Gut dysbiosis correction contributes to the hepatoprotective effects of Thymus quinquecostatus Celak extract against alcohol through the gut-liver axis.

Alcoholic liver disease (ALD) is a major health issue globally due to the consumption of alcoholic beverages. Thymus quinquecostatus Celak is a food additive and an edible herb that is widely used in Asia and possesses hepatoprotective activity, but the underlying mechanisms behind this protective activity are not completely understood. The purpose of this study was to investigate the hepatoprotective effects of Thymus quinquecostatus Celak extract (TQE) against ALD as well as the underlying mechanism based on gut microbiota and the gut-liver axis. TQE supplementation markedly alleviated chronic alcohol-induced liver injury in C57 mice. TQE also ameliorated gut barrier dysfunction induced by alcohol. Consequently, the activation of the lipopolysaccharide (LPS) translocation-mediated TLR4 pathway and the subsequent inflammatory response and ROS overproduction in the liver were suppressed. Meanwhile, alcohol-induced gut microbiota dysbiosis was also corrected by TQE. To further investigate the contribution of gut dysbiosis correction to the beneficial effects of TQE on ALD, a fecal microbiota transplantation study was conducted. TQE-manipulated gut microbiota transplantation markedly counteracted the alcohol-induced gut dysbiosis in the recipient mice. In parallel with gut dysbiosis correction, liver damage was partly ameliorated in the recipient mice. Gut barrier dysfunction, endotoxemia, TLR4 pathway induction as well as downstream inflammatory response and ROS overproduction were also partly suppressed due to gut dysbiosis correction in alcohol-fed recipient mice. In summary, these results suggest that gut dysbiosis correction contributes to the hepatoprotective effects of TQE against alcohol through the gut-liver axis.

An integrated approach to uncover anti-tumor active materials of Curcumae Rhizoma-Sparganii Rhizoma based on spectrum-effect relationship, molecular docking, and ADME evaluation.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumae Rhizoma-Sparganii Rhizoma (CR-SR), an ancient and classical herbal couple, has been extensively used for tumor treatment in clinic of traditional Chinese medicines (TCMs). AIM OF THE STUDY: The study aimed to uncover the anti-tumor active materials of CR-SR water decoction (CR:SR = 1:1) via an integrated approach of spectrum-effect relationship, molecular docking, and ADME evaluation. MATERIALS AND METHODS: The anti-tumor activities toward A549, HepG2, Hela, BGC-823, and MCF-7 cells of the different polar elution fractions (DPEFs) of CR, SR, and CR-SR were determined by Cell Counting Kit-8 (CCK-8) assay. Likewise, the DPEFs' combinations of CR and SR were also tested. The chemical fingerprints of these fractions were profiled by HPLC. Meanwhile, HPLC-ESI-Q-TOF-MS/MS was applied for the identification of chemical components. The main effect-related compounds were screened out by spectrum-effect relationship and molecular docking method. The oral bioavailability and druggability of these active components were subsequently evaluated. Finally, five monomeric compounds were validated experimentally using HepG2 cells. RESULTS: The 80% ethanol elution fraction of CR, SR, and CR-SR showed strong anti-tumor effects toward five cells. Also, the combinations with the 80% ethanol elution fraction of CR and SR showed stronger tumor inhibition effects among the DPEFs' combinations of CR and SR. By spectrum-effect relationship, HPLC-MS, and molecular docking analysis, 24 main effect-related compounds seemed to have potential anti-tumor effects. ADME evaluation showed rutin performed low oral bioavailability and druggability. Therefore, we suppose that 23 compounds (including 4 unknown compounds) are the primary anti-tumor active components of CR-SR water decoction. Among them, zederone, curcumol, chlorogenic acid, calycosin, and curcumenol were validated successfully with good tumor inhibition effects. CONCLUSIONS: In summary, this study demonstrated that the multi-components of CR-SR contribute to its anti-tumor effects. It established a rapid and useful strategy to explore the active material basis of traditional Chinese herbal couples with a multi-technology integrated approach in practice, including chromatography, mass spectrometry, machine algorithm models, online databases, and in vitro cell experiments.

Anti-tumor activity and linear-diarylheptanoids of herbal couple Curcumae Rhizoma-Sparganii Rhizoma and the single herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumae Rhizoma and Sparganii Rhizoma (CR-SR) are the classical herbal couple for activating blood circulation and treating tumor in clinics. AIM OF THE STUDY: To investigate the anti-tumor activity and to clarify the bioactive ingredients of herbal couple CR-SR and the single herbs Curcumae Rhizoma (CR) and Sparganii Rhizoma (SR). MATERIALS AND METHODS: The active fractions of CR-SR decoction were fractioned by column chromatography. And isolated compounds were characterized by IR, ESI-MS, 1D and 2D-NMR techniques. Detecting linear-diarylheptanoids in CR-SR, CR and SR was realized through UPLC-LTQ-Orbitrap MSn, based on the fragmentation pathways established in this study, comparison with MS data of isolated compounds and references. The anti-tumor activities of different solvent fractions from CR-SR, CR and SR, as well as isolated ingredients were tested by CCK-8 method. RESULTS: Ultimately, a new compound (1), having a sulfonic acid group at C-3, named demethoxyshogasulfonic acid, along with another structurally similar 17 known linear-diarylheptanoids were isolated. These linear-diarylheptanoids (1-18) were divided into 12 categories based on the differences of substituents at C-3 and C-5 on the straight chain of seven carbons. Six fragmentation pathways were established by summarizing MS data of the 18 isolated compounds collected from UPLC-MS. Based on that, and retention times and MS fragmentation ions, 47 linear-diarylheptanoids were identified in CR-SR and CR, in which 12 linear-diarylheptanoids were also detected in SR. Most importantly, 5 sulfonated linear-diarylheptanoids were new compounds detected in CR and CR-SR. And the biological assay indicated that compounds 1-4 and 12-15 significantly reduced the proliferation and inhibited colony formation of MCF-7 and HepG2 cells. CONCLUSION: The new compound (1) exhibited good anti-cancer activity, which suggests that a great effort has to be paid to investigate the bioactivity of sulfonated compounds. The fractions of CR-SR decoction exhibited stronger anti-tumor activities than that of CR and SR against 5 different cancer cells. As for chemical composition, it is the first time to report that diarylheptanoids are in Sparganiaceae and the sulfonated compounds in Zingiberaceae. Moreover, the linear-diarylheptanoids found in SR which being tested to possess good anti-tumor activity, plus those compounds in CR enhance the capacity of CR-SR. It shows importance of TCM compatibility.

Dosing-time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics.

To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application.

Clinical study of western medicine combined with Chinese medicine based on syndrome differentiation in the patients with polarized hypertension.

OBJECTIVE: To investigate the effects and safety of Western medicine combined with Chinese medicine (CM) based on syndrome differentiation in the treatment of elderly polarized hypertension (PHPT), or isolated systolic hypertension with low diastolic blood pressure (DBP). METHODS: A total of 125 elderly patients with PHPT were randomly assigned to two groups: 59 in the control group treated by Western medicine and 66 in the intervention group treated by Western medicine combined with CM treatment. Based on syndrome differentiation, the patients in the intervention group were further divided into subgroups of yang-qi deficiency and yin-qi deficiency. All subjects were treated with Western medicine of Amlodipine Besylate Tablets and Irbesartan Tablets (or Irbesartan and Hydrochlorothiazide Tablets), to decrease their systolic blood pressure (SBP) slowly to 125-135 mm Hg in 2-6 weeks. In the intervention group, Shiyiwei Shenqi Capsule was given additionally to the subgroup of yang-qi deficiency at the dosage of 3-5 capsules, thrice a day, while Dengzhan Shengmai Capsule was given additionally to the subgroup of yin-qi deficiency at the dosage of 2 capsules, 2-3 times per day. For all subjects, SBP, pulse pressure (PP), and DBP were measured before treatment and at the terminal of a 6-week treatment. For subjects in the intervention group, left ventricular ejection fraction (LVEF) was also recorded. RESULTS: After a 6-week treatment, the SBP in the two groups and the PP in the intervention group decreased significantly compared to those before treatment (P<0.05), while the PP in the control group showed no significant difference between prior and post-treatment (P>0.05). After treatment, the DBP in the control group decreased (P>0.05), while the DBP and LVEF in the intervention group showed an increase tendency although it had no statistical significance (P>0.05). When subjects in the intervention group were classified further by the course of disease, the DBP and LVEF of subjects whose course of disease were less than 2 years, increased significantly after treatment (P<0.05). CONCLUSION: Western medicine combined with CM treatment based on syndrome differentiation was safer and more effective than Western medicine alone in the treatment of elderly PHPT, because it not only reduced SBP but also improved DBP, which might lower the incidence of the cardiovascular and cerebrovascular events.

Neuroprotective effect of CPDT on THA-induced cortical motor neuron death in an organotypic culture model.

Brain stroke, trauma, and motor neuron disease each can result in cortical motoneuron (CMN) death or impairment. Glutamate excitotoxicity induces motor neuron damage in both acute motor neuron loss and chronic motor neuron degeneration. It is necessary to find effective strategies to protect CMNs from excitotoxicity in a variety of pathological conditions. 5,6-Dihydrocyclopenta-1,2-dithiole-3-thione (CPDT) is one of the phase II enzyme inducers. In our previous report, CPDT was shown to have neuroprotective effects on the spinal cord, by activating the Nrf2/ARE pathway to increase antioxidative capacity. In this study, in order to figure out whether CPDT can prevent CMN's from THA-induced death, we set up an organotypic brain slice culture system. Threo-hydroxyaspartate (THA), a glutamate transport inhibitor, was added to the culture medium to induce CMN death by glutamate excitotoxicity. Brain slices were pretreated with CPDT for 48h, then treated with CPDT and THA simultaneously for 3 weeks. We found that pretreatment with CPDT significantly increased CMN survival. Glutamate concentration in the culture medium was significantly greater following THA treatment, whereas no significant decrease was found in the CPDT pretreatment group. However, both Nrf2 and HO-1 protein expression was significantly elevated in the CPDT pretreatment group, and Nrf2 protein translocated to the nucleus after CPDT stimulation. These findings suggest that CPDT can protect CMNs from THA-induced motor neuron death by activating the Nrf2 pathway and increasing HO-1 protein expression. Therefore, increasing antioxidative defense capacity should benefit to upper motor neuron survival following a glutamate excitotoxicity insult.

[Clinical study of strengthening pi and nourishing shen therapy combined with Western medicine on patients with glucocorticoid resistant myasthenia gravis].

OBJECTIVE: To study the effect of strengthening Pi and nourishing Shen therapy (SPNST) in treating patients with glucocorticoid resistant myasthenia gravis (GR-MG). METHODS: Twenty-seven patients with MG were enrolled, who were relapse cases after treated by cholinesterase inhibitor with systemic glucocorticoid treatment and showed resistance to glucocorticoid. All were treated by Western medicines, methylprednisolone (MP) and pyridostigmine bromide (PSB), together with Chinese medicine (CM) given according to their syndrome types, namely, for the 15 patients of Pi-Shen qi-yin deficiency type, Buzhong Yiqi Pill and Liuwei Dihuang Pill, and for the 12 patients of Pi-Shen yang-deficiency type, Buzhong Yiqi Pill and Zishen Yutai Pill. The dosages of medicines were reduced gradually in MP-PSB-CM order along with the progressing of the therapy in 4 stages (symptom curing, choline receptor restoration, immune regulation, and functional strengthening). Muscle strength and overall state of patients were re-examined before and after each of the 4 stages. RESULTS: After 1-year treatment, the therapeutic effect in 9 patients was judged as completely remitted; in 7 as remitted with continuous medication; in 5, 1 and 3 as significantly improved, moderately improved and unchanged respectively, while 2 patients died. CONCLUSION: Integrative medicine shows definite effects in treating GR-MG, and it is worthy of further studying.