[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen).

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

Histone methylatic modification mediates the tumor-suppressive activity of curcumol in hepatocellular carcinoma via an Hotair/EZH2 regulatory axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma kwangsiensis S. G. Lee & C. F. Liang (Guangxi ezhu, in Chinese) has been used as a traditional Chinese medicine (TCM) for approximately 2000 years. Curcumol is one of the major bioactive components of this herb, which has been demonstrated possesses anti-cancer properties, and was recorded in the Chinese Pharmacopoeia 2020 edition. However, most studies mainly focused on the superficial anti-cancer activity, the underlying mechanism remains poorly understood. AIM OF THE STUDY: In the present study, we aimed to investigate the anti-tumor effect of Curcumol on hepatocellular carcinoma (HCC), and elucidate its underlying mechanism from the perspective of epigenetic modification. MATERIALS AND METHODS: The potential anti-cancer properties of Curcumol were evaluated in HepG2 and SMMC-7721 cells. Its effects on cell growth, cell cycle, apoptosis and migration were examined in these HCC cells. Moreover, the lncRNA HOX transcript antisense intergenic RNA (Hotair) and histone methylatic modification were detected by qPCR and Western blotting assays. RESULTS: In the present study, Curcumol was illustrated to suppress cell growth in HCC cells via inducing apoptosis and cell cycle arrest. And it was also found that Curcumol inhibited the invasion and metastasis of HCC as well. As for the mechanism investigation, it was showed that lncRNA Hotair was significantly downregulated by Curcumol in HCC cells. As is well known, Hotair recruited histone methyltransferase enhancer of zeste homolog 2 (EZH2) to exert transcriptional regulation. Our results showed that EZH2 were downregulated by Curcumol in HCC cells, and thus disrupted the trimethylation of H3K9 and H3K27 which were specifically catalyzed by EZH2. CONCLUSIONS: In conclude, our results demonstrated that Curcumol suppressed tumor growth and metastasis via an Hotair/EZH2/histone modification regulatory axis.

Capsaicin-loaded folic acid-conjugated lipid nanoparticles for enhanced therapeutic efficacy in ovarian cancers.

In this study, folic acid-conjugated lipid nanoparticles were successfully prepared to enhance the active targeting of capsaicin (CAP) in ovarian cancers. The particles were nanosized and exhibited a controlled release of drug in the physiological conditions. The folic acid (FA)-conjugated system exhibited a remarkably higher uptake of nanoparticles in the cancer cells compared to that of non-targeted system. The folate-conjugated CAP-loaded lipid nanoparticles (CFLN) upon interacting with cancer cells were internalized via receptor-mediated endocytosis mechanism and resulted in higher concentration in the cancer cells. Consistently, CFLN showed a remarkably higher toxic effect compared to that of non-targeted nanoparticle system. CFLN showed significantly higher cancer cell apoptosis with nearly 39% of cells in apoptosis chamber (early and late) compared to only ∼21% and ∼11% for CAP-loaded lipid nanoparticles (CLN) and CAP. The loading of drug in the lipid nanoparticle system extended the drug retention in the blood circulation and allowed the active targeting to specific cancer cells. The prolonged circulation of drug attributed to the antifouling property of polyethylene glycol molecule in the structure. Overall, study highlights that using targeting moiety could enhance the therapeutic response of nanomedicines in the treatment of solid tumors.