Hua Li

Danshen-Shanzha Formula (DSF) is a well-known herbal combination comprising Radix Salvia Miltiorrhiza (known as Danshen in Chinese) and Fructus Crataegi (known as Shanzha in Chinese), It has been documented to exhibit considerable benefits for promoting blood circulation and removing blood stasis, and was used extensively in the treatment of atherosclerotic cardiac and cerebral vascular diseases over decades. Despite several breakthroughs achieved in the basic research and clinical applications of DSF over the past decades, there is a lack of comprehensive reviews summarizing its features and research, which hinders further exploration and exploitation of this promising formula. This review aims to provide a comprehensive interpretation of DSF in terms of its ethnopharmacological relevance, preparation methods, chemical constituents, pharmacokinetic properties and pharmacological effects. The related information on Danshen, Shanzha, and DSF was obtained from internationally recognized online scientific databases, including Web of Science, PubMed, Google Scholar, China National Knowledge Infrastructure, Baidu Scholar, ScienceDirect, ACS Publications, Online Library, Wan Fang Database as well as Flora of China. Data were also gathered from documentations, printed works and classics, such as the Chinese Pharmacopoeia, Chinese herbal classics, etc. Three essential avenues for future studies were put forward as follows: a) Develop and unify the standard preparation method of DSF as to achieve optimized pharmacological properties. b) Elucidate the functional mechanisms as well as the rationality and rule for the compatibility art of DSF by focusing on the clinic syndromes together with the subsequent development of preclinic study system in vitro and in vivo with consistent pathological features, pharmacokinetical behaviour and biomarkers. c) Perform more extensive clinical studies towards the advancement of mechanism-based on evidence-based medicine on the safety application of DSF. This review will provide substantial data support and broader perspective for further research on the renowned formula.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In China, the Acacia catechu (AC)-Scutellariae Radix (SR) formula has been widely used for pulmonary infection in clinical practice for several centuries. However, the potential role and mechanisms of this formula against COVID-19 remains unclear. The present study was designed to dissect the active ingredients, molecular targets, and the therapeutic mechanisms of AC-SR formula in the treatment of COVID-19 based on a systems pharmacology strategy integrated by ADME screening, target prediction, network analysis, GO and KEGG enrichment analysis, molecular docking, and molecular dynamic (MD) simulations. Finally, Quercetin, Fisetin(1-), kaempferol, Wogonin, Beta-sitosterol, Baicalein, Skullcapflavone II, Stigmasterol were primarily screened to be the potentially effective active ingredients against COVID-19. The hub-proteins were TP53, JUN, ESR1, MAPK1, Akt1, HSP90AA1, TNF, IL-6, SRC, and RELA. The potential mechanisms of AC-SR formula in the treatment of COVID-19 were the TNF signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway, etc. Furthermore, virtual docking revealed that baicalein, (+)-catechin and fisetin(1-) exhibited high affinity to SARS-CoV-2 3CLpro, which has validated by the FRET-based enzymatic inhibitory assays with the IC50 of 11.3, 23.8, and 44.1 mu M, respectively. And also, a concentration-dependent inhibition of baicalein, quercetin and (+)-catechin against SARS-CoV-2 ACE2 was observed with the IC50 of 138.2, 141.3, and 348.4 mu M, respectively. These findings suggested AC-SR formula exerted therapeutic effects involving "multi-compounds and multi-targets." It might be working through directly inhibiting the virus, improving immune function, and reducing the inflammatory in response to anti-COVID-19. Ultimately, this study would provide new perspective for discovering potential drugs and mechanisms against COVID-19.

Codelivery of chemotherapeutic drugs using polymer–drug carriers represents a promising strategy to achieve ratiometric delivery and a synergistic effect in targeted tissues and cells, which will improve the therapeutic index and reduce the side effects as compared to traditional cancer combination chemotherapy. In this study, a novel biodegradable methoxy poly(ethylene glycol)-poly(β-malic acid) (mPEG-PLMA) nanoparticle is developed for the precise codelivery of two established drugs (doxorubicin and docetaxel) and hypothesized to act synergistically to improve the anticancer efficacy of the two drugs. Doxorubicin (DOX) and docetaxel (DTX) were covalently bound to mPEG-PMLA through a one-step coupling reaction with distinct linkers, resulting in mPEG-PMLA-DOX/DTX conjugates. The conjugates exhibited a significant synergistic inhibitory effect on human breast cancer cells MDA-MB-231 when the molar ratio of conjugated DOX/DTX was 1 : 1, with an IC₅₀ value of about 0.62 μg mL⁻¹ for DOX and 0.91 μg mL⁻¹ for DTX, only accounting for 40% and 7% of the IC₅₀ for free DOX and DTX, respectively. The results of the pharmacokinetic study show that the conjugates were capable of increasing the half-life (DOX with 1.7-fold and DTX with 3.3-fold) and AUC (DOX with 2.2-fold and DTX with 4.5-fold) and maintaining the synergistic drug ratio at the tumor site for over 24 h. Furthermore, the conjugate displayed more potent anti-tumor efficacy and lower systemic toxicity than the free drug combination in vivo. These results confirmed that the combinatorial delivery system could exhibit a fascinating prospect for the synergistic delivery of drugs with diverse physicochemical properties in cancer treatment integrating efficiency and safety considerations.

Many saponins are characterized as exhibiting a wide spectrum of antitumor activities at low concentrations. Most of the previous studies that aimed to understand the mechanisms underlying anticancer saponins have focused on numerous classical signaling pathways. However, at the oncogene level, little is known about the action of saponins, especially asterosaponin. In this study, CN-3, a new asterosaponin isolated from the starfish Culcita novaeguineae, decreased the proliferation of U87 and U251 cells at low doses in a dose- and time-dependent manner. Microarray analysis revealed CN-3 significantly induced the differential expression of 661 genes that are related to its antiglioma effect in U251. Nine downregulated genes (SCUBE3, PSD4, PGM2L1, ACSL3, PRICKLE1, ABI3BP, STON1, EDIL3, and KCTD12) were selected, for further verification of their low expression. Then, shRNA transfection and high-content screening were performed and significantly decreased U251 cell proliferation rate was only observed for the SCUBE3 knockdown. qPCR confirmed SCUBE3 was highly expressed in U251 and U87 cells, and had medium expression levels in U373 cells. Real-time cellular analysis using iCELLigence demonstrated that SCUBE3 is an oncogene in U251 and U87 cells, with knockdown of SCUBE3 inhibiting U251 and U87 cell proliferation while, conversely, SCUBE3 overexpression promoted their proliferation. Afterward, SCUBE3 protein was found to have high expression in primary glioma specimens from patients examined by immunohistochemistry but low expression in normal brain. PathScan ELISA analysis in conjunction with TEM observation demonstrated that the effect of SCUBE3 knockdown in U251 does not appear to be related to the induction of apoptosis. Employing CCK-8, iCELLigence, flow cytometry, western blotting, and shRNA transfection (knockdown and overexpression) experiments, we reveal that the reduction of SCUBE3 expression, induced by CN-3, mediated both inhibition and G1/S arrest of U251 via the Akt/p-Akt/p53/p21/p27/E2F1 pathway.

Although gastroenteritis and pelvic inflammatory disease (PID) occur in the gastrointestinal tract and pelvis, respectively, they display similar pathogeneses. The incidence of inflammation in these conditions is usually associated with dysbacteriosis, and, at times, they are caused by the same pathogenic bacteria, Escherichia coli and Streptococcus aureus. Feiyangchangweiyan capsule (FYC) is a traditional Chinese patent medicine that is widely used to treat bacterial dysentery and acute and chronic gastroenteritis. However, whether it has an effect on PID is unclear. The aim of this study was to investigate the anti-inflammatory effect of FYC and its main components, gallic acid (GA), ellagic acid (EA), and syringin (SY), on a pathogen-induced PID model and illustrate their potential mechanism of action. Female specific pathogen-free SD rats (n = 1110) were randomly divided into control, PID, FYC, GA, EA, SY, GA + EA, GA + SY, EA + SY, GA + EA + SY, and Fuke Qianjin capsule (FKC) positive groups. Histological examination and enzyme-linked immunosorbent assay (ELISA) were carried out as well as western blot analysis to detect the expression of NF-κB, BAX, BCL-2, and JNK. In this study, FYC and its main components dramatically suppressed the infiltration of inflammatory cells, reduced the production of IL-1β, TNF-α, and MCP-1, and elevated the IL-10 level to varying degrees. We also found that FYC and its main components inhibited the expression of BAX induced by infection and increased the expression of Bcl-2. FYC, GA, EA, and SY could also block the activation of the NF-κB pathway. Finally, we found that the phosphorylation of JNK could be decreased by FYC, GA, and SY. FYC and its main components exhibit anti-inflammatory effect on a pathogen-induced PID model by regulating the NF-κB and apoptosis signaling pathways.

Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both in vitro and in vivo, further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGFβ1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers α-SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.

FeiYangchangweiyan capsule (FY capsule), a traditional Chinese medicinal preparation consisting of three medicinal herbs, has been used to treat bacterial dysentery, acute, and chronic gastroenteritis for several decades. In this study, a novel, convenient, accurate, and valid method was developed by using high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) to obtain a chromatographic fingerprint of FeiYangchangweiyan capsule (FY capsule). Then, fourteen peaks were identified according to MS/MS fragmentation behavior of the reference standards by using HPLC-DAD-ESI-MS/MS analysis. At the same time, the fingerprint similarity was calculated and the contents of known ingredients were also determined simultaneously. The result demonstrated that the HPLC fingerprint combining similarity evaluation and quantification analysis can be successfully applied to control the quality of FY capsule.

Gallic acid (GA) is a polyphenolic natural product widely distributed in food, beverage, and traditional Chinese herbs with beneficial effects on the cardiovascular system. In this research, a comparative study was conducted to investigate the possible difference of pharmacokinetic process in normal and isoproterenol-induced myocardial infarcted rats after oral administration of GA monohydrate with the dose of 50 and 100 mg/kg, respectively. Quantification of GA in rat plasma was achieved by using a simple and rapid high-performance liquid chromatographic method. The results revealed that pharmacokinetics of GA were greatly different between normal and pathological state. GA exhibited slower absorption into the bloodstream, and yielded 1.7-fold (50 mg/kg GA) and 1.3-fold (100 mg/kg GA) less values of area under concentration–time curve as well as 2.5-fold lower of maximum blood concentration (C_max) in MI rats than those in normal rats. In addition, significant prolonged T_1/2 and MRT as well as decreased CL were also registered in MI rats. Our findings suggest that myocardial infarction could alter the pharmacokinetic process of GA, and thus the potential pharmacokinetic differences of herbal preparations (or dietary nutrition) containing GA between normal and pathological conditions should be brought to the forefront seriously in clinical practice.