HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

MicrobeTCM: A comprehensive platform for the interactions of microbiota and traditional Chinese medicine.

Thanks to the advancements in bioinformatics, drugs, and other interventions that modulate microbes to treat diseases have been emerging continuously. In recent years, an increasing number of databases related to traditional Chinese medicine (TCM) or gut microbes have been established. However, a database combining the two has not yet been developed. To accelerate TCM research and address the traditional medicine and micro ecological system connection between short board, we have developed the most comprehensive micro-ecological database of TCM. This initiative includes the standardization of the following advantages: (1) A repeatable process achieved through the standardization of a retrieval strategy to identify literature. This involved identifying 419 experiment articles from PubMed and six authoritative databases; (2) High-quality data integration achieved through double-entry extraction of literature, mitigating uncertainties associated with natural language extraction; (3) Implementation of a similar strategy aiding in the prediction of mechanisms of action. Leveraging drug similarity, target entity similarity, and known drug-target entity association, our platform enables the prediction of the effects of a new herb or acupoint formulas using the existing data. In total, MicrobeTCM includes 171 diseases, 725 microbes, 1468 herb-formulas, 1032 herbs, 15780 chemical compositions, 35 acupoint-formulas, and 77 acupoints. For further exploration, please visit https://www.microbetcm.com.

Green tea polysaccharide conjugates and bovine serum albumin have a synergistic effect in improving the emulsification ability.

Our previous study revealed that green tea polysaccharide conjugate (gTPC) has emulsion effect, but its emulsifying ability is weak. In order to improve the emulsification ability of gTPC, gTPC and bovine serum albumin (BSA) were combined to form five different mass proportions of the TPC/BSA (TB) complex: TPC/BSA: 5:1, 5:2, 5:3, 5:4, and 5:5 w/w. We observed that the 5:5 w/w TB emulsion was more hydrophobic and surface-active. Furthermore, the emulsions prepared using 50.00 wt% medium-chain triglycerides exhibited the best stability. In addition, the TB emulsion exhibited stability in adverse environments of pH, salt, and heat; in particular, under salt conditions, no significant changes were observed in zeta potential. Subsequently, in vitro simulated digestion experiments were performed to investigate the use of TB emulsions for ß-carotene encapsulation. We observed that the encapsulation efficiency for ß-carotene was approximately 90.0 %; it was subsequently released in the intestine.

Moisture content of tea dhool for the scenting process affects the aroma quality and volatile compounds of osmanthus black tea.

To improve the quality of osmanthus black tea, samples produced with different scenting methods were prepared. The sensory quality was assessed and the characteristic aromatic components were explored using solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry. According to the results, osmanthus black tea obtained by adding osmanthus scenting in the fermentation process had the strongest floral aroma. The major contributors to the aroma of osmanthus black tea were identified as ß-ionone, dihydro-ß-ionone, benzeneacetaldehyde, citral, geraniol, and linalool by calculating their relative odor activity values. An analysis of the causes revealed that the moisture content of tea dhool significantly affected the adsorption of fresh flower aroma by tea. The experimental results showed that osmanthus black tea produced using tea dhool containing 30% moisture content had the highest content of crucial aroma components, suggesting the tea dhool under this condition had the strongest adsorption capacity for osmanthus aroma.

Investigation of anti-depression effects and potential mechanisms of the ethyl acetate extract of Cynomorium songaricum Rupr. through the integration of in vivo experiments, LC-MS/MS chemical analysis, and a systems biology approach.

Background: Cynomorium songaricum Rupr. has long been used as an anti-inflammatory, antidepressant, and anti-aging agent in traditional Chinese medicine in Asia. Its ethyl acetate extract (ECS) has been identified as the main antioxidant component with neuroprotective and estrogen-like effects. However, the potential of ECS in treating depression has not been explored yet. Methods: We identified the primary metabolites in ECS in this study using liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). Network analysis was used to find the potential targets and pathways associated with the anti-neuroinflammatory depression action of the ECS. In addition, we established a corticosterone (CORT)-induced depression mouse model to assess ECS's antidepressant effects by monitoring various behavioral changes (e.g., sucrose preference, forced swimming, tail suspension, and open field tests) and biochemical indices of the hippocampus, and validating the network analysis results. Significant pathways underwent verification through western blotting based on network analysis prediction. Results: Our study demonstrates that ECS possesses significant antidepressant activity. The LC-MS/MS analysis of ECS identified 30 main metabolites, including phloridzin, phlorizin, ursolic acid, and naringenin, as well as other flavonoids, terpenoids, and phenolic acids. These metabolites were found to be associated with 64 candidate target proteins related to neuroinflammatory depression from the database, and ten hub proteins were identified through filtration: CXCL8, ICAM1, NOS2, SELP, TNF, IL6, APP, ACHE, MAOA and ADA. Functional enrichment analyses of the candidate targets revealed their primary roles in regulating cytokine production, inflammatory response, cytokine activity, and tumor necrosis factor receptor binding. In vivo, ECS improved hippocampal neuroinflammation in the mouse model. Specifically, ECS reduced the expression of inflammatory factors in the hippocampus, inhibited M1 microglial cell polarization, and alleviated depression through the regulation of the NF-κB-NLRP3 inflammation pathway. Conclusion: Based on experimental and network analysis, this study revealed for the first time that ECS exerted antidepression effect via anti-neuroinflammation. Our research provides valuable information on the use of ECS as an alternative therapeutic approach for depression.

Erratum: Author correction to 'Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice' [Acta Pharmaceutica Sinica B 13 (2023) 1164-1179].

[This corrects the article DOI: 10.1016/j.apsb.2022.10.016.].

Effects of brewing water on the volatile composition of tea infusions.

There is a huge demand for brewing water in tea consumption, and the sensory flavor of tea infusion is significantly affected by the water used for brewing. To investigate the impact of brewing water on the aroma of tea infusions made from Camelia senensis, the three tea infusions of green, oolong and black tea brewed by six different drinking waters were analyzed by sensory evaluation, solid-phase microextraction, gas chromatography-mass spectrometry, and chemometrics. Brewing water with high pH values (>8.10) and high TDS content (>140 ppm) resulted in a lower overall aroma acceptability for tea infusion, where HCO3-, Ca2+ and Mg2+ were key influencing ions. A total of 86, 106, and 131 volatiles were identified in green, oolong and black tea infusions, respectively, which were strongly influenced by six different brands of waters. Decanal, dimethyl sulfide, ß-ionone and linalool were potent volatiles in tea aroma changes caused by brewing water.

Effects of natural spring water on the sensory attributes and physicochemical properties of tea infusions.

The sensory quality of tea is influenced by water quality, with natural spring water (NSW) gaining much attention for its natural and healthy qualities. The effects of NSW on the sensory attributes, physicochemical composition, and antioxidant capacity of Chinese tea were investigated. Tea brewed with pure water was the most resistant to oxidation and darkening. NSW with low total dissolved solids (TDS) was most suitable for brewing unfermented or mildly fermented teas, improving their sensory quality. The simulated green tea infusion system was used to investigate further the dramatic darkening of tea infusions in NSW. Exposure of infusions to air promoted the degradation, epimerization, and oxidative polymerization of catechins, and further formed theabrownins which darkened the tea infusions. These findings enabled tea consumers to choose the most suitable NSW for brewing Chinese teas and illustrated the darkening mechanism of tea infusion in high pH/TDS water.

Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice.

Sepsis-induced liver injury (SILI) is an important cause of septicemia deaths. BaWeiBaiDuSan (BWBDS) was extracted from a formula of Panax ginseng C. A. Meyer, Lilium brownie F. E. Brown ex Miellez var. viridulum Baker, Polygonatum sibiricum Delar. ex Redoute, Lonicera japonica Thunb., Hippophae rhamnoides Linn., Amygdalus Communis Vas, Platycodon grandiflorus (Jacq.) A. DC., and Cortex Phelloderdri. Herein, we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota. BWBDS protected mice against SILI, which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity. BWBDS selectively promoted the growth of Lactobacillus johnsonii (L. johnsonii) in cecal ligation and puncture treated mice. Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects. Notably, L. johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity, increasing interleukin-10+ M2 macrophage production and enhancing intestinal integrity. Furthermore, heat inactivation L. johnsonii (HI-L. johnsonii) treatment promoted macrophage anti-inflammatory activity and alleviated SILI. Our findings revealed BWBDS and gut microbiota L. johnsonii as novel prebiotic and probiotic that may be used to treat SILI. The potential underlying mechanism was at least in part, via L. johnsonii-dependent immune regulation and interleukin-10+ M2 macrophage production.

Antiviral Effect of Ginsenosides rk1 against Influenza a Virus Infection by Targeting the Hemagglutinin 1-Mediated Virus Attachment.

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a good target for developing anti-IAV drugs. Panax ginseng is a widely used herb in traditional medicine with extensive biological effects in various disease models, and its extract was reported to show protection in IAV-infected mice. However, the main effective anti-IAV constituents in panax ginseng remain unclear. Here, we report that ginsenoside rk1 (G-rk1) and G-rg5, out of the 23 screened ginsenosides, exhibit significant antiviral effects against 3 different IAV subtypes (H1N1, H5N1, and H3N2) in vitro. Mechanistically, G-rk1 blocked IAV binding to sialic acid in a hemagglutination inhibition (HAI) assay and an indirect ELISA assay; more importantly, we showed that G-rk1 interacted with HA1 in a dose-dependent manner in a surface plasmon resonance (SPR) analysis. Furthermore, G-rk1 treatment by intranasal inoculation effectively reduced the weight loss and mortality of mice challenged with a lethal dose of influenza virus A/Puerto Rico/8/34 (PR8). In conclusion, our findings reveal for the first time that G-rk1 possesses potent anti-IAV effects in vitro and in vivo. We have also identified and characterized with a direct binding assay a novel ginseng-derived IAV HA1 inhibitor for the first time, which could present potential approaches to prevent and treat IAV infections.

Toosendanin suppresses African swine fever virus replication through upregulating interferon regulatory factor 1 in porcine alveolar macrophage cultures.

African swine fever virus (ASFV) is a highly infectious and lethal swine pathogen that causes severe socio-economic consequences in affected countries. Unfortunately, effective vaccine for combating ASF is unavailable so far, and the prevention and control strategies for ASFV are still very limited. Toosendanin (TSN), a triterpenoid saponin extracted from the medicinal herb Melia toosendan Sieb. Et Zucc, has been demonstrated to possess analgesic, anti-inflammatory, anti-botulism and anti-microbial activities, and was used clinically as an anthelmintic, while the antiviral effect of TSN on ASFV has not been reported. In this study, we revealed that TSN exhibited a potent inhibitory effect on ASFV GZ201801-38 strain in porcine alveolar macrophages (PAMs; EC50 = 0.085 µM, SI = 365) in a dose-dependent manner. TSN showed robust antiviral activity in different doses of ASFV infection and reduced the transcription and translation levels of ASFV p30 protein, viral genomic DNA quantity as well as viral titer at 24 and 48 h post-infection. In addition, TSN did not affect virion attachment and release but intervened in its internalization in PAMs. Further investigations disclosed that TSN played its antiviral role by upregulating the host IFN-stimulated gene (ISG) IRF1 rather than by directly inactivating the virus particles. Overall, our results suggest that TSN is an effective antiviral agent against ASFV replication in vitro and may have the potential for clinical use.

Optimal PET-based radiomic signature construction based on the cross-combination method for predicting the survival of patients with diffuse large B-cell lymphoma.

PURPOSE: To develop and externally validate models incorporating a PET radiomics signature (R-signature) obtained by the cross-combination method for predicting the survival of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 383 patients with DLBCL from two medical centres between 2011 and 2019 were included. The cross-combination method was used on three types of PET radiomics features from the training cohort to generate 49 feature selection-classification candidates based on 7 different machine learning models. The R-signature was then built by selecting the optimal candidates based on their progression-free survival (PFS) and overall survival (OS). Cox regression analysis was used to develop the survival prediction models. The calibration, discrimination, and clinical utility of the models were assessed and externally validated. RESULTS: The R-signatures determined by 12 and 31 radiomics features were significantly associated with PFS and OS, respectively (P<0.05). The combined models that incorporated R-signatures, metabolic metrics, and clinical risk factors exhibited significant prognostic superiority over the clinical models, PET-based models, and the National Comprehensive Cancer Network International Prognostic Index in terms of both PFS (C-index: 0.801 vs. 0.732 vs. 0.785 vs. 0.720, respectively) and OS (C-index: 0.807 vs. 0.740 vs. 0.773 vs. 0.726, respectively). For external validation, the C-indices were 0.758 vs. 0.621 vs. 0.732 vs. 0.673 and 0.794 vs. 0.696 vs. 0.781 vs. 0.708 in the PFS and OS analyses, respectively. The calibration curves showed good consistency, and the decision curve analysis supported the clinical utility of the combined model. CONCLUSION: The R-signature could be used as a survival predictor for DLBCL, and its combination with clinical factors may allow for accurate risk stratification.

Effects of baking treatment on the sensory quality and physicochemical properties of green tea with different processing methods.

Seven batches of raw tea leaves, processed by different methods (steaming, pan-frying) and from two different harvesting seasons (spring, autumn), were used to investigate the effect of baking treatment on changes in the composition and content of nonvolatile and volatile compounds. The results showed that baking had a greater impact on sensory and flavor quality, which chemically modified some of taste and aroma components. The aroma concentrations of steamed teas (4,168-10,706 µg/L) were significantly higher than those of pan-fried teas (959-2,608 µg/L), and the aroma concentrations of baked green teas (2,608-10,706 µg/L) were significantly higher than those of unbaked teas (959-4,213 µg/L). Based on VIP > 1 and ACI > 1, (E, E)-3,5-octadien-2-one, hexanal, ß-ionone, 5-methylfurfural, ß-cyclocitral, and linalool were identified as the main aroma compounds. Chemical changes resulting from Maillard reaction were greater during baking of steamed, than pan-fried green tea. These results help improve the quality of green tea with baking.

A targeted and nontargeted metabolomics study on the oral processing of epicatechins from green tea.

Oral processing (OP), referring to the whole process of food digestion in human mouth, has a major influence on food flavor perception. This study focused on the compositional changes of the four green tea epicatechins (viz., EC, EGC, ECG, EGCG) during OP, based on targeted and nontargeted metabolomics. It was found that the four epicatechins were all extensively lost through transformation undergoing OP, among which EC was the most stable one, whereas EGCG the least. EGCG was further revealed to be susceptible to human oral cavity in the simulated OP in vitro. It could be converted physically by precipitating with mucin in saliva, and chemically through hydrolysis and dimerization, mediated mainly by the neutral pH condition. The OP of epicatechins also caused salivary composition changes possibly involving health benefits of green tea. These findings could raise awareness of the interactions between epicatechins, or any other food materials, with human mouth.

Constructing tongue coating recognition model using deep transfer learning to assist syndrome diagnosis and its potential in noninvasive ethnopharmacological evaluation.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongue coating has been used as an effective signature of health in traditional Chinese medicine (TCM). The level of greasy coating closely relates to the strength of dampness or pathogenic qi in TCM theory. Previous empirical studies and our systematic review have shown the relation between greasy coating and various diseases, including gastroenteropathy, coronary heart disease, and coronavirus disease 2019 (COVID-19). However, the objective and intelligent greasy coating and related diseases recognition methods are still lacking. The construction of the artificial intelligent tongue recognition models may provide important syndrome diagnosis and efficacy evaluation methods, and contribute to the understanding of ethnopharmacological mechanisms based on TCM theory. AIM OF THE STUDY: The present study aimed to develop an artificial intelligent model for greasy tongue coating recognition and explore its application in COVID-19. MATERIALS AND METHODS: Herein, we developed greasy tongue coating recognition networks (GreasyCoatNet) using convolutional neural network technique and a relatively large (N = 1486) set of tongue images from standard devices. Tests were performed using both cross-validation procedures and a new dataset (N = 50) captured by common cameras. Besides, the accuracy and time efficiency comparisons between the GreasyCoatNet and doctors were also conducted. Finally, the model was transferred to recognize the greasy coating level of COVID-19. RESULTS: The overall accuracy in 3-level greasy coating classification with cross-validation was 88.8% and accuracy on new dataset was 82.0%, indicating that GreasyCoatNet can obtain robust greasy coating estimates from diverse datasets. In addition, we conducted user study to confirm that our GreasyCoatNet outperforms TCM practitioners, yet only consuming roughly 1% of doctors' examination time. Critically, we demonstrated that GreasyCoatNet, along with transfer learning, can construct more proper classifier of COVID-19, compared to directly training classifier on patient versus control datasets. We, therefore, derived a disease-specific deep learning network by finetuning the generic GreasyCoatNet. CONCLUSIONS: Our framework may provide an important research paradigm for differentiating tongue characteristics, diagnosing TCM syndrome, tracking disease progression, and evaluating intervention efficacy, exhibiting its unique potential in clinical applications.

TMNP: a transcriptome-based multi-scale network pharmacology platform for herbal medicine.

One of the most difficult problems that hinder the development and application of herbal medicine is how to illuminate the global effects of herbs on the human body. Currently, the chemo-centric network pharmacology methodology regards herbs as a mixture of chemical ingredients and constructs the 'herb-compound-target-disease' connections based on bioinformatics methods, to explore the pharmacological effects of herbal medicine. However, this approach is severely affected by the complexity of the herbal composition. Alternatively, gene-expression profiles induced by herbal treatment reflect the overall biological effects of herbs and are suitable for studying the global effects of herbal medicine. Here, we develop an online transcriptome-based multi-scale network pharmacology platform (TMNP) for exploring the global effects of herbal medicine. Firstly, we build specific functional gene signatures for different biological scales from molecular to higher tissue levels. Then, specific algorithms are designed to measure the correlations of transcriptional profiles and types of gene signatures. Finally, TMNP uses pharmacotranscriptomics of herbal medicine as input and builds associations between herbs and different biological scales to explore the multi-scale effects of herb medicine. We applied TMNP to a single herb Astragalus membranaceus and Xuesaitong injection to demonstrate the power to reveal the multi-scale effects of herbal medicine. TMNP integrating herbal medicine and multiple biological scales into the same framework, will greatly extend the conventional network pharmacology model centering on the chemical components, and provide a window for systematically observing the complex interactions between herbal medicine and the human body. TMNP is available at http://www.bcxnfz.top/TMNP.

Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis.

BACKGROUND: The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment. METHODS: A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0. RESULTS: A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50-0.90). CONCLUSIONS: The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.

Effect of Ferrous Ion on Heat-Induced Aroma Deterioration of Green Tea Infusion.

Aroma deterioration is one of the biggest problems in processing tea beverages. The aroma of tea infusion deteriorates fast during heat sterilization and the presence of ferrous ion (Fe2+) aggravates it. The underlying mechanism remains unveiled. In this study, Fe2+ was verified to deteriorate the aroma quality of green tea infusion with heat treatment. Catechins were necessary for Fe2+-mediated aroma deterioration. By enhancing the degradation of catechins, Fe2+ dramatically increased the production of hydrogen peroxide (H2O2). Fe2+ and H2O2 together exacerbated the aroma of green tea infusion with heat treatment. GC-MS analysis revealed that the presence of Fe2+ enhanced the loss of green/grassy volatiles and promoted the formation of new volatiles with diversified aroma characteristics, resulting in a dull scent of green tea infusion. Our results revealed how Fe2+ induced aroma deterioration of green tea infusion with heat treatment and could help guide tea producers in attenuating the aroma deterioration of tea infusion during processing.