Licorice flavonoid ameliorates ethanol-induced gastric ulcer in rats by suppressing apoptosis via PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is the dry roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L. and Glycyrrhiza inflata Bat., which was first recorded in Shengnong's herbal classic. Licorice flavonoid (LF) is the main compound isolated from licorice with an indispensable action in treating gastric ulcer (GU). However, the underlying mechanisms need to be further explored. AIM OF THE STUDY: This study aimed to investigate and further elucidate the mechanisms of LF against ethanol-induced GU using an integrated approach. MATERIALS AND METHODS: The anti-GU effects of LF were evaluated in an ethanol-induced gastric injury rat model. Then, the metabolomics approach was applied to explore the specific metabolites and metabolic pathways. Next, the network pharmacology combined with metabolomics strategy was employed to predict the targets and pathways of LF for GU. Finally, these predictions were validated by molecular docking, RT-qPCR, and western blotting. RESULTS: LF had a positive impact on gastric injury and regulated the expression of GU-related factors. Upon serum metabolomics analysis, 25 metabolic biomarkers of LF in GU treatment were identified, which were primarily involved in amino acid metabolism, carbohydrate metabolism, and other related processes. Subsequently, a "components-targets-metabolites" network was constructed, revealing six key targets (HSP90AA1, AKT1, MAPK1, EGFR, ESR1, PIK3CA) that may be associated with GU treatment. More importantly, KEGG analysis highlighted the importance of the PI3K/AKT pathway including key targets, as a critical route through which LF exerted its anti-GU effects. Molecular docking analyses confirmed that the core components of LF exhibited a strong affinity for key targets. Furthermore, RT-qPCR and western blotting results indicated that LF could reverse the expression of these targets, activate the PI3K/AKT pathway, and ultimately reduce apoptosis. CONCLUSION: LF exerted a gastroprotective effect against gastric ulcer induced by ethanol, and the therapeutic mechanism may involve improving metabolism and suppressing apoptosis through the PI3K-AKT pathway.

Licorice flavonoid alleviates gastric ulcers by producing changes in gut microbiota and promoting mucus cell regeneration.

Licorice flavonoid (LF) is the main component of Glycyrrhizae Radix et Rhizoma, a "medicine food homology" herbal medicine, which has anti-digestive ulcer activity, but the mechanism in anti-gastric ulcer (GU) remains to be elucidated. In this study, we manifested that LF increased the viability of human gastric mucosal epithelial (GES-1) cells, attenuated ethanol (EtOH)-induced manifestations, reduced histological injury, suppressed inflammation, and restored gastric mucosal barrier in GU rats. After LF therapy, the EtOH-induced gut dysbiosis was partly modulated, and short-chain fatty acids (SCFAs) like butyric acid, propionic acid, and valeric acid were found in higher concentrations. We discovered that the majority of genera that increased in the GU group had a negative correlation with SCFAs in the intestinal tract. In addition, LF-upregulated SCFAs boosted mucus secretion in the gastric epithelium and the expression of mucoprotein (MUC) 5AC and MUC6, particularly the MUC5AC in the gastric foveola. Moreover, LF triggered the EGFR/ERK signal pathway which promoted gastric mucus cell regeneration. Therefore, the findings indicated that LF could inhibit inflammation, promote mucosal barrier repair and angiogenesis, regulate gut microbiota and SCFA metabolism; more importantly, promote epithelial proliferation via activation of the EGFR/ERK pathway, exerting a protective and regenerative effect on the gastric mucosa.

Effect of return activated sludge diversion ratio on phosphorus removal performance in side-stream enhanced biological phosphorus removal (S2EBPR) process.

In this study, a lab-scale continuous flow side-stream enhanced biological phosphorus (P) removal (S2EBPR) reactor was operated for 247 days treating synthetic wastewater with influent carbon to phosphorus (C/P) ratio of 25.0 g COD/g P and influent PO43--P of 7.4 ± 0.3 mg P/L. The effect of the return activated sludge (RAS) diversion ratio on S2EBPR reactor was investigated by comparing P removal performance, microbial activity, and community structure. The results showed that the RAS diversion ratio of 8.0%, by yielding a side-stream sludge retention time (SRTSS) of ∼60 h, resulted in the lowest effluent PO43--P concentration of 0.5 ± 0.3 mg P/L. The results of in situ process profiles and ex situ P release and uptake batch tests under different RAS diversion conditions showed that the more anaerobic P release was obtained in the side-stream reactor, the higher the P removal efficiency and EBPR activity were achieved. The stoichiometric ratios observed in EBPR activity tests indicated a polyphosphate accumulating organisms (PAOs) metabolism mainly dependent on the glycolysis pathway. The results of microbial ecology analysis revealed that the optimized SRTSS would give a competitive advantage to PAOs in the S2EBPR process. By obtaining statistically reliable results, this study would provide guidance for wastewater treatment plants to achieve optimal P removal performance in S2EBPR configuration.

Risk of cardiac-related death in astrocytoma patients treated with chemotherapy: A competing risk analysis using the SEER database.

Purpose: To explore the impact of chemotherapy on the risk of cardiac-related death in astrocytoma patients. Methods: We retrospectively evaluated astrocytoma patients diagnosed between 1,975 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Using Cox proportional hazards models, we compared the risks of cardiac-related death between a chemotherapy group and non-chemotherapy group. Competing-risks regression analyses were used to evaluate the difference in cardiac-related death. Also, propensity score matching (PSM) was employed to reduce confounding bias. The robustness of these findings was evaluated by sensitivity analysis, and E values were calculated. Results: A total of 14,834 patients diagnosed with astrocytoma were included. Chemotherapy (HR = 0.625, 95%CI: 0.444-0.881) was associated with cardiac-related death in univariate Cox regression analysis. Chemotherapy was an independent prognostic factor for a lower risk of cardiac-related death before (HR = 0.579, 95%CI: 0.409-0.82, P = 0.002) and after PSM (HR = 0.550, 95%CI: 0.367-0.823 P = 0.004). Sensitivity analysis determined that the E-value of chemotherapy was 2.848 and 3.038 before and after PSM. Conclusions: Chemotherapy did not increase the risk of cardiac-related death in astrocytoma patients. This study highlights that cardio-oncology teams should provide comprehensive care and long-term monitoring for cancer patients, especially those with an increased risk of cardiovascular disease.

[Isolation and quantification of a 17-epi-dammarane triterpenoid rhuslactone from roots of Rhus chinensis and its preventive effects on coronary heart disease and thrombosis in zebrafish].

Based on mass spectrometry(MS)-guided separation strategy, compound 1 was obtained from the roots of Rhus chinensis. By comprehensive analysis of high resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR) data, and quantum chemical calculation of NMR(qcc-NMR) parameters, compound 1 was elucidated as rhuslactone, a 17-epi-dammarane triterpenoid with a rare 17α-side chain. An HPLC-ELSD method for its quantification in R. chinensis was established and adopted for the quantification of rhuslactone in different batches of R. chinensis. Rhuslactone displayed a good linear relationship within the range of 0.021 3-1.07 µmol·mL~(-1 )(r=0.997 6), and the average recovery was 99.34% [relative standard deviation(RSD) 2.9%). Moreover, the results of the evaluation test of the preventive effects of rhusalctone on coronary heart disease(CHD) and thrombosis showed that rhuslactone(0.11 nmol·mL~(-1)) significantly alleviated heart enlargement and venous congestion and increased cardiac output(CO), blood flow velocity(BFV), and heart rate, thereby reducing thrombus formation in zebrafish with CHD. The effects of rhuslactone on CO and BFV were superior to that of digoxin(1.02 nmol·mL~(-1)), and its effect on improving heart rate was comparable to that of digoxin. This study provides experimental references for the isolation, identification, quality control, and application of rhuslactone from R. chinensis against CHD. It is worth mentioning that this study has discussed some omissions in the determination of the stereochemistry of C-17 in dammarane triterpenoids in the present coursebook Chemistry of Chinese Medicine and some research papers, that is, the compound may be 17-epi-dammarane triterpenoid. This paper has also proposed steps for the establishment of C-17 stereochemistry.

Mechanism insight on licorice flavonoids release from Carbopol hydrogels: Role of "release steric hindrance" and drug solubility in the release medium.

The present study was to systematically evaluate different licorice flavonoids (LFs) compounds release behaviors from the single payload hydrogel and LFs extracts hydrogels based on the drug solubility in the release medium (DSRM), intermolecular strength of the hydrogel and the "release steric hindrance" (RSH). Two kinds of LFs (LFs 1: LFs 2 = 5:1, W/W) hydrogels were prepared with Carbopol 940 (CBP) as the thickener, and ten LFs single payload hydrogels were prepared according to the actual content in the LFs 1 extracts. The drug release mechanisms were confirmed by in vitro release experiments and molecular dynamic simulation analysis, and evaluated using novel indicators of ERLFs 1/Sin (the enhancement ratio (ER) of drug release percent of LFs 1-CBP hydrogel to the single payload hydrogel), ERLFs 2/ LFs 1 (ER of drug release percent of LFs 2-CBP hydrogel to LFs 1-CBP hydrogel) and ERrelease medium (ER of drug release percent in different release medium). We found that LFs 1-CBP possessed a significantly higher intermolecular strength and RSH than LFs 2-CBP, resulting in a higher viscosity, which had a positive correlation with the payload content and a negative correlation with the drug release percent. Therefore, the ERLFs 2/ LFs 1 values of ten LFs compounds were all higher than 1. For liquiritigenin and retrochalcone with higher DSRM, they displayed similar ERLFs 1/ Sin, ERLFs 2/ LFs 1 and ERrelease medium values (≈1). For formononetin, licoflavone A and licochalcone A with low DSRM, they exhibited ERLFs 1/Sin values >1. The low DSRM was the decisive factor to restrict their release from the single payload hydrogel. The presence of glycyrrhizin acid (GA) in the LFs could facilitate their release from the LFs extracts hydrogel. For isoliquiritin, isoliquiritigenin and glabridin with a lower content in the LFs extracts, they exhibited ERLFs 1/Sin values <1. The RSH predominantly restricted its release. The study provided guidelines for the reasonable design of LFs extracts hydrogel in pharmaceutical topical formulations.

Network pharmacology, molecular docking and in vivo and in vitro experiments to explore the molecular mechanism of licorice green tea beverage to scavenge oxygen free radicals.

Excessive oxygen free radicals can lead to aging, cancer, and other diseases. Therefore, searching for effective antioxidants to scavenge oxygen free radicals has become the focus of modern medicine. In this study, the molecular mechanism of Licorice Green Tea Beverage (LGTB) in scavenging oxygen free radicals was investigated by means of network pharmacology, molecular docking and experimental verification. Network pharmacology studies have shown that paeonol, eugenol, cinnamaldehyde, swertisin, rutin, glycyrrhetinic acid, oleic, pelargonidin-3-O-glucoside and quercetin, kaferempol were the main active components of LGTB, and SOD and CAT are important targets for LGTB in scavenging oxygen free radicals. The results of molecular docking showed that these representative compounds had good affinity to SOD and CAT target proteins. In vitro free radical scavenging experiments showed that LTGB had significant scavenging effects on both DPPH and ABTS radicals, and had strong total reducing power. In vitro cell experiments showed that LGTB could protect HaCaT cells from oxidative stress induced by H2 O2 . The mechanism of LGTB was related to the increase of SOD and CAT activity. Western blotting showed that LGTB could inhibit PI3K/AKT/HIF-1 signaling pathway and improve the antioxidant capacity of HaCaT cells. In vivo experiments showed that LGTB could significantly increase mouse visceral index, increase serum SOD and GSH-Px activity, decrease the content of MDA, and improve liver and kidney pathological state. This study reported the molecular mechanism of LTGB scavenging oxygen free radicals, which provided scientific basis for the treatment and clinical research of aging and other diseases caused by excessive free radicals. PRACTICAL APPLICATIONS: Free radicals are produced by the normal response of cells during aerobic respiration and perform various functions, such as signaling and providing protection against infection. However, excessive free radicals can lead to aging, cancer, and other diseases. The antioxidant can overcome the harm caused by excessive free radicals. In this study, we investigated the molecular mechanism of scavenging oxygen free radicals of Licorice Green Tea Beverage (LGTB) through network pharmacology and molecular docking, and its efficacy was verified by free radical scavenging experiment in vitro, HaCaT cell oxidative stress injury induced by H2 O2 , D-galactose to establish an aging model in mice and Western blotting experiment. It not only elucidates its mechanism at the system level, but also proves its validity at the biological level. It provides the theoretical basis and experimental evidence for the follow-up research and promotion of the product.

Skin microbiome reconstruction and lipid metabolism profile alteration reveal the treatment mechanism of Cryptotanshinone in the acne rat.

BACKGROUND: Acne has become one of the most prevalent skin disorders, affecting mostly young people's physical and mental health globally. Cryptotanshinone (CPT) is a potential drug for acne, but its mechanism of acne treatment has not been thoroughly studied on the microbiota. Till date, only a few studies are directed to the impact of acne therapy on skin microbiota and lipid metabolites. PURPOSE: The action mechanism of CPT treatment of acne was investigated by the strategy of microbiome integration with lipidomics. METHODS: The 16Sr DNA sequencing was used to detect skin microbiota composition, and absolute quantitative lipidomics was utilized to identify lipid metabolites profiles levels. Four key proteins of the glycolysis pathway were detected with the immunochemistry method. Antibacterial analysis was used to evaluate CPT treatment of acne. RESULTS: CPT significantly inhibited Staphylococcus epidermidis and Staphylococcus aureus. Combination of the skin microbiome and lipidomics analysis, 29 types of differentially expressed flora (DEFs) and 782 differentially expressed lipid metabolites (DELMs) were significantly altered, especially Staphylococcus, Corynebacterium, Ralstonia, Enhydrobacter, Burkholderia, and Streptococcus. Cer was mainly regulated by Staphylococcus and Corynebacterium, whereas TG and DG were mainly regulated by Ralstonia, Enhydrobacter, Burkholderia, and Streptococcus. The glycolysis pathway was significantly regulated by Staphylococcus on CPT treatment of acne. The energy metabolism, lipid metabolism, immune system, glycan biosynthesis, and metabolism could be reversed by CPT. CONCLUSION: CPT might help acne rats rebuild their skin microbiota and alter lipid metabolism signatures. Furthermore, since skin microbes and skin lipid metabolites have a close correlation and are both regulated by CPT, the findings potentially provide a research foundation for the discovery of biomarkers of skin microbiome imbalance and targeted treatment of acne development mechanisms.

Pharmacological Effects and Underlying Mechanisms of Licorice-Derived Flavonoids.

Glycyrrhizae Radix et Rhizoma is the most frequently prescribed natural medicine in China and has been used for more than 2,000 years. The flavonoids of licorice have garnered considerable attention in recent decades due to their structural diversity and myriad pharmacological effects, especially as novel therapeutic agents against inflammation and cancer. Although many articles have been published to summarize different pharmacological activities of licorice in recent years, the systematic summary for flavonoid components is not comprehensive. Therefore, in this review, we summarized the pharmacological and mechanistic data from recent researches on licorice flavonoids and their bioactive components.

A Skin Lipidomics Study Reveals the Therapeutic Effects of Tanshinones in a Rat Model of Acne.

Tanshinone (TAN), a class of bioactive components in traditional Chinese medicinal plant Salvia miltiorrhiza, has antibacterial and anti-inflammatory effects, can enhance blood circulation, remove blood stasis, and promote wound healing. For these reasons it has been developed as a drug to treat acne. The purpose of this study was to evaluate the therapeutic effects of TAN in rats with oleic acid-induced acne and to explore its possible mechanisms of action through the identification of potential lipid biomarkers. In this study, a rat model of acne was established by applying 0.5 ml of 80% oleic acid to rats' back skin. The potential metabolites and targets involved in the anti-acne effects of TAN were predicted using lipidomics. The results indicate that TAN has therapeutic efficacy for acne, as supported by the results of the histological analyses and biochemical index assays for interleukin (IL)-8, IL-6, IL-ß and tumor necrosis factor alpha. The orthogonal projection of latent structure discriminant analysis score was used to analyze the lipidomic profiles between control and acne rats. Ninety-six potential biomarkers were identified in the skin samples of the acne rats. These biomarkers were mainly related to glycerophospholipid and sphingolipid metabolism, and the regulation of their dysfunction is thought to be a possible therapeutic mechanism of action of TAN on acne.