with increased dementia risk was found in participants living in rural areas. [ABSTRACT FROM AUTHOR]

Thirty-seven lactic acid bacteria (LAB) strains were isolated from traditional dry sausages collected from Northeast China, including Latilactobacillus sakei (29 strains), Lactiplantibacillus plantarum (4 strains), Latilactobacillus curvatus (2 strains), Weissella hellenica (1 strain), and Lactococcus lactis (1 strain). Some LAB strains had tolerance to high concentrations of sodium chloride (6%), sodium nitrite (150 mg/L NaNO 2), and acid (pH 4.0). They showed good growth and acidification properties and antimicrobial activity. Among them, five LAB strains that exhibited the best technological properties were selected and inoculated in the sausage model to explore their roles in flavor development. The contents of total free amino acids (FAAs) decreased ranging from 109.11 mg/g to 58.06 mg/g. A total of 46 volatile compounds were identified and the contents of volatile compounds increased in the sausage model during fermentation. Partial least squares regression analysis showed that Lb. sakei HRB10, Lb. plantarum MDJ2, W. hellenica HRB6, and Lc. lactis HRB0 promoted the generation of FAAs and volatile compounds in the sausage model. These findings demonstrated that the autochthonous LAB species are promising for the production of sausage with better flavor and fermentation performance. [Display omitted] • Thirty-seven LAB strains were isolated from traditional dry fermented sausages. • The selected strains exhibited high tolerance to salt, sodium nitrite, and acid. • LAB inoculation promoted free amino acid (FAA) and flavor generation. • The FAAs were responsible for the differences in the flavor of sausage models. [ABSTRACT FROM AUTHOR]

The traditional dry sausage is highly appreciated in China because of its unique quality characteristics, but it contains high salt content. Hence, this study aimed to evaluate the effects of lactic acid bacteria (LAB) comprising Lactobacillus sakei (LS), Lactobacillus curvatus (LC), Lactobacillus plantarum (LP), and Weissella hellenica (WH) on the quality attributes of the reduced-salt dry fermented sausages. The results indicated that the LP sausage showed higher (P < 0.05) shear force value compared to the other sausages, while the LP, LC, and WH sausages had higher (P < 0.05) lightness values than the control sausages. Seventy-six volatile compounds were detected, and nine compounds were identified as the key differential volatile compounds among the sausages based on partial least squares discriminant analysis. Clustering analysis of electronic nose results corresponded well to the volatile compound results. The sensory evaluation confirmed that the inoculation with LC and LP had a positive impact on the aroma, color, and hardness attributes of the reduced-salt sausages. Besides, partial least squares regression analysis further indicated that L. curvatus and L. plantarum could be used as the potential starter cultures to manufacture reduced-salt dry fermented sausage having improved texture, color, and flavor. [Display omitted] • The LP sausage shows higher shear force value compared to the other sausages. • The LP, LC, and WH sausages have higher lightness values than the control sausages. • Seventy-six volatile compounds are detected in dry fermented sausage. • Sensory attributes correlate with the key volatile compounds using PLSR analysis. • L. curvatus and L. plantarum can improve the quality of reduced-salt dry sausage. [ABSTRACT FROM AUTHOR]

The technological properties and flavour formation potential of yeast strains isolated from traditional dry fermented sausages were evaluated. A total of 46 yeast strains were isolated and characterized at the strain level by genotyping. Among them, 34 strains were selected for evaluation of technological properties (tolerance to acid, salt, and sodium nitrite stresses; proteolytic and lipolytic activities; and biogenic amine formation capacity) based on their genetic profiles. Then, seven strains (Debaryomyces hansenii HRB2, SH4, and HG2; Torulaspora delbrueckii DQ3 and HG7; Pichia kudriavzevii MDJ1; and Candida zeylanoides DQ7) were selected to investigate their flavour formation potential in a fermented sausage model. A total of 56 volatile compounds were detected in all models, of which 17 volatile compounds were the most important flavour contributors with an odour activity value (OAV) > 1. The most remarkable result was the significant production of acid, alcohol, and esters in the inoculated models, such as acetic acid, hexanoic acid, ethanol, phenethyl alcohol, ethyl acetate, and ethyl hexanoate. Of all the strains, D. hansenii SH4 was considered to be the best flavour producer because it produced multiple compounds with the highest OAVs, which are associated with the development of desirable sensory characteristics in dry sausages. • A total of 46 yeast strains were isolated from traditional dry fermented sausages. • Intraspecific genetic diversity of yeast strains was explored using ISSR-PCR. • Eight strains exhibited high tolerance to acid, salt, and sodium nitrite stresses. • Seven strains showed specific capacities to produce acids, alcohols, and esters. • Debaryomyces hansenii SH4 produced multiple compounds with high odour activity value. [ABSTRACT FROM AUTHOR]

Cyclin D1 (CCND1) has been identified as a metastatic promoter in various tumors including lung adenocarcinoma (LUAD), a subtype of non small cell lung cancer (NSCLC). The previous observation revealed that CCND1 was upregulated in NSCLC and predicted poor prognosis of LUAD patients. In this study, we examined a chaperonin containing TCP1 subunit 5 (CCT5) protein interacts with CCND1 in LUAD. Immunofluorescence demonstrated the co-localization of CCT5 and CCND1 protein in LUAD cells. CCT5 expression was detected with both immunohistochemistry (IHC) and bioinformatics analyses. Similar with the expression pattern of CCND1, CCT5 displayed a high level in LUAD tissues compared to non cancerous lung specimens. Patients with high CCT5 expression showed a significant shorter overall survival relative to those with low expression level. Furthermore, upregulated CCT5 exhibited significant positive correlation with TNM stage of LUAD patients in both IHC analyses and bioinformatics. Knocking down CCT5 remarkably inhibited LUAD cell migration and invasion in vitro by inactivating PI3K/AKT and its downstream EMT signals, which could abrogated the accelerated migration and invasion caused by CCND1 overexpression. In summary, our study discovered a highly expressed protein CCT5 in LUAD which interacted with CCND1 and promoted migration and invasion of LUAD cells by positively moderating PI3K/AKT-induced EMT pathway. ∙ CCT5 functions as a role for promoting tumor progression. ∙CCT5 interacts with CCND1 to promote the migration and invasion of lung carcinoma. ∙Patients with high CCT5 expression showed a poor overall survival prognosis. [ABSTRACT FROM AUTHOR]