Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

[Ferroptosis pathway and its intervention regulated by Chinese materia medica].

Ferroptosis is a new form of regulated cell death which is different from apoptosis, necrosis and autophagy, and results from iron-dependent lipidperoxide accumulation. Now, it is found that ferroptosis is involved in multiple physiological and pathological processes, such as cancer, arteriosclerosis, neurodegenerative diseases, diabetes, antiviral immune response, acute renal failure, hepatic and heart ischemia/reperfusion injury. On the one hand, it could be found the appropriate drugs to promote ferroptosis to clear cancer cells and virus infected cells, etc. On the other hand, we could inhibit ferroptosis to protect healthy cells. China has a wealth of traditional Chinese medicine resources. Chinese medicine contains a variety of active ingredients that regulate ferroptosis. Here, this paper reported the research of ferroptosis pathway, targets of its inducers and inhibitors that have been discovered, and the regulatory effects of the discovered Chinese herbs and its active ingredients on ferroptosis to help clinical and scientific research.

The rhizome of Gastrodia elata Blume - An ethnopharmacological review.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (Orchidaceae) is commonly called Tian ma in Chinese and mainly distributed in the mountainous areas of eastern Asia, such as China, Korea, Japan and India. It is an extensively used traditional Chinese herbal medicine in the clinical practice of traditional Chinese medicine, to treat headache, migraine, dizziness, epilepsy, infantile convulsion, tetany and so on. The present paper reviews the advancements in investigation of botany and ethnopharmacology, phytochemistry, pharmacology, toxicology and quality control of Gastrodia elata Blume. Finally, the possible tendency and perspective for future investigation of this plant are also put forward. MATERIALS AND METHODS: The information on Gastrodia elata Blume was collected via piles of resources including classic books about Chinese herbal medicine, and scientific databases including Pubmed, Google Scholar, ACS, Web of science, ScienceDirect databases, CNKI and others. Plant taxonomy was validated by the databases "The Plant List", and "Mansfeld's Encyclopedia". RESULTS: Over 81 compounds from this plant have been isolated and identified, phenolics and polysaccharides are generally considered as the characteristic and active constituents of Gastrodia elata Blume. Its active compounds possess wide-reaching biological activities, including sedative, hypnotic, antiepileptic, anticonvulsive, antianxietic, antidepressant, neuroprotective, antipsychotic, anti-vertigo, circulatory system modulating, anti-inflammationary, analgesic, antioxidative, memory-improving and antiaging, antivirus and antitumor effects. CONCLUSION: Despite the publication of various papers on Gastrodia elata Blume, there is still, however, the need for definitive research and clarification of other bioactive compounds using bioactivity-guided isolation strategies, and the possible mechanism of action as well as potential synergistic or antagonistic effects of multi-component mixtures derived from Gastrodia elata Blume need to be evaluated. It is also necessary and important to do more quality control and toxicological study on human subjects in order to maintain its efficacy stable in the body and validate its safety in clinical uses. In addition, more investigations on other parts of this plant beyond the tubers are needed. Further studies on Gastrodia elata Blume will lead to the development of new drugs and therapeutics for various diseases, and how to utilize it better should be paid more attention to.

Reciprocal effects of Guizhi decoction to the Guizhi decoction syndrome by toll-like receptor mRNA expression and cytokines secretion.

OBJECTIVE: To explore the pathological mechanisms of Guizhi Decoction () syndrome and the therapeutic molecular mechanisms of the Guizhi Decoction, Mahuang Decoction (), Sangju Decoction ( ) and Yinqiao Powder (), as well as the potentially biological basis that Guizhi Decoction is most effective only for the patients with Guizhi Decoction syndrome in clinical practice. METHODS: We first got serum samples from the patients suffering from both upper respiratory tract infection and Guizhi Decoction syndrome identified by the doctors of Chinese medicine (CM) in the clinic. Four formulas with therapeutic actions of pungent warmth or pungent coolness for superficial syndromes were chosen and four kinds of rat serum samples each containing one of the above-mentioned herbal formulas were collected, then the effects of Guizhi Decoction syndromes' patient serum as well as the effects of sera containing the formulas after being stimulated by the patient serum samples on both the mRNA expression of certain toll-like receptor (TLR) subtypes and the release of some inflammatory cytokines in RAW264.7 cells were tested and analyzed in vitro. RESULTS: The expression of TLR-3, TLR-4 and TLR-9 mRNA among the 9 tested TLR subforms were up-regulated in the macrophages stimulated by the sera from untreated upper respiratory infection patients with the Guizhi Decoction syndrome (symptomcomplex). The products such as interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-ß from stimulated macrophages through TLR signaling pathways were also increased correspondingly. Interestingly, the changes induced by the Guizhi Decoction syndrome patients' sera were masked significantly after the macrophages were incubated with the sera from donors treated with Guizhi Decoction. Similarly, the three other exterior-releasing formulas were all effective in reversing the up-regulated changes of certain TLR subforms to different degrees, but both the number of targeted TLRs and efficacy of them seemed to be inferior to that of Guizhi Decoction. CONCLUSION: Evidence from these experiments might contribute to the scientific explanation of both the pharmacological mechanisms of Guizhi Decoction and also the CM theory that Guizhi Decoction is specifically prescribed for the treatment of Guizhi Decoction syndrome (The gearing formula to the symptom-complex).

Effects of 3-phenyl-propenal on the expression of toll-like receptors and downstream signaling components on raw264.7 murine macrophages.

3-phenyl-propenal is one of the principle compounds isolated from Guizhi (Ramulus Cinnamomi), the principal drug in Guizhi-Tang (GZT), a famous traditional Chinese medical formula. The aim of the present study was to investigate the effects of 3-phenyl-propenal on the expression of toll-like receptor 3 (TLR3), TLR4 and the downstream signaling components on Raw264.7 murine microphages. Raw264.7 cells were cultured in RPMI-1640 medium containing LPS (lipopolysaccharide) or poly (I:C) in the presence or absence of 3-phenyl-propenal. After 24-hour incubation, the medium was collected and the amount of TNF-alpha and IFN-beta was measured by ELISA. mRNA expression of TLR3, TLR4, myeloid differentiation factor (MyD88), TRAF-6 (tumor necrosis factor receptor-associated), TRAM (toll-like receptor-associated molecule) and TRIF (TIR domain-containing adaptor inducing IFN-beta) were analyzed by real-time PCR with SYBR green dye. Protein expression of TLR3 and TLR4 was analyzed by Western blotting and that of MyD88 and TRAF-6 was analyzed by immunofluorescence assay. The results indicate that LPS increased the expression of TLR4, MyD88, TRAF-6, TRAM and TRIF, but had no influence on TLR3, while poly (I:C) up-regulated the expression of TLR3, MyD88, TRAM and TRIF. 3-phenyl-propenal significantly decreased the expression of LPS-induced TLR4, MyD88, TRAF-6, while possessing no effect on LPS-induced TRAM and TRIF expression in Raw264.7 cells. When cells were stimulated by poly (I:C), 3-phenyl-propenal significantly decreased TLR3 and MyD88 expression. In conclusion, 3-phenyl-propenal blocked the over-expression of TLR3, TLR4, their downstream signaling components MyD88 and TRAF-6, which indicate that it had an antagonistic effect on TLR3 and TLR4.

[Effect of Shensu Yin on the expression of toll-like receptors and the downstream signaling components on RAW 264.7 cells].

OBJECTIVE: To investigate the influences of Shensu Yin to RAW 264.7 on the expression of TLR3, TLR4 and the factors of the downstream in RAW 264. 7 cells. METHOD: RAW 264.7 cell line was stimulated with Lipopolysaccharide and POLY I: C, respectively, and treated with the drug serum of Shensuyin simultaneously. 24 hours later, collected the supernatant and measured the inflammatory factors TNF-alpha and IFN-beta, extracted mRNA and measured the expression of TLR3, TLR4 and other correlated indexes of the downstream, analyzed and evaluated Shensu Yin's substance basis of pharmacodynamic actions. RESULT: Shensu Yin drug serum depressed the expression of TLR4, MyD88, TRAF-6, TRAM and TRIF mRNA, as a result, it decreased the amount of TNF-alpha and IFN-beta. CONCLUSION: Depressing the expression of TLR3, MyD88, TRAM and TRIF mRNA may be the elementary basis of Shensu Yin to play heat-clearing and detoxicating effect.