Exploring the pharmacological mechanisms of the flower of Rhododendron molle in rheumatoid arthritis rats based on metabolomics integrated network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, the flower of Rhododendron molle G. Don (RMF) is record in the Chinese pharmacopoeia, and is commonly utilized for treating rheumatoid arthritis (RA) in clinical practice. However, its precise mechanisms necessitate further exploration. AIM OF THE STUDY: To expound the effective components, targets, metabolites, and pathways participated in RMF's anti-RA effects by metabolomics integrated network pharmacology. MATERIALS AND METHODS: CIA rats were intragastric administered RMF for 2 weeks, following which the therapeutic effects were comprehensively evaluated. Serum metabolomics was adopted to investigate the differential metabolites (DEMs). UHPLC-Q-Exactive-MS method was applied to identify the components of RMF, and then network pharmacology was utilize to select the component-RA-targets. Molecular docking and Western blotting were utilized to validate the key targets. RESULTS: RA symptoms were alleviated by RMF through the inhibition secretion of pro-inflammatory factors IL-1ß, IL-6 and TNF-α, along with relief in bone destruction observed in CIA rats. Four targets, namely AKR1B1, TPH1, CYP1A1, and CYP1A2, were identified, along with their corresponding metabolites, namely D-glucose, D-mannose, L-tryptophan, 11-deoxycorticosterone, and 17α-hydroxyprogesterone. These were found to be involved in three key metabolic pathways: steroid hormone biosynthesis, tryptophan metabolism, and galactose metabolism. Additionally, five significant anti-RA active components were identified from RMF, including Rhodojaponin (Rj)-Ⅱ, Rj-Ⅲ, Rj-Ⅴ, Rj-Ⅵ, and quercetin. CONCLUSIONS: The anti-RA mechanisms of RMF were investigated in this study, focusing on active components, upstream targets, and downstream metabolites. These findings lay a foundation for the clinical practice and drug development of RMF.

Integrated HS-GC-IMS and UPLC-Q-Orbitrap HRMS-based metabolomics revealed the characteristics and differential volatile and nonvolatile metabolites of different citrus peels.

Citrus is an important genus in the Rutaceae family, and citrus peels can be used in both food and herbal medicine. However, the bulk of citrus peels are discarded as waste by the fruit processing industry, causing environmental pollution. This study aimed to provide guidelines for the rational and effective use of citrus peels by elucidating the volatile and nonvolatile metabolites within them using metabolomics based on headspace-gas chromatography-ion mobility spectrometry and ultra-high-performance liquid chromatography-Q-Orbitrap high-resolution mass spectrometry. In addition, the antioxidant activities of the citrus peels were evaluated using DPPH radical scavenging, ABTS radical scavenging, and ferric reducing antioxidant power. In total, 103 volatile and 53 nonvolatile metabolites were identified and characterized. Alcohols, aldehydes, and terpenes constituted 87.36% of the volatile metabolites, while flavonoids and carboxylic acids accounted for 85.46% of the nonvolatile metabolites. Furthermore, (Z)-2-penten-1-ol, L-pipecolinic acid, and limonin were identified as characteristic components of Citrus reticulata Blanco cv. Ponkan (PK), C. reticulata 'Unshiu' (CLU), and C. reticulata 'Wo Gan' (WG), respectively. Principal component analysis and partial least squares discriminant analysis indicated that C. reticulata Blanco 'Chun Jian' (CJ), PK, CLU, and C. reticulata 'Dahongpao' (DHP) were clustered together. DHP is a traditional Chinese medicine documented in the Chinese Pharmacopoeia, suggesting that the chemical compositions of CJ, PK, and CLU may also have medicinal values similar to those of DHP. Moreover, DHP, PK, C. reticulata 'Ai Yuan 38'(AY38), CJ, C. reticulata 'Gan Ping'(GP), and C. reticulata 'Qing Jian'(QJ) displayed better antioxidant activities, recommending their use as additives in cosmetics and food. Correlation analysis suggested that some polyphenols including tangeritin, nobiletin, skullcapflavone II, genistein, caffeic acid, and isokaempferide were potential antioxidant compounds in citrus peel. The results of this study deepen our understanding of the differences in metabolites and antioxidant activities of different citrus peel varieties and ultimately provide guidance for the full and rational use of citrus peels.

Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience.

OBJECTIVE: Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC. METHODS: Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery. RESULTS: Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0-151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS. CONCLUSIONS: Due to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

Influence of microorganisms on flavor substances and functional components of sojae semen praeparatum during fermentation: A study integrating comparative metabolomics and high-throughput sequencing.

Sojae semen praeparatum (SSP), a fermented product known for its distinctive flavor and medicinal properties, undergoes a complex fermentation process due to the action of various microorganisms. Despite its widespread use, the effect of these microorganisms on the flavor compounds and functional components of SSP remains poorly understood. This study aimed to shed light on this aspect by identifying 20 metabolites as potential key flavor substances in SSP. Moreover, glycine and lysine were identified as crucial flavor substances. Additionally, 24 metabolites were identified as key functional components. The dominant microorganisms involved in the fermentation process were examined, revealing six genera of fungi and 12 genera of bacteria. At the species level, 16 microorganisms were identified as dominant through metagenome sequencing. Spearman correlation analysis demonstrated a strong association between dominant microorganisms and both flavor substances and functional components. Furthermore, the study validated the significance of four core functional microorganisms in improving the flavor and quality of SSP. This comprehensive exploration of functional microorganisms of SSP on key flavor substances/functional components during SSP fermentation. The study findings serve as a valuable reference for enhancing the overall flavor and quality of SSP.

Effects of the epiphytic patterns on endophytes and metabolites of Dendrobium nobile Lindl.

Introduction: Dendrobium is an epiphytic herb plant with neuroprotective, gastroprotective, anti-inflammatory, and immunomodulatory effects. It is often found attached to tree trunks or rocks. With the development of the dendrobium industry, numerous epiphytic patterns exist, such as crushed stone, stump, and sawdust. The study of metabolites and endophytes of D. nobile under different epiphytic patterns, which revealed the effects of epiphytic patterns on D. nobile from the perspectives of metabolomics and microbiology, is of great significance for the healthy development of D. nobile. Methods: In the study, the D. nobile under five epiphytic patterns grown in the same environment were selected. The metabolites were investigated by widely targeted metabolomics, and the endophytes were sequenced using high-throughput sequencing methods. Then, a correlation analysis between the different metabolites and endophytes was performed. Results: A total of 1,032 metabolites were annotated in D. nobile. There are more flavonoids and phenolic acids accumulated on the epiphytic pattern of Danxia stone, whereas the accumulation of lipids on the other epiphytic patterns and 16 differential metabolites was screened out. The endophyte composition of D. nobile was dominated by Proteobacteria, Actinomycetes, unidentified bacteria, Firmicutes, and Cyanobacteria. For endophytic fungi, Basidiomycota and Ascomycota were the dominant phyla of D. nobile. The relative abundance of Spirosoma, Nocardioides, and Arrhenia in the Danxia stone was significantly higher than that of other epiphytic patterns. According to correlation analysis, we found a significant correlation between differential metabolites and Spirosoma, Nocardioides, and Arrheni. Discussion: This study confirmed that Dendrobium quality was affected by its epiphytic patterns and revealed its possible causes from a microbiological point of view.

Insights into metabolic characteristics and biological activity changes in Zangju (Citrus reticulata cv. Manau Gan) peel at different maturity stages through UPLC-MS/MS-based metabolomics.

In this study, comprehensive and systematic nontargeted metabolomics analysis was performed with the metabolites of Zangju peel (Citrus reticulata cv. Manau Gan, CRZP, which has been cultivated for over 400 years in Derong County, China.) at four different mature stages. A total of 1878 metabolites were identified, among which flavonoids were the most abundant (62.04 %), and identified 62 key differential metabolites significantly affected by maturity. Based on biological activity measurements, CRZP showed better antioxidant activity, lipase inhibition ability, inhibition of adipogenic differentiation in 3TT-L1 cells and promotion of lipid metabolism, with the biological activity of CRZP at different maturity stages being associated with key differential metabolite. Thus, CRZP is natural antioxidants and possess anti-obesity potential, and industrial production needs to consider the Maturity stage of its collection.

Systematic screening of hepatoprotective components from traditional Chinese medicine: Zuojin Pill as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP), composed of Coptis chinensis Franch. and Euodia ruticarpa (A. Juss.) Benth. in a mass ratio of 6:1, is a famous traditional Chinese medicine (TCM) formula recorded in "Danxi's Experiential Therapy", an ancient medical book from the Ming Dynasty of China. It is used to treat liver fire invading the stomach, which is caused by liver stagnation transforming into fire and disharmony between the liver and stomach. AIM OF THE STUDY: To develop a systematic strategy to screen hepatoprotective components from TCM using ZJP as a model sample. MATERIALS AND METHODS: A CCl4-induced mouse model of acute liver injury was used for the verification of the hepatoprotective effects of ZJP. UPLC-Q-Exactive Plus Orbitrap MS/MS was used for the identification of the components in mouse serum after intragastric administration of ZJP. The hepatoprotective activities of the components found in mouse serum were tested in primary cultured mouse hepatocytes induced by CCl4. RESULTS: Nine components with significant hepatoprotective activity including berberine, epiberberine, coptisine, palmatine, jatrorrhizine, rutaecarpin, dehydroevodiamine, evocarpine and chlorogenic acid were successfully screened out. CONCLUSIONS: Our developed strategy has the advantages of high efficiency and low cost, and would provide a powerful tool for screening potential hepatoprotective components from TCM.

Integrated metabolomics and network pharmacology revealed the key active ingredients for the treatment of ulcerative colitis in the Citrus reticulata 'Dahongpao' peel.

Citrus reticulata pericarpium (CRP), the peel of Citrus reticulata 'Dahongpao' (DHP) is a medicinal herb with significant therapeutic value for treating ulcerative colitis (UC). However, the active therapeutic components of CRP are unclear. This study aims to reveal the metabolites potentially associated with the pharmacological properties of CRP. We performed flavonoid-targeting metabolomics to characterize the components of CRP (anti-UC part), tangerine pith and Citrus reticulata semen (no anti-UC effects parts) of DHP and further screened active components of CRP using network pharmacology and molecular docking. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the anti-inflammatory effect of the selected biologically active components. The therapeutic effects of the selected components were further investigated in a mouse model of UC induced by DSS. Three compounds, namely nobiletin, sinensetin, and hispidulin had the lowest docking scores among all screened ingredients. IL-6 and NO concentrations were significantly decreased in the LPS-stimulated RAW264.7 cells compared with control cells treated with these compounds. Moreover, UC mice treated with these compounds showed a reversal in weight loss, inhibition of shortening of colon length, and amelioration of colon injury. Our results indicated that sinensetin, nobiletin, and hispidulin can be potentially used for the treatment of UC.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Molecular PET/CT mapping of rhACE2 distribution and quantification in organs to aid in SARS-CoV-2 targeted therapy.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, poses a significant threat to public health. Angiotensin-converting enzyme 2 (ACE2) is a key receptor for SARS-CoV-2 infection. Recombinant human ACE2 (RhACE2), as a soluble supplement for human ACE2, can competitively block SARS-CoV-2 infection. In this study, a mouse organ in situ rhACE2 high aggregation model was constructed for the first time, and in vivo real-time positron emission tomography (PET) imaging of rhACE2 in the mouse model was performed using an ACE2-specific agent 68 Ga-HZ20. This radiotracer exhibits reliable radiochemical properties in vitro and maintains a high affinity for rhACE2 in vivo. In terms of probe uptake, 68 Ga-HZ20 showed a good target-to-nontarget ratio and was rapidly cleared from the circulatory system and excreted by the kidneys and urinary system. PET imaging with this radiotracer can noninvasively and accurately monitor the content and distribution of rhACE2 in the body, which clarifies that rhACE2 can aggregate in multiple organs, suggesting the preventive and therapeutic potential of rhACE2 for SARS-CoV-2 and COVID-19.

Exploring the roles of microorganisms and metabolites in the 30-year aging process of the dried pericarps of Citrus reticulata 'Chachi' based on high-throughput sequencing and comparative metabolomics.

GuangChenpi (GCP), the dried pericarps of Citrus reticulata 'Chachi', has been consumed daily as a food and dietary supplement in China for centuries. Its health benefits are generally recognized to be dependent on storage time. However, the specific roles of microorganisms and metabolites during long-term storage are still unclear. In this study, comparative metabolomics and high-throughput sequencing techniques were used to investigate the effects of co-existing microorganisms on the metabolites in GCP stored from 1 to 30 years. In total, 386 metabolites were identified and characterized. Most compounds were flavonoids (37%), followed by phenolic acids (20%). Seventeen differentially upregulated metabolites were identified as potential key metabolites in GCP, and 8 of them were screened out as key active ingredients by Venn diagram comparative analyses and verified by network pharmacology and molecular docking. In addition, long-term storage could promote the accumulation of secondary metabolites. Regarding the GCP microbiota, Xeromyces dominated the whole 30-year aging process.Moreover, Spearman correlation analysis indicated that Bacillus thuringiensis and Xeromyces bisporus, the dominant bacterial and fungal species, were strongly associated with the key active metabolites. Our results suggested that the change of active ingredients caused by the dominant microbial is one of the mechanisms affecting the GCP aging process. Our study provides novel functional insights and research perspectives on microorganism-associated metabolite changes that may improve the GCP aging process.

Electronic Nose and Head Space GC-IMS Provide Insights into the Dynamic Changes and Regularity of Volatile Compounds in Zangju (Citrus reticulata cv. Manau Gan) Peel at Different Maturation Stages.

Zangju (Citrus reticulata cv. Manau Gan) is the main citrus cultivar in Derong County, China, with unique aroma and flavour characteristics, but the use of Zangju peel (CRZP) is limited due to a lack of research on its peel. In this study, electronic nose, headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS), and partial least squares-discriminant analysis (PLS-DA) methods were used to rapidly and comprehensively evaluate the volatile compounds of dried CRZP and to analyse the role of dynamic changes at different maturation stages. The results showed that seventy-eight volatile compounds, mainly aldehydes (25.27%) and monoterpenes (55.88%), were found in the samples at four maturity stages. The contents of alcohols and aldehydes that produce unripe fruit aromas are relatively high in the immature stage (October to November), while the contents of monoterpenoids, ketones and esters in ripe fruit aromas are relatively high in the full ripening stage (January to February). The PLS-DA model results showed that the samples collected at different maturity stages could be effectively discriminated. The VIP method identified 12 key volatile compounds that could be used as flavour markers for CRZP samples collected at different maturity stages. Specifically, the relative volatile organic compounds (VOCs) content of CRZP harvested in October is the highest. This study provides a basis for a comprehensive understanding of the flavour characteristics of CRZP in the ripening process, the application of CRZP as a byproduct in industrial production (food, cosmetics, flavour and fragrance), and a reference for similar research on other C. reticulata varieties.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Integrated physicochemical, hormonal, and transcriptomic analysis reveals the underlying mechanism of callus formation in Pinellia ternata hydroponic cuttings.

Introduction: P. ternata is a perennial herb of the family Araceae that grows in China and has various medicinal properties and applications. At present, the artificial cultivation of P. ternata is constrained by seedling propagation. To address the problems of low seedling breeding propagation efficiency and high cost, our group has developed a highly efficient cultivation technology for "hydroponic cuttings of P. ternata "for the first time. P. ternata is used as the source material and is grown in a hydroponic system, increasing the seedling production rate 10-fold compared with the traditional cultivation mode. However, the callus formation mechanism in cuttings from hydroponic cultivation is still remains unclear. Methods: In order to better understand the biological process of callus formation in cuttings from hydroponic P. ternata, anatomical characterization, endogenous hormone content determination and transcriptome sequencing were performed on five callus stages from early growth to early senescence. Results: Regarding the four major hormones during the callus developmental stages of P. ternata hydroponic cuttings, cytokinins showed an increasing trend during callus formation. IAA(indole-3-acetic acid) and abscisic acid contents increased at 8d and then decreased, while jasmonic acid content gradually decreased. A total of 254137 unigenes were identified by transcriptome sequencing in five callus formation stages. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the differentially expressed genes (DEGs) that differentially expressed unigenes were involved in various plant hormone signaling and hormone synthesis-related pathways. The expression patterns of 7 genes were validated using quantitative real-time PCR. Discussion: This study presented integrated transcriptomic and metabolic analysis approach to obtain insights into the underlying biosynthetic mechanisms and function of key hormones involved in the callus formation process from hydroponic P. ternata cuttings.

Fosaprepitant Weekly vs Every 3 Weeks for the Prevention of Concurrent Chemoradiotherapy-Induced Nausea and Vomiting: A Pilot Randomized Clinical Trial.

Importance: Unlike substantial evidence in the prevention of chemotherapy-induced nausea and vomiting (CINV), research in the prevention of nausea and vomiting caused by concurrent chemoradiotherapy (CCRT) is currently lacking. Objective: To compare the efficacy and safety of fosaprepitant weekly vs every 3 weeks for the prevention of nausea and emesis caused by CCRT among patients with nasopharyngeal carcinoma. Design, Setting, and Participants: This pilot randomized clinical trial was conducted at a single cancer center from November 24, 2020, to July 26, 2021, among patients with nasopharyngeal carcinoma who had achieved CINV control after 2 to 3 cycles of induction chemotherapy. Efficacy analyses were performed in the intention-to-treat population. Data were analyzed on November 4, 2022. Interventions: Eligible patients were randomly assigned (1:1) to receive fosaprepitant either weekly or every 3 weeks. Main Outcomes and Measures: The primary end point was the proportion of patients with sustained complete response (defined as no emesis and no rescue therapy) during CCRT. Secondary end points were sustained no emesis, no nausea, no significant nausea, mean time to first emetic episode, quality of life, and 1-year progression-free survival (PFS). Results: A total of 100 patients (mean [SD] age, 46.6 [10.9] years; 83 [83.0%] male) who had achieved CINV control after induction chemotherapy were randomly assigned to receive fosaprepitant weekly (50 patients) or every 3 weeks (50 patients). There was no significantly significant difference in cumulative risk of emesis or rescue therapy in the group that received weekly fosaprepitant compared with those who received fosaprepitant every 3 weeks (subhazard ratio, 0.66 [95% CI, 0.43-1.02]; P = .06). The proportion of patients with sustained no emesis (38% vs 14%; P = .003) or no significant nausea (92% vs 72%; P = .002) was significantly higher in the group that received fosaprepitant weekly vs those who received fosaprepitant every 3 weeks. Treatments were well tolerated. Patients in the weekly group had improved scores for multiple quality-of-life measures. There was no significant difference in survival outcomes between groups (91.8% vs 93.7%; P = .99). In the mean brainstem dose subgroups, a possible treatment interaction effect was observed in sustained complete response (mean brainstem dose ≥36 Gy: hazard ratio [HR], 0.32 [95% CI, 0.15-0.69]; mean brainstem dose <36 Gy: HR, 0.95 [95% CI, 0.55-1.63]) and sustained no emesis (mean brainstem dose ≥36 Gy: HR, 0.21 [95% CI, 0.08-0.53]; mean brainstem dose <36 Gy: HR, 0.73 [95% CI, 0.41-1.28]). Conclusions and Relevance: In this pilot randomized clinical trial, there was no statistically significant difference in the complete response primary end point, but patients receiving weekly fosaprepitant were less likely to experience emesis compared with those who received fosaprepitant every 3 weeks, especially in the subgroup with a mean brainstem dose of 36 Gy or more. Weekly fosaprepitant was well tolerated and improved quality of life of patients without compromising survival. Trial Registration: ClinicalTrials.gov Identifier: NCT04636632.

[Assay of amino acids in leaves of Eucommia ulmoides under arbor forest mode and leaf-oriented cultivation mode by pre-column derivatization HPLC].

This study aims to develop the pre-column derivatization high performance liquid chromatography(HPLC) method for the determination of 16 kinds of amino acids in Eucommia ulmoides leaves, and compare the content of amino acids in the leaves harvested at different time and under leaf-oriented cultivation mode(LCM) and arbor forest mode(AFM). The HPLC conditions are as below: phenyl isothiocyanate(PITC) as pre-column derivatization agent, Agilent ZORBAX C_(18 )column(4.6 mm×250 mm, 5 µm), mobile phase A of acetonitrile-water(80∶20), mobile phase B of 0.1 mol·L~(-1) sodium acetate solution-acetonitrile(94∶6), gradient elution, flow rate of 1.0 mL·min~(-1), injection volume of 5 µL, column temperature of 40 ℃, and detection wavelength of 254 nm. The HPLC profile indicated well separation of 16 kinds of amino acids and the amino acid content in E. ulmoides leaves was up to 16.26%. In addition, the amino acid content in leaves of E. ulmoides under LCM was higher than under AFM. The amino acid content varied with the harvesting time. Through orthogonal partial least squares discriminant analysis, the amino acids of E. ulmoides under LCM and AFM were compared, which can distinguish the leaves under LCM from those under AFM. Principal component analysis was applied to comprehensively score the amino acids of E. ulmoides leaves. The results showed that the score of leaves under LCM was higher than that under AFM. Nutritional evaluation results indicated that the proteins in E. ulmoides leaves belonged to high-quality vegetable proteins. The established method for the determination of amino acid content is reliable. With the amino acid content as index, the leaf quality of E. ulmoides under LCM is better than that under AFM. This study lays a theoretical basis for the promotion of LCM for E. ulmoides and the development of medicinal and edible products from E. ulmoides leaves.

[Effects of different drying methods on quality of male flowers of Eucommia ulmoides based on color and chemical composition].

To study the effects of different drying methods on the quality of male flowers of Eucommia ulmoides(MFOEU), we treated fresh MFOEU samples with drying in the shade(DS), vacuum freeze drying(VFD), high-or low-temperature hot air drying(HTHAD, LTHAD), microwave drying(MD), and vacuum drying(VD), respectively. The color, total flavonoid content, total polysaccharide content, and main active components such as geniposide, geniposidic acid, rutin, chlorogenic acid, galuteolin, pinoresinol diglucoside, and aucubin in MFOEU were taken as the evaluation indicators. The quality of MFOEU was comprehensively evaluated by entropy weight method combined with color index method, partial least squares discriminant analysis and content clustering heat map. The experimental results showed that VFD and DS basically kept the original color of MFOEU. The MFOEU treated with MD had higher content of total polysaccharides, phenylpropanoids, lignans, and iridoids. The MFOEU treated with LTHAD had higher content of total flavonoids and that treated with VD had lower content of active components. According to the results of comprehensive evaluation, the quality of MFOEU dried with different methods followed the order of MD>HTHAD>VFD>LTHAD>DS>VD. Considering the color of MFOEU, the suitable drying methods were DS and VFD. Considering the color, active components, and economic benefits of MFOEU, MD was the suitable drying method. The results of this study are of a reference value for the determination of suitable methods for MFOEU processing in the producing areas.

Comparison of the volatile organic compounds in Citrus reticulata 'Chachi' peel with different drying methods using E-nose, GC-IMS and HS-SPME-GC-MS.

Introduction: Citrus reticulata 'Chachi' peel (CRCP), which is named "Guangchenpi" in China, is a geographical indication product with unique flavor properties. CRCP has been used for centuries as a traditional genuine herb because of its excellent therapeutic effects. In addition, owing to its unique odor and high nutrition, it is widely used in various food preparations. Volatile organic compounds (VOCs) are regarded as an important quality marker for CRCP and are highly susceptible to effects in the drying process due to their thermal instability. Methods: In the current study, the main VOCs in CRCP were processed using different drying methods, including sun-drying, hot air drying, and vacuum-freeze drying. The VOCs were identified by the electronic nose (E-nose), gas chromatography-ion mobility spectrometry (GC-IMS), and headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). Results: The results showed that the CRCP dried by vacuum-freeze exhibited the highest VOCs contents and retained the richest compounds compared to those dried by other methods, which indicated that vacuum-freeze drying is the most suitable for CRCP production. Furthermore, the chemometrics analysis revealed that the primary differential metabolites of the samples generated using different drying methods were terpenes and esters. Discussion: Overall, our study would help better understand the VOCs present in CRCP with different drying methods. The outcomes of the current study would guide the drying and processing of CRCP, which is beneficial for large-scale storage and industrial production of CRCP.

Integrated network pharmacology, transcriptomics, and metabolomics analysis to reveal the mechanism of salt Eucommiae cortex in the treatment of chronic kidney disease mineral bone disorders via the PPARG/AMPK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The skeletal complications associated with chronic kidney diseases from stages 3-5 in individuals are called Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), which increases the incidence of cardiovascular diseases drastically and affects the quality of life of patients seriously. Eucommiae cortex has the effect of tonifying kidneys and strengthening bones, and salt Eucommiae cortex is one of the most commonly used traditional Chinese medicines in the clinical treatment of CKD-MBD instead of Eucommiae cortex. However, its mechanism still remains unexplored. AIM OF THE STUDY: The aim of this study was to investigate the effects and mechanisms of salt Eucommiae cortex on CKD-MBD by integrating network pharmacology, transcriptomics, and metabolomics. MATERIALS AND METHODS: The CKD-MBD mice induced by 5/6 nephrectomy and low calcium/high phosphorus diet were treated with salt Eucommiae cortex. The renal functions and bone injuries were evaluated by serum biochemical detection, histopathological analyses, and femur Micro-CT examinations. Differentially expressed genes (DEGs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by transcriptomic analysis. The differentially expressed metabolites (DEMs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by metabolomics analysis. The common targets and pathways were obtained by integrating transcriptomics, metabolomics, and network pharmacology, which were identified and verified by in vivo experiments. RESULTS: The negative impacts on the renal functions and bone injuries were alleviated with salt Eucommiae cortex treatment effectively. Compared with CKD-MBD model mice, the levels of serum BUN, Ca, and urine Upr were significantly decreased in the salt Eucommiae cortex group. And the Integrated network pharmacology, transcriptomics, and metabolomics analysis revealed that Peroxisome Proliferative Activated Receptor, Gamma (PPARG) was the only common target, mainly involved by AMP-activated Protein Kinase (AMPK) signaling pathways. The activation of PPARG in the kidney tissue was significantly decreased in CKD-MBD mice but increased in the salt Eucommiae cortex treatment. The AMPK signaling pathway was verified and the AMPK expression levels were found to decrease in CKD-MBD mice but increase given salt Eucommiae cortex treatment. CONCLUSIONS: Our study presented that salt Eucommiae cortex alleviated the negative impact of CKD-MBD on the renal injury and bone injury of mice induced by 5/6 nephrectomy with the low calcium/high phosphorus diet effectively, which is highly likely achieved through the PPARG/AMPK signaling pathway.