Hyperoside Protects Trastuzumab-Induced Cardiotoxicity via Activating the PI3K/Akt Signaling Pathway.

PURPOSE: Trastuzumab is a landmark agent in the treatment of human epidermal growth factor receptor-2(HER2)-positive breast cancer. Nevertheless, trastuzumab also comes with unexpected cardiac side effects. Hyperoside is a natural product that serves beneficial roles in cardiovascular disease. This study aimed to explore the effect and mechanism of hyperoside in trastuzumab-induced cardiotoxicity. METHODS: A female C57BL/6 mice cardiotoxicity model was established via intraperitoneally injecting with trastuzumab (10 mg/kg/day, once every other day, cumulative dosage to 40 mg/kg) with or without hyperoside (15 or 30 mg/kg/day) administration. In vitro, the H9c2 cells were exposed to 1 µM trastuzumab with or without hyperoside (100 or 200 µM) administration. Cardiac function was evaluated by echocardiographic, myocardial enzymes levels, and pathological section examinations. TUNEL staining and Annexin V-FITC/ propidium iodide flow cytometry were used to analyze the cardiomyocyte apoptosis. RESULTS: Compared to the control group, the LVEF, LVFS was decreased and the concentrations of cTnT, CK, CK-MB and LDH in mice were significantly increased after treatment with trastuzumab. Collagen deposition and cardiomyocyte hypertrophy were observed in the myocardium of the trastuzumab group. However, these changes were all reversed by different doses of hyperoside. In addition, hyperoside attenuated trastuzumab-induced myocardium apoptosis and H9c2 cells apoptosis through inhibiting the expressions of cleaved caspase-3 and Bax. Trastuzumab abolished the PI3K/Akt signaling pathway in mice and H9c2 cells, while co-treatment of hyperoside effectively increased the ratio of p-Akt/Akt. CONCLUSION: Hyperoside inhibited trastuzumab-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Hyperoside may be a promising therapeutic approach to trastuzumab-induced cardiotoxicity.

Differential diagnosis of lung cancer and tuberculosis based on 18 F-fluorodeoxyglucose PET/CT multi-time points imaging.

OBJECTIVE: To investigate the value of 18 F-fluorodeoxyglucose(FDG) PET/CT multi-time points imaging (MTPI) on the differential diagnosis between lung cancer (LC) and tuberculosis (TB). METHODS: Sixty-four patients underwent 18 F-FDG PET/CT MTPI. The stdSUVmax, stdSUVavg, retention index, metabolic tumor volume, total lesion glycolysis at four-time points and slope of metabolic curve were measured and calculated, and the sex, age, and uniformity of FDG uptake were recorded. The difference in each index between LC and TB was analyzed, and dynamic metabolic curves (DMCs) of LC and TB were fitted by significance indexes. Artificial neural network (ANN) prediction models were established between squamous cell carcinoma (SCC) and TB, as well as between adenocarcinomas and TB. RESULTS: Differences between SCC and TB, stdSUVmax/avg at four-time points, total lesion glycolysis, stdSUVmax/avg slope (1-2 h,1-3 h and 1-4 h), uniformity of FDG uptake and age were significant. stdSUVavg has the largest area under the 4 h curve; age was only significant between adenocarcinomas and TB. DMCs at 1-4 h fitted by stdSUVavg were more helpful in differentiating LC and TB than stdSUVmax. stdSUVavg(1 h and 4 h), stdSUVavg slope 1-4 h, age, and uniformity of FDG uptake were selected to establish an ANN prediction model between SCC and TB; the area under the curve (AUC) was 100.0%. The same indices were used to establish the prediction model between adenocarcinomas and TB; the AUC was up to 83.5, and after adding stdSUVavg (2 and 4 h) to adenocarcinomas and TB models, the AUC was 87.7%. CONCLUSION: 18 F-FDG PET/CT MTPI fitting DMCs and establishing an ANN prediction model would distinguish SCC from TB relatively accurately and provide certain help in the differentiation between adenocarcinomas and TB.

Trastuzumab potentiates doxorubicin-induced cardiotoxicity via activating the NLRP3 inflammasome in vivo and in vitro.

Trastuzumab (Tra), the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), is commonly used alongside doxorubicin (Dox) as a combination therapy in HER2-positive breast cancer. Unfortunately, this leads to a more severe cardiotoxicity than Dox alone. NLRP3 inflammasome is known to be involved in Dox-induced cardiotoxicity and multiple cardiovascular diseases. However, whether the NLRP3 inflammasome contributes to the synergistic cardiotoxicity of Tra has not been elucidated. In this study, primary neonatal rat cardiomyocyte (PNRC), H9c2 cells and mice were treated with Dox (15 mg/kg in mice or 1 µM in cardiomyocyte) or Tra (15.75 mg/kg in mice or 1 µM in cardiomyocyte), or Dox combined Tra as cardiotoxicity models to investigate this question. Our results demonstrated that Tra significantly potentiated Dox-induced cardiomyocyte apoptosis and cardiac dysfunction. These were accompanied by the increased expressions of NLRP3 inflammasome components (NLRP3, ASC and cleaved caspase-1), the secretion of IL-ß and the pronounced production of ROS. Inhibiting the activation of NLRP3 inflammasome by NLRP3 silencing significantly reduced cell apoptosis and ROS production in Dox combined Tra-treated PNRC. Compared with the wild type mice, the systolic dysfunction, myocardial hypertrophy, cardiomyocyte apoptosis and oxidative stress induced by Dox combined Tra were alleviated in NLRP3 gene knockout mice. Our data revealed that the co-activation of NLRP3 inflammasome by Tra promoted the inflammation, oxidative stress and cardiomyocytes apoptosis in Dox combined Tra-induced cardiotoxicity model both in vivo and in vitro. Our results suggest that NLRP3 inhibition is a promising cardioprotective strategy in Dox/Tra combination therapy.

Hyperoside prevents doxorubicin-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway.

Clinical application of doxorubicin (Dox) in cancer chemotherapy is limited by its cardiotoxicity. Present study aimed to demonstrate the effect and mechanism of hyperoside in Dox-induced cardiotoxicity. C57BL/6 mice were injected with 12 mg/kg of Dox, and 1 µM Dox was exposed to primary cardiomyocytes. Cardiac function was evaluated by echocardiographic and myocardial enzyme levels. Cardiomyocyts apoptosis was analyzed by TUNEL staining and flow cytometry. Network pharmacology and molecular docking were utilized to explore potential targets of hyperoside. Protein expressions were detected by western blot and enzyme activities were determined by colorimetry. Cardiac dysfunction and cardiomyocyte apoptosis induced by Dox were attenuated by hyperoside. Mechanism of hyperoside was mainly related to "oxidative stress" pathway. Hyperoside exhibited strong binding activities with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs, the main source of ROS in cardiomyocytes) and cyclooxygenases (COXs). Experiments proved that hyperoside suppressed the ROS generation and the elevated activities of NOXs and COXs induced by Dox. Dox also triggered the activation of NLRP3 inflammasome, which was reversed by hyperoside. Hyperoside bound to NOXs and COXs, which prevents Dox-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway. Hyperoside holds promise as a therapeutic strategy for Dox-induced cardiotoxicity.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Aroma characterisation of Liu-pao tea based on volatile fingerprint and aroma wheel using SBSE-GC-MS.

Liu-pao tea (LPT) has unique aroma characteristics, and is a special microbial fermented tea produced using dark raw tea (LPM) as its raw material. In this study, stir bar sorptive extraction (SBSE) combined with gas chromatography-mass spectrometry (GC-MS) was applied to investigate the volatiles of 16 LPTs and 6 LPMs. Moreover, variations in volatile profiles between LPTs and LPMs were explored. Results showed that a total of 132 volatile compounds were identified from LPTs. The volatile fingerprint was constructed with a similarity ranged from 0.85 to 0.99. Furthermore, twenty-six aroma compounds were selected to depict the molecular aroma wheel of LPT. Multivariate statistical analysis revealed that the contents of 24 aroma compounds changed significantly (P < 0.05) when LPMs were processed into LPTs. These results reveal the volatile profiles of LPTs and aroma composition changes during microbial fermentation process, which might provide chemical basis of the aroma quality of LPT.

Value of dynamic metabolic curves and artificial neural network prediction models based on 18F-FDG PET/CT multiphase imaging in differentiating nonspecific solitary pulmonary lesions: a pilot study.

OBJECTIVE: To investigate the value of dynamic metabolic curves and artificial neural network prediction models based on 18F-FDG PET multiphase imaging in differentiating nonspecific solitary pulmonary lesions. METHODS: This study enrolled 71 patients with solitary pulmonary lesions (48 malignant and 23 benign lesions) who underwent multiphase 18F-fluorodeoxyglucose (18F-FDG)-PET/CT imaging. We recorded information on age, sex and uniformity of FDG uptake, measured standardized uptake value, metabolic tumor volume and total lesion glycolysis at various time points, and calculated individual standardized uptake values, retention index (RI) and slope of metabolic curve. Variables with high diagnostic efficiency were selected to fit dynamic metabolic curves for various lesions and establish different artificial neural network prediction models. RESULTS: There were no significant differences in the retention index, metabolic tumor volume, total lesion glycolysis or sex between benign and malignant lesions; standardized uptake values, the slopes of five metabolic curves, uniformity of FDG uptake, and age showed significant differences. Dynamic metabolic curves for various solitary pulmonary lesions exhibited characteristic findings. Model-1 was established using metabolic parameters with high diagnostic efficacy (area under the curve, 83.3%). Model-2 was constructed as Model-1 + age (area under the curve, 86.7%), whereas Model-3 was established by optimizing Model-2 (area under the curve, 86.0%). CONCLUSIONS: Dynamic metabolic curves showed varying characteristics for different lesions. Referring to these findings in clinical work may facilitate the differential diagnosis of nonspecific solitary pulmonary lesions. Establishing an artificial neural network prediction model would further improve diagnostic efficiency.

Characterisation of the volatile compounds profile of Chinese pan-fried green tea in comparison with baked green tea, steamed green tea, and sun-dried green tea using approaches of molecular sensory science.

Pan-fried green tea (PGT) is an easily acceptable tea drink for general consumers. In this study, volatile profiles and characteristic aroma of 22 representative Chinese PGT samples were extracted using stir bar sorptive extraction (SBSE) and analysed by gas chromatography-mass spectrometry (GC-MS), gas chromatography-olfactometry (GC-O) analysis, and odour activity value (OAV) calculations. In total, 88 volatile compounds were identified. Alcohols (45%), esters (19%), and ketones (16%) were the dominant volatiles, and geraniol (484.8 µg/kg) was the most abundant volatile component in PGT, followed by trans-ß-ionone and linalool. In addition, the differences of aroma characteristics among PGT and other three types of green tea, namely baked green tea, steamed green tea, and sun-dried green tea, were also observed using partial least squares discriminant analysis (PLS-DA) and heatmap analysis, and it was found that ß-myrcene, methyl salicylate, (E)-nerolidol, geraniol, methyl jasmonate were generally present at higher content in PGT. This is the first comprehensive report describing the volatile profiles of Chinese PGT, and the findings from this study can advance our understanding of PGT aroma quality, and provide important theoretical basis for processing and quality control of green tea products.

Comprehensive investigation on non-volatile and volatile metabolites in four types of green teas obtained from the same tea cultivar of Longjing 43 (Camellia sinensis var. sinensis) using the widely targeted metabolomics.

In this study, we produced roasted, baked, steamed, and sun-dried green tea products using the same batch of fresh tea leaves (FTL) of Longjing 43 (Camellia sinensis var. sinensis), and explored processing effects on the metabolic profiles of four types of green teas (FGTs) using the widely targeted metabolomics. Results showed that 146 differential metabolites including flavonoids, amino acids, lipids, and phenolic acids were screened among 1034 non-volatiles. In addition, nineteen differential metabolites were screened among 79 volatiles. Most of non-volatiles and volatiles metabolites changed notably in different manufacturing processes, whereas there were no significant differences (p＞0.05) in the levels of total catechins between FGTs and FTL. The transformation of metabolites was the dominant trend during green tea processing. The results contribute to a better understanding of how the manufacturing process influences green tea quality, and provide useful information for the enrichment of tea biochemistry theory.

Insights into crucial odourants dominating the characteristic flavour of citrus-white teas prepared from citrus reticulata Blanco 'Chachiensis' and Camellia sinensis 'Fudingdabai'.

Citrus-white teas (CWs), which possess a balanced flavour of tea and citrus, are becoming more popular worldwide; however, their characteristic flavour and odourants received limited research. Volatile components of two types of CWs prepared from Citrus reticulata Blanco 'Chachiensis' and Camellia sinensis 'Fudingdabai' were comprehensively investigated using a combination of stir bar sorptive extraction and gas chromatography-mass spectrometry (GC-MS). Ninety-nine crucial odourants in the CWs were quantified by applying GC-olfactometry/MS, significant differences were compared, and their odour activity values (OAVs) were calculated. Twenty-two odourants (in total 2628.09 and 1131.18 mg/kg respectively) were further confirmed as traditional CW (CW-A) and innovated CW (CW-B) characteristic flavour crucial contributors which all possessed > 1 OAVs, particularly limonene (72919 in CW-A) and trans-ß-ionone (138953 in CW-B). The unravelling of CWs aroma composition will greatly expanding our understanding of tea aroma chemistry and the potential aroma interactions will offer insights into tea blending technologies.

Hypolipidaemic and antioxidant effects of various Chinese dark tea extracts obtained from the same raw material and their main chemical components.

In order to investigate the hypolipidaemic and antioxidant effects of various dark teas produced from different post-fermentation using the same raw material, a hyperlipidaemia zebrafish model combined with binding bile salts assay and antioxidant assays were performed in this study. Results showed that the hypolipidaemic effect of dark tea extracts increased significantly (p < 0.05) while the antioxidant ability decreased sharply compared with raw material. Particularly, Liupao tea (50%) and Pu-erh tea (48%) showed promising hypolipidaemic potential; however, the antioxidant capacity of Pu-erh tea decreased (31-49%) most dramatically. Besides, the levels of total polyphenols and catechins decreased sharply, but theabrownin, gallic acid, and caffeine increased significantly after post-fermentation. Moreover, the potential mechanisms of regulating hyperlipidaemia by dark tea extracts were discussed. These results suggest that microbial fermentation significantly affects the bioactivity of dark teas, and provide theoretical basis for processing and improving of dark tea products for hyperlipidaemia therapy.

Corrigendum to "Antioxidant Effect of Polygonatum sibiricum Polysaccharides in D-Galactose-Induced Heart Aging Mice".

[This corrects the article DOI: 10.1155/2021/6688855.].

Assessment of the contribution of chiral odorants to aroma property of baked green teas using an efficient sequential stir bar sorptive extraction approach.

Chiral volatile compounds are known to be distributed in teas at various enantiomeric ratios. However, the performance of each enantiomer, including aroma characteristics, aroma intensities, and contribution to the overall flavor of tea, is still unclear. In this study, aroma characteristics and intensities of 38 volatile enantiomers in standards and baked green teas with chestnut-like aroma and clean aroma were evaluated by an efficient sequential headspace-stir bar sorptive extraction (seq-HS-SBSE) approach combined with the enantioselective gas chromatography-olfactometry/mass spectrometry (Es-GC-O/MS) technique. Moreover, aroma recombination results for the two types of baked green teas using 14 chiral odorants and four achiral odorants indicated that the combinations of the detected odorants mainly contributed to the "floral", "sweet", and "chestnut-like" aromas. R-Linalool simultaneously enhanced the "floral", "sweet", and "chestnut-like" aromas; R-limonene mainly contributed to the "sweet" and "clean" aromas; and S-α-terpineol promoted the "sweet" and "floral" aromas of baked green tea.

Insight into the pigmented anthocyanins and the major potential co-pigmented flavonoids in purple-coloured leaf teas.

Tea cultivars possessing purple shoots have attracted global interest. In order to gain a better understanding of the major chemical constituents responsible for the purple colouration, we applied widely targeted metabolomics to investigate the pigmented flavonoids of freeze-dried purple-coloured tea leaves (PTLs) in comparison with green-coloured tea leaves (GTLs). Thirty-three anthocyanins were identified, and delphinidin 3-O-galactoside and cyanidin 3-O-galactoside were found to be the most abundant in PTLs. A total of 226 metabolites including 193 flavonoids and 33 tannins were identified, and the methylated, acylated, and glycosylated flavonoids differed significantly between PTLs and GTLs. Moreover, significant differences (p < 0.01) in the average anthocyanin, flavonoid, chlorophyll and catechin contents were also observed. Four PTLs were found to contain high levels of (-)-epigallocatechin-3-(3″-O-methyl) gallate (>10 mg/g). These results suggest that structurally modified anthocyanins and major potential co-pigmented flavonoids are the chemicals primarily responsible for the purple colouration of the tea leaves.

Antioxidant Effect of Polygonatum sibiricum Polysaccharides in D-Galactose-Induced Heart Aging Mice.

Polygonatum sibiricum polysaccharides (PSP), the extract of Polygonatum sibiricum, are demonstrated to exhibit a wide range of pharmacological activities. A recent study reported that PSP alleviated the aging of the kidney and meninges. However, the effect of PSP on heart aging remains unclear. The present study is aimed at investigating the protection of PSP on D-galactose- (D-gal-) induced heart aging. Results showed that irregularly arranged cardiac muscle fibers were observed in heart tissues of D-gal-treated mice, and the levels of cardiac troponin T (cTnT), creatine kinase (CK), p21, and p53 were increased after D-gal treatment. D-gal-induced heart aging and injury can be attenuated by oral administration of PSP. Moreover, PSP also decreased reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the level of superoxide dismutase (SOD) in the hearts of D-gal-treated mice. DNA damages and lipid peroxidation induced by oxidative stress were also inhibited by PSP as indicated by reduced levels of 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE). Collectively, PSP attenuated D-gal-induced heart aging via inhibiting oxidative stress, suggesting that PSP might serve as a potential effective Chinese herbal active constituent for antiaging therapy.

Impact of Various Microbial-Fermented Methods on the Chemical Profile of Dark Tea Using a Single Raw Tea Material.

In the present study, we produced Pu-erh, Liubao, Qingzhuan, and Fuzhuan teas using a single raw tea material and applied widely targeted metabolomics to study the impact of various microbial-fermented methods on the chemical profile of dark tea. The contents of catechins and free amino acids decreased drastically, whereas the contents of gallic acid and theabrownins increased significantly during microbial fermentation. Pu-erh tea had the highest content of theabrownins (11.82 ± 0.49%). Moreover, MS-based metabolomics analysis revealed that the different types of dark teas were significantly different from their raw material. A total of 85 differential metabolites were screened among 569 metabolites identified referring to self-compiled database. Glycosylated, hydroxylated, methylated, and condensed and oxidated products originating from microbial bioconversion of their corresponding primitive forms were significantly increased in dark teas. These results suggest that various microbial-fermented methods greatly affect the metabolic profile of dark tea, which can provide useful information for dark tea biochemistry research.

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity.

Drug-induced toxicity, which impairs human organ function, is a serious problem during drug development that hinders the clinical use of many marketed drugs, and the underlying mechanisms are complicated. As a sensor of infections and external stimuli, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in the pathological process of various diseases. In this review, we specifically focused on the role of NLRP3 inflammasome in drug-induced diverse organ toxicities, especially the hepatotoxicity, nephrotoxicity, and cardiotoxicity. NLRP3 inflammasome is involved in the initiation and deterioration of drug-induced toxicity through multiple signaling pathways. Therapeutic strategies via inhibiting NLRP3 inflammasome for drug-induced toxicity have made significant progress, especially in the protective effects of the phytochemicals. Growing evidence collected in this review indicates that NLRP3 is a promising therapeutic target for drug-induced toxicity.

Insight into the volatile profiles of four types of dark teas obtained from the same dark raw tea material.

Various dark teas are quite different in their volatile profiles, mainly due to the huge differences in the phytochemical profiles of dark raw tea and the diverse post-fermentation processing technologies. In this study, gas chromatography-mass spectrometry (GC-MS), qualitative GC-olfactometry (GC-O), and enantioselective GC-MS coupled with multivariate analysis were applied to characterise the volatile profiles of various dark teas obtained from the same dark raw tea material. A total of 159 volatile compounds were identified by stir bar sorptive extraction (SBSE) combined with GC-MS, and 49 odour-active compounds were identified. Moreover, microbial fermentation could greatly influence the distribution of volatile enantiomers in tea, and six pairs of enantiomers showed great diversity of enantiomeric ratios among various dark teas. These results suggest that post-fermentation processing technologies significantly affect the volatile profiles of various dark teas and provide a theoretical basis for the processing and quality control of dark tea products.

Calcitonin gene­related peptide­mediated pharmacological effects in cardiovascular and gastrointestinal diseases (Review).

Calcitonin gene­related peptide (CGRP) is the predominant neurotransmitter located in sensory nerves. This peptide is extensively distributed in central and peripheral tissues. CGRP causes relaxation of cardiovascular smooth muscle cells and confers protection against ischaemic myocardium and cardiac remodeling. The pharmacological effects of nitroglycerine and rutaecarpine have been demonstrated to be associated with an increase in the synthesis and release of CGRP. In the gastrointestinal tissues, CGRP participates in the regulation of gastrointestinal function, and exerts protective effects on gastric mucosa. Rutaecarpine, capsaicin and its derivatives, such as evodiamine, decrease gastric mucosal damage induced by several factors, including increased synthesis and release of CGRP. Taken together, this review focuses on the pharmacological effects of several CGRP related canonical drugs and suggests that synthesis and secretion of CGRP exhibit significant therapeutic effects in the occurrence and development of cardiovascular and gastrointestinal diseases.