Detection of trace components in Xiangdan injection of Dalbergia odorifera based on microextraction and back-extraction along with bar-form-diagram strategy.

Xiangdan Injection are commonly used traditional Chinese medicine formulations for the clinical treatment of cardiovascular diseases. However, the trace components of Dalbergia odorifera in Xiangdan Injection pose a challenge for evaluating its quality due to the difficulty of detection. This study proposes a technology combining dispersive liquid-liquid microextraction and back-extraction (DLLME-BE) along with Bar-Form-Diagram (BFD) to address this issue. The proposed combination method involves vortex-mixing tetradecane, which has a lower density than water, with the sample solution to facilitate the transfer of the target components. Subsequently, a new vortex-assisted liquid-liquid extraction step is performed to enrich the components of Dalbergia odorifera in acetonitrile. The sample analysis was performed on HPLC-DAD, and a clear overview of the chemical composition was obtained by integrating spectral and chromatographic information using BFD. The combination of BFD and CRITIC-TOPSIS strategies was used to optimize the process parameters of DLLME-BE. The determined optimal sample pre-treatment process parameters were as follows: 200 µL extraction solvent, 60 s extraction time, 50 µL back-extraction solvent, and 90 s back-extraction time. Based on the above strategy, a total of 29 trace components, including trans-nerolidol, were detected in the Xiangdan Injection. This combination technology provides valuable guidance for the enrichment analysis of trace components in traditional Chinese medicines.

Bibliometric Analysis of Research on Traditional Chinese Exercise and Osteoarthritis.

Background: Osteoarthritis (OA) is a common disease in geriatric rehabilitation medicine caused by the progressive destruction of articular cartilage. Traditional Chinese exercise (TCE) is an important component of traditional sports in China and aims to stretch the musculoskeletal tract and relieve joint pain. Bibliometrics can help researchers find suitable partners and understand the research hotspots and trends in a certain field. However, there is still a lack of bibliometric analysis in the field of TCE and OA. Methods: All the literature was obtained from the Web of Science Core Collection database. The last search was performed on July 28, 2023. The bibliometric indicators, such as publications, citations, and H-index, were recorded. Bibliometrix and CiteSpace were used for visualization analysis. In addition, randomized controlled trials were included to summarize the exercise prescription of TCE for OA. Results: A total of 170 articles were included. The field of OA with TCE had great development potential and was in the rising period. The countries, institutions, and authors with the most publications were the United States, Tufts Medical Center, and Harvey WF, respectively. The most popular journal was Osteoarthritis and Cartilage. The recent burst keywords in this field were mainly "hip", "pilot", and "risk". Tai Chi was the most studied TCE with the most detailed content of exercise prescription, followed by Baduanjin and Wuqinxi. Conclusion: Our study provides a basis for researchers in this field to choose appropriate partner and academic journals. Moreover, pain, muscle strength, and quality of life management of elderly OA patients are research hotspots in this field. The intervention of hip OA risk through TCE is expected to become a research direction for emerging teams. The TCE prescription we summarized can better provide researchers with more treatment details.

Blocked conversion of Lactobacillus johnsonii derived acetate to butyrate mediates copper-induced epithelial barrier damage in a pig model.

BACKGROUND: High-copper diets have been widely used to promote growth performance of pigs, but excess copper supplementation can also produce negative effects on ecosystem stability and organism health. High-copper supplementation can damage the intestinal barrier and disturb the gut microbiome community. However, the specific relationship between high-copper-induced intestinal damage and gut microbiota or its metabolites is unclear. OBJECTIVE: Using fecal microbiota transplantation and metagenomic sequencing, responses of colonic microbiota to a high-copper diet was profiled. In addition, via comparison of specific bacteria and its metabolites rescue, we investigated a network of bacteria-metabolite interactions involving conversion of specific metabolites as a key mechanism linked to copper-induced damage of the colon. RESULTS: High copper induced colonic damage, Lactobacillus extinction, and reduction of SCFA (acetate and butyrate) concentrations in pigs. LefSe analysis and q-PCR results confirmed the extinction of L. johnsonii. In addition, transplanting copper-rich fecal microbiota to ABX mice reproduced the gut characteristics of the pig donors. Then, L. johnsonii rescue could restore decreased SCFAs (mainly acetate and butyrate) and colonic barrier damage including thinner mucus layer, reduced colon length, and tight junction protein dysfunction. Given that acetate and butyrate concentrations exhibited a positive correlation with L. johnsonii abundance, we investigated how L. johnsonii exerted its effects by supplementing acetate and butyrate. L. johnsonii and butyrate administration but not acetate could correct the damaged colonic barrier. Acetate administration had no effects on butyrate concentration, indicating blocked conversion from acetate to butyrate. Furthermore, L. johnsonii rescue enriched a series of genera with butyrate-producing ability, mainly Lachnospiraceae NK4A136 group. CONCLUSIONS: For the first time, we reveal the microbiota-mediated mechanism of high-copper-induced colonic damage in piglets. A high-copper diet can induce extinction of L. johnsonii which leads to colonic barrier damage and loss of SCFA production. Re-establishment of L. johnsonii normalizes the SCFA-producing pathway and restores colonic barrier function. Mechanistically, Lachnospiraceae NK4A136 group mediated conversion of acetate produced by L. johnsonii to butyrate is indispensable in the protection of colonic barrier function. Collectively, these findings provide a feasible mitigation strategy for gut damage caused by high-copper diets. Video Abstract.

Identification of Fangjihuangqi Decoction as a late-stage autophagy inhibitor with an adjuvant anti-tumor effect against non-small cell lung cancer.

BACKGROUND: Clinically, although chemotherapy is one of the most commonly used methods of treating tumors, chemotherapeutic drugs can induce autophagic flux and increase tumor cell resistance, leading to drug tolerance. Therefore, theoretically, inhibiting autophagy may improve the efficacy of chemotherapy. The discovery of autophagy regulators and their potential application as adjuvant anti-cancer drugs is of substantial importance. In this study, we clarified that Fangjihuangqi Decoction (FJHQ, traditional Chinese medicine) is an autophagy inhibitor, which can synergistically enhance the effect of cisplatin and paclitaxel on non-small cell lung cancer (NSCLC) cells. METHODS: We observed the changes of autophagy level in NSCLC cells under the effect of FJHQ, and verified the level of the autophagy marker protein and cathepsin. Apoptosis was detected after the combination of FJHQ with cisplatin or paclitaxel, and NAC (ROS scavenger) was further used to verify the activation of ROS-MAPK pathway by FJHQ. RESULTS: We observed that FJHQ induced autophagosomes in NSCLC cells and increased the levels of P62 and LC3-II protein expression in a concentration- and time-gradient-dependent manner, indicating that autophagic flux was inhibited. Co-localization experiments further showed that while FJHQ did not inhibit autophagosome and lysosome fusion, it affected the maturation of cathepsin and thus inhibited the autophagic pathway. Finally, we found that the combination of FJHQ with cisplatin or paclitaxel increased the apoptosis rate of NSCLC cells, due to increased ROS accumulation and further activation of the ROS-MAPK pathway. This synergistic effect could be reversed by NAC. CONCLUSION: Collectively, these results demonstrate that FJHQ is a novel late-stage autophagy inhibitor that can amplify the anti-tumor effect of cisplatin and paclitaxel against NSCLC cells.

An intelligent extraction approach of feature information from three-dimensional DAD chromatogram for integrated quality control of traditional Chinese medicines: Gardenia jasminoides root as an example.

Traditional Chinese medicine (TCM) fingerprinting, which has the characteristics of holism and ambiguity, is a conventional strategy for the holistic quality control of TCMs. However, the fingerprinting of TCMs at the current stage generally adopts a single wavelength or few wavelengths, lacking the effective utilization of diode-array detector (DAD) chromatogram data. This study proposes an intelligent extraction approach of feature information from a three-dimensional DAD chromatogram to establish a novel bar-form-diagram (BFD) for integrated quality control of TCMs. The BFD was automatically established by the chromatographic and spectral information of a complex hybrid system in a DAD chromatogram. This covered the peak areas of target compositions at the optimal absorption wavelength. Taking 27 batches of Gardenia jasminoides root as samples, the BFD combined with chemometrics was applied for assessing the quality of samples completely, which improved the accuracy of origin classification using hierarchical cluster analysis, principal component analysis, soft independent modeling of class analogy and orthogonal partial least squares discriminant analysis. Single-wavelength fingerprinting and BFD used 23 and 38 common peaks as variables respectively, and the adjusted rand index results of the single wavelength and BFD were 0.559 and 0.819, respectively. Compared with the ergodic methods of each single wavelength, the peak recognition method in this study improved the operation speed from 180 s to 4 s and the computational complexity. The established BFD approach performed more abundant characteristic information of chemical components of TCMs and more accurate origin classification ability, and it had great advantages in the overall quality control of TCMs.

Recognition of the rhizome of red ginseng based on spectral-image dual-scale digital information combined with intelligent algorithms.

Red ginseng is a widely used and extensively researched food and medicinal product with high nutritional value, derived from steamed fresh ginseng. The components in various parts of red ginseng differ significantly, resulting in distinct pharmacological activities and efficacies. This study proposed to establish a hyperspectral imaging technology combined with intelligent algorithms for the recognition of different parts of red ginseng based on the dual-scale of spectrum and image information. Firstly, the spectral information was processed by the best combination of first derivative as pre-processing method and partial least squares discriminant analysis (PLS-DA) as classification model. The recognition accuracy of the rhizome and the main root of red ginseng is 96.79% and 95.94% respectively. Then, the image information was processed by the You Only Look Once version 5 small (YOLO v5s) model. The best parameter combination is epoch = 30, learning rate = 0.01, and activation function is leaky ReLU. In the red ginseng dataset, the highest accuracy, recall and mean Average Precision at IoU (Intersection over Union) threshold 0.5 (mAP@0.5) were 99.01%, 98.51% and 99.07% respectively. The application of spectrum-image dual-scale digital information combined with intelligent algorithms in the recognition of red ginseng is successful, which provides a positive significance for the online and on-site quality control and authenticity identification of crude drugs or fruits.

What happens to gut microorganisms and potential repair mechanisms when meet heavy metal(loid)s.

Heavy metal (loid) pollution is a significant threat to human health, as the intake of heavy metal (loid)s can cause disturbances in intestinal microbial ecology and metabolic disorders, leading to intestinal and systemic diseases. Therefore, it is important to understand the effects of heavy metal (loid)s on intestinal microorganisms and the necessary approaches to restore them after damage. This review provides a summary of the effects of common toxic elements, such as lead (Pb), cadmium (Cd), chromium (Cr), and metalloid arsenic (As), on the microbial community and structure, metabolic pathways and metabolites, and intestinal morphology and structure. The effects of heavy metal (loid)s on metabolism are focused on energy, nitrogen, and short-chain fatty acid metabolism. We also discussed the main solutions for recovery of intestinal microorganisms from the effects of heavy metal (loid)s, namely the supplementation of probiotics, recombinant bacteria with metal resistance, and the non-toxic transformation of heavy metal (loid) ions by their own intestinal flora. This article provides insight into the toxic effects of heavy metals and As on gut microorganisms and hosts and provides additional therapeutic options to mitigate the damage caused by these toxic elements.

Extraction and Purification of Flavonoids from Buddleja officinalis Maxim and Their Attenuation of H2O2-Induced Cell Injury by Modulating Oxidative Stress and Autophagy.

Cataracts are an ailment representing the leading cause of blindness in the world. The pathogenesis of cataracts is not clear, and there is no effective treatment. An increasing amount of evidence shows that oxidative stress and autophagy in lens epithelial cells play a key role in the occurrence and development of cataracts. Buddleja officinalis Maxim flavonoids (BMF) are natural antioxidants and regulators that present anti-inflammatory and anti-tumor effects, among others. In this study, we optimized the extraction method of BMFs and detected three of their main active monomers (luteolin, apigenin, and acacetin). In addition, a model of oxidative damage model using rabbit lens epithelial cells induced by hydrogen peroxide (H2O2). By detecting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and OH (OH), the expression of autophagosomes and autolysosomes were observed after MRFP-GFP-LC3 adenovirus was introduced into the cells. Western blotting was used to detect the expression of Beclin-1 and P62. Our research results showed that the optimal extraction parameters to obtain the highest yield of total flavonoids were a liquid−solid ratio of 1:31 g/mL, an ethanol volume fraction of 67%, an extraction time of 2.6 h, and an extraction temperature of 58 °C. Moreover, the content of luteolin was 690.85 ppb, that of apigenin was 114.91 ppb, and the content of acacetin was 5.617 ppb. After oxidative damage was induced by H2O2, the cell survival rate decreased significantly. BMFs could increase the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decrease the levels of malondialdehyde (MDA) and OH (OH). After the MRFP-GFP-LC3 virus was introduced into rabbit lens epithelial cells and detecting the expression of P62 and Beclin-1, we found that the intervention of BMF could promote the binding of autophagosomes to lysosomes. Compared with the model group, the level of P62 in the low-, middle-, and high-dose groups of BMF was significantly down-regulated, the level of Beclin-1 was significantly increased, and the difference was statistically significant (p < 0.05). In other words, the optimized extraction method was better than others, and the purified BMF contained three main active monomers (luteolin, apigenin, and acacetin). In addition, BMFs could ameliorate the H2O2-induced oxidative damage to rabbit lens cells by promoting autophagy and regulating the level of antioxidation.

Alginate Alleviates Dextran Sulfate Sodium-Induced Colitis by Promoting Bifidobacterium animalis and Intestinal Hyodeoxycholic Acid Synthesis in Mice.

Alginate (ALG) is known to alleviate intestinal inflammation in inflammatory bowel disease, but its mechanism of action remains elusive. In the present study, we studied the involvement of the intestinal microbiota and bile acid (BA) metabolism in ALG-mediated anti-inflammatory effects in mice. A combination of 16S rRNA gene amplicon sequencing, shotgun metagenomic sequencing, and targeted BA metabolomic profiling was employed to investigate structural and functional differences in the colonic microbiota and BA metabolism in dextran sulfate sodium (DSS)-treated mice with or without dietary supplementation of ALG. We further explored the role of the intestinal microbiota as well as a selected ALG-enriched bacterium and BA in DSS-induced colitis. Dietary ALG alleviated DSS-mediated intestinal inflammation and enriched a small set of bacteria including Bifidobacterium animalis in the colon (P < 0.05). Additionally, ALG restored several bacteria carrying secondary BA-synthesizing enzymes such as 7α-hydroxysteroid dehydrogenase and BA hydrolase to healthy levels in DSS-treated mice. Although a majority of BAs were suppressed by DSS, a few secondary BAs such as hyodeoxycholic acid (HDCA) were markedly enriched by ALG. Furthermore, ALG significantly upregulated the expression of a major BA receptor, the farnesoid X receptor, while suppressing NF-κB and c-Jun N-terminal kinase (JNK) activation. Depletion of the intestinal microbiota completely abrogated the protective effect of ALG in DSS-treated mice. Similar to ALG, B. animalis and HDCA exerted a strong anti-inflammatory effect in DSS-induced colitis by downregulating inflammatory cytokines (interleukin-1ß [IL-1ß], IL-6, and tumor necrosis factor alpha [TNF-α]). Taken together, these results indicated that ALG achieves its alleviating effect on intestinal inflammation through regulation of the microbiota by enriching B. animalis to promote the biosynthesis of specific secondary BAs such as HDCA. These findings have revealed intricate interactions among the intestinal microbiota, BA metabolism, and intestinal health and further provided a novel strategy to improve intestinal health through targeted manipulation of the intestinal microbiota and BA metabolism. IMPORTANCE ALG has been shown to ameliorate inflammatory bowel disease (IBD), but little is known about the mechanism of its anti-inflammatory action. This study was the first to demonstrate that ALG provided a preventive effect against colitis in an intestinal microbiota-dependent manner. Furthermore, we confirmed that by selectively enriching intestinal B. animalis and secondary BA (HDCA), ALG contributed to the attenuation of DSS-induced colitis. These findings contribute to a better understanding of the mechanism of action of ALG on the attenuation of colitis and provide new approaches to IBD therapy by regulating gut microbial BA metabolism.

Multi-wavelength fusion column fingerprint technology combined with chemometric analysis to evaluate the overall quality of the Gardenia jasminoides root.

Chromatographic fingerprinting provides effective technical means for quality evaluation of traditional Chinese medicine. In this work, a novel multi-wavelength fusion column fingerprint was obtained by intelligent selection of chromatographic peaks from different wavelengths, which displayed the maximum peak area information under the optimal wavelength at the same retention time. Here, the Gardenia jasminoides root was selected as a sample. The multi-wavelength fusion column fingerprint graph of the Gardenia jasminoides root was constructed from five wavelengths (203 nm, 210 nm, 238 nm, 250 nm and 330 nm). The peak capacity, peak resolution, the number of common peaks and similarity were used to evaluate the performance. The 19 batches of Gardenia jasminoides root were classified into three categories with clear distinction between origin categories based on the multi-wavelength fusion column fingerprint combined with chemometrics, including hierarchical cluster analysis and principal component analysis. Nine markers of variation that led to differences between batches were screened by orthogonal partial least squares discriminant analysis. This study demonstrated that the classification model based on the multi-wavelength fusion column fingerprint was better than that on a single-wavelength, and the fusion fingerprint was suitable for the identification and quality control of traditional Chinese medicine with more comprehensive chemical composition information and more accurate prediction ability.

IR792-MCN@ZIF-8-PD-L1 siRNA drug delivery system enhances photothermal immunotherapy for triple-negative breast cancer under near-infrared laser irradiation.

BACKGROUND: Despite extensive investigations on photothermal therapy, the clinical application is restricted due to poor stability, low therapeutic efficacy of photothermal therapy agents and its affinity loss in the multistep synthesis of delivery carriers. To address this, we designed an IR792-MCN@ZIF-8-PD-L1 siRNA (IM@ZP) nanoparticle drug delivery system. IM@ZP was prepared by in situ synthesis and physical adsorption, followed by characterization. Photothermal conversion ability of IM@ZP was assessed by irradiation of near-infrared (NIR) laser, followed by analysis of its effect on 4T1 cell viability, maturation of dendritic cells (DCs) and the secretion of related cytokines in vitro, and the changes of tumor infiltrating T cells and natural killer (NK) cells in vivo. Subcutaneous 4T1 tumor-bearing mouse and lung metastasis models were established to investigate the role of IM@ZP in killing tumor and inhibiting metastasis in vivo. RESULTS: IM@ZP was uniform nanoparticles of 81.67 nm with the characteristic UV absorption peak of IR792, and could effectively adsorb PD-L1 siRNA. Under the irradiation of 808 nm laser, IM@ZP exhibited excellent photothermal performance. IM@ZP could be efficiently uptaken by 4T1 cells, and had high transfection efficiency of PD-L1 siRNA. Upon NIR laser irradiation, IM@ZP effectively killed 4T1 cells, upregulated HSP70 expression, induced DC maturation and increased secretion of TNF-α and IL-6 in vitro. Moreover, in vivo experimental results revealed that IM@ZP enhanced photothermal immunotherapy as shown by promoted tumor infiltrating CD8 + and CD4 + T cells and NK cells, and inhibited tumor growth and lung metastasis. CONCLUSION: Together, biocompatible IM@ZP nanoparticles result in high photothermal immunotherapy efficiency and may have a great potential as a delivery system for sustained cancer therapy.

Chemical Distance Measurement and System Pharmacology Approach Uncover the Novel Protective Effects of Biotransformed Ginsenoside C-Mc against UVB-Irradiated Photoaging.

Long-term exposure to ultraviolet light induces photoaging and may eventually increase the risk of skin carcinogenesis. Rare minor ginsenosides isolating from traditional medicine Panax (ginseng) have shown biomedical efficacy as antioxidation and antiphotodamage agents. However, due to the difficulty of component extraction and wide variety of ginsenoside, the identification of active antiphotoaging ginsenoside remains a huge challenge. In this study, we proposed a novel in silico approach to identify potential compound against photoaging from 82 ginsenosides. Specifically, we calculated the shortest distance between unknown and known antiphotoaging ginsenoside set in the chemical space and applied chemical structure similarity assessment, drug-likeness screening, and ADMET evaluation for the candidates. We highlighted three rare minor ginsenosides (C-Mc, Mx, and F2) that possess high potential as antiphotoaging agents. Among them, C-Mc deriving from American ginseng (Panax quinquefolius L.) was validated by wet-lab experimental assays and showed significant antioxidant and cytoprotective activity against UVB-induced photodamage in human dermal fibroblasts. Furthermore, system pharmacology analysis was conducted to explore the therapeutic targets and molecular mechanisms through integrating global drug-target network, high quality photoaging-related gene profile from multiomics data, and skin tissue-specific expression protein network. In combination with in vitro assays, we found that C-Mc suppressed MMP production through regulating the MAPK/AP-1/NF-κB pathway and expedited collagen synthesis via the TGF-ß/Smad pathway, as well as enhanced the expression of Nrf2/ARE to hold a balance of endogenous oxidation. Overall, this study offers an effective drug discovery framework combining in silico prediction and in vitro validation, uncovering that ginsenoside C-Mc has potential antiphotoaging properties and might be a novel natural agent for use in oral drug, skincare products, or functional food.

In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L.

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health. Isatis tinctoria L. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-based in silico framework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were built via the integration of compound-target networks and influenza virus-host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for the in silico identification of novel drug candidates from complex components of herbal medicine.

Genome-wide association study identifies candidate genes related to oleic acid content in soybean seeds.

BACKGROUND: Soybean oil is a complex mixture of five fatty acids (palmitic, stearic, oleic, linoleic, and linolenic). Soybean oil with a high oleic acid content is desirable because this monounsaturated fatty acid improves the oxidative stability of the oil. To investigate the genetic architecture of oleic acid in soybean seeds, 260 soybean germplasms from Northeast China were collected as natural populations. A genome-wide association study (GWAS) was conducted on a panel of 260 germplasm resources. RESULTS: Phenotypic identification results showed that the oleic acid content varied from 8.2 to 35.0%. A total of 2,311,337 single-nucleotide polymorphism (SNP) markers were obtained. GWAS analysis showed that there were many genes related to oleic acid content with a contribution rate of 7%. The candidate genes Glyma.11G229600.1 on chromosome 11 and Glyma.04G102900.1 on chromosome 4 were detected in a 2-year-long GWAS. The candidate gene Glyma.11G229600.1 showed a positive correlation with the oleic acid content, and the correlation coefficient was 0.980, while Glyma.04G102900.1 showed a negative correlation, with a coefficient of - 0.964. CONCLUSIONS: Glyma.04G102900.1 on chromosome 4 and Glyma.11G229600.1 on chromosome 11 were detected in both analyses (2018 and 2019). Glyma.04G102900.1 and Glyma.11G229600.1 are new key candidate genes related to oleic acid in soybean seeds. These results will be useful for high-oleic soybean breeding.

Therapeutic effects of Aconiti Lateralis Radix Praeparata combined with Zingiberis Rhizoma on doxorubicin-induced chronic heart failure in rats based on an integrated approach.

OBJECTIVES: This study was aimed to explore the mechanism of Aconiti Lateralis Radix Praeparata (ALRP) and Zingiberis Rhizoma (ZR) on doxorubicin (DOX)-induced chronic heart failure (CHF) in rats by integrated approaches. METHODS: Effects of ALRP and ZR on cardiac function, serum biochemical indicators and histopathology in rats were analysed. Moreover, UHPLC-Q-TOF/MS was performed to identify the potential metabolites affecting the pathological process of CHF. Metabolomics and network pharmacology analyses were conducted to illustrate the possible pathways and network in CHF treatment. The predicted gene expression levels in heart tissue were verified and assessed by RT-PCR. KEY FINDINGS: ALRP-ZR demonstrated remarkable promotion of hemodynamic indices and alleviated histological damage of heart tissue. Metabolomics analyses showed that the therapeutic effect of ALRP and ZR is mainly associated with the regulation of eight metabolites and ten pathways, which may be responsible for the therapeutic efficacy of ALRP-ZR. Moreover, the results of RT-PCR showed that ALRP-ZR could substantially increase the expression level of energy metabolism-related genes, including PPARδ, PPARγ, Lpl, Scd, Fasn and Pla2g2e. CONCLUSIONS: The results highlighted the role of ALRP-ZR in the treatment of CHF by influencing the metabolites related to energy metabolism pathway via metabolomics and network pharmacology analyses.

New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions.

Epimedii Folium (EF) combined with Psoraleae Fructus (PF) is a common modern preparation, but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years. Zhuangguguanjiewan pills (ZGW), which contain EF and PF, could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide (LPS) model. This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model. Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats; however, EF or PF alone could lead to liver injury in LPS-treated rats. Moreover, EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats. Furthermore, EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production, implying that IL-1ß, which is processed and released by activating the NLRP3 inflammasome, is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity. Thus, EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome. In addition, the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model, suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways. Therefore, EF and PF combination indicates traditional Chinese medicine incompatibility, considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.

Components synergy between stilbenes and emodin derivatives contributes to hepatotoxicity induced by Polygonum multiflorum.

Polygonum multiflorum Thunb. (PM) is a famous traditional Chinese medicine with liver tonic effect, but arousing great concerns for hepatotoxicity issue. In this study, we elucidated the contribution of the two major compounds, emodin-8-O-ß-D-glucoside (EG) and 2,3,5,4´-tetrahydroxyl diphenylethylene-2-O-glucoside (TSG), in PM-induced liver injury.Based on LC-MS, the two concerned compounds were detected simultaneously in the sera of patients with PM-induced liver injury. In the lipopolysaccharide (LPS)-mediated inflammatory stress rat model, by the analysis of plasma biochemistry and liver histopathology, we observed that the solo treatment of EG, not TSG, could induce significant liver injury; and the combined administration of EG and TSG caused more severe liver injury than that of EG.Metabolomics analysis revealed that the EG-triggered liver injury was associated with significant disturbances of sphingolipids and primary bile acids metabolism pathways. In the combined administration group, much more disturbances in EG-triggered metabolic pathways, as well as alterations of several additional pathways such as retinol metabolism and vitamin B6 metabolism, were observed.Taken together, we considered EG was involved in the idiosyncratic liver injury of PM, and TSG played a synergetic role with EG, which contributed to the understanding of the hepatotoxic basis of PM.

3'-Desmethylarctigenin induces G2/M cell cycle arrest and apoptosis through reactive oxygen species generation in hepatocarcinoma cells.

Previous studies have shown that arctigenin is a promising chemopreventive or therapeutic agent against various cancers. However, less is known about anticancer activity of 3'-desmethylarctigenin (3'-DMAG), which is a biotransformed product from arctigenin or arctin. In this study, we compared the anticancer activity of 3'-DMAG with its parent compound arctigenin and demonstrated that 3'-DMAG exerted a more potent inhibitory effect on HepG2 cells than arctigenin. Mechanistically, reactive oxygen species generation played an apical role in 3'-DMAG-induced G2/M cell cycle arrest and apoptosis in HepG2 cells. Furthermore, the Chk2-Cdc25c-Cdc2-cyclin B1 cascade was found to contribute to the cell cycle arrest, whereas the activation of mitochondrial pathway was involved in the cell apoptosis by 3'-DMAG. Additionally, a mouse xenograft hepatocellular carcinoma model was used to evaluate the antitumor effect of 3'-DMAG in vivo, and the results indicated that 3'-DMAG treatment significantly inhibited tumor growth without apparent toxicity. Taken together, 3'-DMAG is highly effective against liver cancer both in vitro and in vivo. The findings of the present study suggest that this compound deserves to be further investigated for its potential anticancer activity.

Integrated Metabolomics and Network Pharmacology Study on Immunoregulation Mechanisms of Panax ginseng through Macrophages.

Panax ginseng (PG) is a widely used functional food and herbal with immunoregulation activity. Currently, immunoregulation studies of PG mainly focused on the specific actions of individual constituents. However, the integral immunoregulation mechanisms of PG need further research. In this study, an integrated metabolomics and network pharmacology approach were used to investigate it. High-content screening was used to evaluate macrophage phagocytosis activity of PG. Untargeted metabolomics profiling of murine macrophage cells with UHPLC-Q-TOF-MS and a multivariate data method were performed to discover the potential biomarkers and metabolic pathways. Then, a macrophage phenotype related "ingredients-targets-metabolites" network of PG was constructed using network pharmacology for further research. As a result, PG can significantly enhance macrophage phagocytosis of GFP-E. coli. A total of twenty potential biomarkers and ten main pathways for which levels changed markedly upon treatment were identified, including glycerophospholipid metabolism, glutathione metabolism, choline metabolism, and taurine metabolism. Twenty compounds of PG associated with metabolomic changes were selected by the network pharmacology analysis, including ginsenoside Re, ginsenoside Rg1, frutinone A, and kaempferol. The network pharmacology results also showed that PG can polarize macrophages to both M1 and M2 phenotype but may be prone to M2 phenotype. In conclusion, our results indicated that PG may be prone to polarize macrophages to M2 phenotype by mainly regulating the glutathione and choline metabolism, which was related to twenty compounds of PG.