Acetyltanshinone IIA reduces the synthesis of cell cycle-related proteins by degrading p70S6K and subsequently inhibits drug-resistant lung cancer cell growth.

Targeted therapies using tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) have improved the outcomes of patients with non-small cell lung cancer (NSCLC). However, due to genetic mutations of EGFR or activation of other oncogenic pathways, cancer cells can develop resistance to TKIs, resulting in usually temporary and reversible therapeutic effects. Therefore, new anticancer agents are urgently needed to treat drug-resistant NSCLC. In this study, we found that acetyltanshinone IIA (ATA) displayed much stronger potency than erlotinib in inhibiting the growth of drug-resistant NSCLC cells and their-derived xenograft tumors. Our analyses revealed that ATA achieved this effect by the following mechanisms. First, ATA could bind p70S6K at its ATP-binding pocket to prevent phosphorylation, and second by increasing the ubiquitination of p70S6K to cause its degradation. Since phosphorylation of S6 ribosome protein (S6RP) by p70S6K can induce protein synthesis at the ribosome, the dramatic reduction of p70S6K after ATA treatment led to great reductions of new protein synthesis on several cell cycle-related proteins including cyclin D3, aurora kinase A, polo-like kinase, cyclin B1, survivin; and reduced the levels of EGFR and MET. In addition, ATA treatment increased the levels of p53 and p21 proteins, which blocked cell cycle progression in the G1/S phase. Taken together, as ATA can effectively block multiple signaling pathways essential for protein synthesis and cell proliferation, ATA can potentially be developed into a multi-target anti-cancer agent to treat TKI-resistant NSCLC.

Potential therapeutic compounds from traditional Chinese medicine targeting endoplasmic reticulum stress to alleviate rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which affects about 0.5-1% of people with symptoms that significantly impact a sufferer's lifestyle. The cells involved in propagating RA tend to display pro-inflammatory and cancer-like characteristics. Medical drug treatment is currently the main avenue of RA therapy. However, drug options are limited due to severe side effects, high costs, insufficient disease retardation in a majority of patients, and therapeutic effects possibly subsiding over time. Thus there is a need for new drug therapies. Endoplasmic reticulum (ER) stress, a condition due to accumulation of misfolded proteins in the ER, and subsequent cellular responses have been found to be involved in cancer and inflammatory pathologies, including RA. ER stress protein markers and their modulation have therefore been suggested as therapeutic targets, such as GRP78 and CHOP, among others. Some current RA therapeutic drugs have been found to have ER stress-modulating properties. Traditional Chinese Medicines (TCMs) frequently use natural products that affect multiple body and cellular targets, and several medicines and/or their isolated compounds have been found to also have ER stress-modulating capabilities, including TCMs used in RA treatment by Chinese Medicine practitioners. This review encourages, in light of the available information, the study of these RA-treating, ER stress-modulating TCMs as potential new pharmaceutical drugs for use in clinical RA therapy, along with providing a list of other ER stress-modulating TCMs utilized in treatment of cancers, inflammatory diseases and other diseases, that have potential use in RA treatment given similar ER stress-modulating capacity.

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. With increasing in-depth studies of ALI/ARDS, significant breakthroughs have been made, however, there are still no effective pharmacological therapies for treatment of ALI/ARDS. Especially, the novel coronavirus pneumonia (COVID-19) is ravaging the globe, and causes severe respiratory distress syndrome. Therefore, developing new drugs for therapy of ALI/ARDS is in great demand, which might also be helpful for treatment of COVID-19. Natural compounds have always inspired drug development, and numerous natural products have shown potential therapeutic effects on ALI/ARDS. Therefore, this review focuses on the potential therapeutic effects of natural compounds on ALI and the underlying mechanisms. Overall, the review discusses 159 compounds and summarizes more than 400 references to present the protective effects of natural compounds against ALI and the underlying mechanism.

Regulatory roles of phytochemicals on circular RNAs in cancer and other chronic diseases.

As novel non-coding RNAs (ncRNAs), circular RNAs (circRNAs) play an essential role in the pathogenesis of many chronic diseases, and the regulation of these functional molecules has become a research hotspot gradually. Within the past decade, phytochemicals were reported to regulate the expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in various chronic diseases, and more recently, most studies focus on the regulatory roles of phytochemicals on circRNAs. Abnormal expression of circRNAs has been identified in chronic diseases like cancer, heart failure, depression and atherosclerosis, and numerous studies have revealed the modulation of circRNAs by phytochemicals including berberine, celastrol, cinnamaldehyde, curcumin, et al. The expression of circRNAs, such as circSATB2 and circFOXM1, were modulated by phytochemicals, and these regulations further affected cell proliferation, apoptosis, migration, invasion, autophagy, chemosensitivity, radiosensitivity and other biological processes. Mechanismly, the circRNAs mainly functioned as miRNA sponge, subsequently affecting miRNA-mediated regulation of target genes and related cell signaling pathways. In this review, we summarized the impact of phytochemicals on circRNAs expression and biological function, and discussed the mechanisms underlying phytochemicals regulating circRNAs in cancer and other chronic diseases.

Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy.

Metabolic reprogramming, characterized by alterations of cellular metabolic patterns, is fundamentally important in supporting the malignant behaviors of cancer cells. It is considered as a promising therapeutic target against cancer. Traditional Chinese medicine (TCM) and its bioactive components have been used in cancer therapy for an extended period, and they are well-known for their multi-target pharmacological functions and fewer side effects. However, the detailed and advanced mechanisms underlying the anticancer activities of TCM remain obscure. In this review, we summarized the critical processes of cancer cell metabolic reprogramming, including glycolysis, mitochondrial oxidative phosphorylation, glutaminolysis, and fatty acid biosynthesis. Moreover, we systemically reviewed the regulatory effects of TCM and its bioactive ingredients on metabolic enzymes and/or signal pathways that may impede cancer progress. A total of 46 kinds of TCMs was reported to exert antitumor effects and/or act as chemosensitizers via regulating metabolic processes of cancer cells, and multiple targets and signaling pathways were revealed to contribute to the metabolic-modulating functions of TCM. In conclusion, TCM has its advantages in ameliorating cancer cell metabolic reprogramming by its poly-pharmacological actions. This review may shed some new light on the explicit recognition of the mechanisms of anticancer actions of TCM, leading to the development of natural antitumor drugs based on reshaping cancer cell metabolism.

Interactions of antithrombotic herbal medicines with Western cardiovascular drugs.

Thrombotic events act as a critical factor that interferes with Cardiovascular Diseases (CVDs), and antithrombotic herbal medicine is a long-standing controversial issue. Although a dispute is involved in their clinical application, all parties unanimously agree that herbal products have been widely used in folk medicine, and their interactions with conventional drugs are of high concern. This study aims to investigate how antithrombotic herbal medicines interact with Western cardiovascular drugs on the molecular level by taking an example of the most frequently used herbal pair, Danshen-Chuanxiong (DS-CX), and to discover more scientific evidence on their potential herb-drug interactions. Network pharmacology (NP), as an analytical approach of a complex system, is used to visualize and compare target profiles of DS-CX and Western cardiovascular drugs, which can be applied to predict common herb-drug targets and to construct a solid context for discussing herb-drug interactions. These interactions are further validated by in vitro assays, while in vivo zebrafish model employed for evaluating an overall pharmacological efficacy of herbal pairs in specific combination ratios. The study finds that DS could react directly to the Western cardiovascular drug targets relevant to antithrombotic pathways (i.e., thrombin, coagulation factor Xa and cyclooxygenase-1), whereas CX could not react directly and can synergistically affect antithrombotic effects with DS in specific combination ratios. Moreover, it is indicated that DS-CX may generate wide biological functions by a complicated mechanism of "neuro-immune-metabolism/endocrine" (NIM), which can further cause multiple direct and indirect interactions with Western cardiovascular drugs. From the clinical perspective, herb-drug interactions should be given high attention, especially when multiple herbs are used simultaneously.

Ethanol extracts of Danlou tablet attenuate atherosclerosis via inhibiting inflammation and promoting lipid effluent.

As a chronic inflammatory disease, atherosclerosis is characterized by accumulation of lipid-rich macrophages on the inner walls of arteries. Deposited macrophages promote atherosclerotic lesion progression; therefore they are viewed as the main targets in order to alleviate atherosclerosis. Danlou tablet, a patented Chinese Medicine, has long been used to treat cardiovascular diseases. In the present study, we used Apolipoprotein E-deficient (ApoE-/-) mice model and in vitro cell line of RAW264.7 to explore the mechanisms of ethanol extracts of Danlou tablet (EEDT) in treating atherosclerosis. The potential targets that EEDT works to treat atherosclerosis were predicted by "Network pharmacology analysis", based on which we designed mRNA array of 93 genes. Then mRNA array and oil red O staining were performed in aortic extracted from the cohorts of Control (C57BL/6 mice, chow fed), Model (ApoE-/- C57BL/6 mice, 20 weeks of high-fat diet) and EEDT intervening (ApoE-/- mice, 20 weeks of high-fat diet with 12 weeks of EEDT treatment) group. Furthermore, mRNA array, inflammation cytokines and lipid content were examined in RAW264.7 cell line. It was showed that EEDT decreased the expressions of inflammation cytokines by down regulating NF-κB singling pathway and accelerated cholesterol effluent through activating PPARα/ABCA1 signaling pathway. On the other hand, activation of NF-κB pathway or suppression of PPARα/ABCA1 signaling pathway both abolished the therapeutic effect of EEDT. In conclusion, EEDT played a key role in anti-inflammation and preventing lipid deposition in macrophages of atherosclerosis via suppressing NF-κB signaling and triggering PPARα/ABCA1 signaling pathway.

Natural medicines for the treatment of fatigue: Bioactive components, pharmacology, and mechanisms.

It is a common phenomenon that people are in a sub-health condition and facing "unexplained fatigue", which seriously affects their health, work efficiency and quality of life. Meanwhile, fatigue is also a common symptom of many serious diseases such as HIV/AIDS, cancer, and schizophrenia. However, there are still no official recommendations for the treatment of various forms of fatigue. Some traditional natural medicines are often used as health care products, such as ginseng, Cordyceps militaris (L.ex Fr.Link) and Rhodiola rosea L., and these have been reported to have specific anti-fatigue effects with small toxic and side effects and rich pharmacological activities. It may be promising treatment strategy for sub-health. In this review, we first outline the generation of fatigue. Furthermore, we put emphasis on the anti-fatigue mechanism, bioactive components, and clinic trials of natural medicines, which will contribute to the development of potential anti-fatigue agents and open up novel treatments for sub-health.

Down regulation of pro-inflammatory pathways by tanshinone IIA and cryptotanshinone in a non-genetic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and ß-amyloid (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of ß-amyloid (Aß)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3µg/3µl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100ß, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aß1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100ß, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.

Identification of a novel 11ß-HSD1 inhibitor from a high-throughput screen of natural product extracts.

Selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential as a treatment for metabolic syndrome including type 2 diabetes mellitus and obesity. To identify 11ß-HSD1 inhibitors, we conducted high-throughput screening (HTS) of active natural product extracts from the Korea Chemical Bank, including Tanshinone I, Tanshinone IIA, and flavanone derivatives, and 2- and 3-phenyl-4H-chromen-4-one. Then Tanshinone IIA and its derivatives were targeted for the development of a lead compound according to the HTS results. However, the mechanism for anti-adipogenic effect through 11ß-HSD1 enzyme inhibition by Tanshinone IIA is not clear. Tanshinone IIA (2a) concentration-dependently inhibited 11ß-HSD1 activity in human and mouse 11ß-HSD1 overexpressed cells and 3T3-L1 adipocytes. Tanshinone IIA (2a) also inhibited 11ß-HSD1 enzyme activities in murine liver and fats. Furthermore, Tanshinone IIA (2a)-suppressed adipocyte differentiation of cortisone-induced adipogenesis in 3T3-L1 cells was associated with the suppression of the cortisone-induced adipogenesis-specific markers mRNA and protein expression. In 3T3-L1 preadipocytes, Tanshinone IIA (2a)-inhibited cortisone induced reactive oxygen species formation in a concentration-dependent manner. Thus, these results support the therapeutic potential of Tanshinone IIA (2a) as a 11ß-HSD1 inhibitor in metabolic syndrome patients.

A network pharmacology-based study on the quality control markers of antithrombotic herbs: Using Salvia miltiorrhiza - Ligusticum chuanxiong as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza (Danshen, DS), the dried root and rhizome of Salvia miltiorrhiza Bunge and Ligusticum chuanxiong (Chuanxiong, CX), the dried rhizomes of Ligusticum striatum DC are effective in invigorating blood circulation and eliminating stasis which is highly related with cardiovascular disease (CVD). AIM OF STUDY: The identification of activity-based chemical markers is very important, but the complex mechanism of "multi-component, multi-target, and multi-effect" within traditional Chinese medicine (TCM) poses a great challenge to this work. In this study, we combined network pharmacological prediction with experimental validation of the DS and CX to explore an effective method for discovering quality control (QC) of antithrombotic herbs by clarifying the intermediate layer "module/cluster" between the whole complex system and a single component. MATERIALS AND METHODS: Based on structural similarity analysis of compound and the thrombosis network published before, we firstly modularized two layers called chemical cluster (CC) network and functional module (FM) network respectively and linked them into one bilayer modularized compound target (BMCT) network. "Two-step" calculation was applied on identifying the significant compounds as the potential QC markers from CC. The in vitro inhibitory activity of selected QC marker compounds on thrombin was evaluated to partially verify their pharmacological activities. HPLC was used to determine contents. RESULTS: According to the network-based analysis, nine compounds with great importance in the BMCT network were identified as QC markers of DS-CX, including tanshinone I, tanshinone IIA, cryptotanshinone, salvianolic acid B, ferulic acid, salvianolic acid A, rosmarinic acid, chlorogenic acid, and coniferyl ferulate. Enzyme inhibitory test partially verified the activity of tanshinone I and tanshinone IIA. Chemical profiling indicated that the nine marker compounds are the main components in the herbal pair. CONCLUSIONS: This study identified activity-based QC markers of DS-CX herbal pair and provided a new methodology that can be used in the QC of other herbs, herbal pairs, or formulas.

The AP2/ERF transcription factor SmERF1L1 regulates the biosynthesis of tanshinones and phenolic acids in Salvia miltiorrhiza.

Tanshinones and phenolic acids are two important metabolites synthesized by the traditional Chinese medicinal plant Salvia miltiorrhiza. There is increasing market demand for these compounds. Here, we isolated and functionally characterized SmERF1L1, a novel JA (Jasmonic acid)-responsive gene encoding AP2/ERF transcription factor, from Salvia miltiorrhiza. SmERF1L1 was responsive to methyl jasmonate (MJ), yeast extraction (YE), salicylic acid (SA) and ethylene treatments. Subcellular localization assay indicated that SmERF1L1 located in the nucleus. Overexpression of SmERF1L1 significantly increased tanshinones production in transgenic S. miltiorrhiza hairy roots by comprehensively upregulating tanshinone biosynthetic pathway genes, especially SmDXR. Yeast one-hybrid (Y1H) and electrophoretic mobility shift assay (EMSA) showed that SmERF1L1 binds to the GCC-box of SmDXR promoter while dual luciferase (Dual-LUC) assay showed that SmERF1L1 positively regulated the expression of SmDXR. Our study suggested that the SmERF1L1 may be a good potential target for further metabolic engineering of bioactive component biosynthesis in S. miltiorrhiza.

Tanshinones from Salvia miltiorrhiza Bunge revert chemotherapy-induced neuropathic pain and reduce glioblastoma cells malignancy.

Medicinal plants and herbal extracts from traditional Chinese medicine are used increasingly commonly worldwide for their benefits to health and quality of life as dietary supplements or as ingredients in functional foods. Among them, Salvia miltiorrhiza Bunge (a natural strong remedy for the treatment of a variety of conditions) is traditionally used for centuries in Asian countries as antioxidant, anticancer, and anti-inflammatory agent. In this context, several evidences support the hypothesis that some tanshinones (in particular tanshinone IIA and cryptotanshinone) extracted from the roots (Danshen) of Salvia miltiorrhiza exert neuroprotective and analgesic activities. Oxaliplatin (OXA), a platinum-based drug used for the treatment of solid tumors, induces neuropathic pain which hampers the chemotherapy success. While several attempts were made to prevent oxaliplatin-induced painful neuropathy, a growing number of evidences look to natural sources as an effective remedy to counterbalance the OXA-mediated side effects. The aim of the present study was to investigate the pain-relieving profile of Danshen and its active constituents tanshinone IIA (TIIA) and cryptotanshinone (CRY) in animal models of neuropathic pain induced by OXA, anticancer drug characterized by a dose-limiting neurotoxicity. Contextually, the neuroprotective and anticancer activities of the selected compounds were tested in different cells lines. A single administration per os of CRY (30 mg mg/kg) significantly, in a dose dependent manner, attenuated chemotherapy-induced pain. A 7 days repeated administrations highlighted the effectiveness and potency of both CRY and TIIA (10 mg/kg). On the other hand, Danshen showed a painkiller profile against oxaliplatin-induced neuropathy. Contextually, Danshen and its active constituents showed remarkable and selective inhibitory activities on glioblastoma cells lines LN-229 (IC50: 50.0 ±â€¯4.0, 48.2 ±â€¯4.9 and 51.9 ±â€¯2.3 µM respectively for Danshen standardized extract, TIIA and CRY) next to healthy but high proliferative cell lines enterocytes (IC50:> 250 µM for TIIA and CRY) and keratinocytes (IC50: >100 and 97 ±â€¯2 µM respectively for TIIA and CRY). Taken together the results reported here demonstrated the long-lasting pain-relieving effects of Danshen and its related bioactive constituents in animal models of neuropathic pain and their selective in vitro neuroprotective properties on certain central malignancy cells lines. Thus, suggest that S. miltiorrhiza roots could be considered as a new potential source of active diterpenoidic compounds useful for pharmaceutical or nutraceutical industries and beneficial as food complements.

Ethnopharmacology, phytochemistry, and pharmacology of Chinese Salvia species: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Salvia is one of the largest genera of the Lamiaceae family. In China, about 40 Salvia species have been used as medicinal plants for treatment of various diseases, specifically hepatic and renal diseases and those of the cardiovascular and immune systems. AIM OF THIS REVIEW: This review aims to provide systematically organized information on the ethnopharmacology, phytochemistry, pharmacology, and toxicology of medicinal Salvia species in China to support their therapeutic potential in the treatment of human diseases. MATERIALS AND METHODS: Relevant information on the Chinese Salvia species was obtained from scientific online databases such as Google Scholar, PubMed, and SciFinder. Additional information was derived from other literature sources (e.g. Chinese Pharmacopoeia 2015 edition, Chinese herbal classic books, PhD and MSc thesis, etc). RESULTS: Our comprehensive analysis of the scientific literature indicates that many Chinese Salvia species are valuable and popular herbal medicines with therapeutic potentials to cure various ailments. Phytochemical analyses identified diterpenoids and phenolic acids as the major bioactive substances in Chinese Salvia species. Crude extracts and pure compounds isolated from the Chinese Salvia species exhibited various pharmacological activities, typically targeting the cardiovascular and immune systems and hepatic and renal diseases. CONCLUSION: This review summarizes the results from current studies about basic properties of medicinal Salvia species in China, such as active constituents and their mechanism of action, pharmacokinetics, underlying molecular mechanisms, toxicology, and efficacy, which are still being studied and explored to achieve integration into medical practice.

Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen is a crude herbal drug isolated from dried roots of Salvia miltiorrhiza Bunge. This plant is widely used in oriental medicine for the treatment of cardiovascular and cerebrovascular diseases. The supercritical CO2 extract from Danshen (SCED) (57.85%, 5.67% and 4.55% for tanshinone IIA, tanshinone I and cryptotanshinone respectively) was studied in this article, whose potential molecular mechanism remains unclear, especially in anti-thrombosis. AIM OF THE STUDY: The present study was designed to observe the protective effect of SCED on ischemic stroke in rats and to explore the underlying anti-thrombosis mechanism. MATERIALS AND METHODS: Following induction of cerebral ischemia in rats by permanent middle cerebral artery occlusion (pMCAO). Neurological defect score, cerebral blood flow, infarct size, and brain edema were measured to evaluate the injury. Arteriovenous shunt thrombosis model and adenosine 5'-diphosphate (ADP) induced acute pulmonary embolism model were conducted to estimate the antithrombotic effect of SCED. In order to investigate the effects of SCED on platelet aggregation, rat platelet-rich-plasma (PRP) were incubated with SCED prior to the addition of the stimuli (ADP or 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619)). Aggregation was monitored in a light transmission aggregometer. Inhibitory effect of SCED on thromboxane A2 (TXA2) release was detected by ELISA kit. Phospholipase C (PLC)/ Protein kinase C (PKC) signaling pathway was analyzed by a Western blot technique. The effect of the SCED was also studied in vivo on bleeding time in mice. RESULTS: SCED improved the neurological defect score, increased cerebral blood flow, reduced infarct size and alleviated brain edema in rats exposed to pMCAO. After administration of SCED, thrombosis formation in arteriovenous shunt was inhibited and recovery time in pulmonary embolism was shortened. The inhibitory effect of SCED on platelet activation was further confirmed by TXB2 ELISA kit and Western blot analysis of PLC/PKC signaling pathway. CONCLUSIONS: SCED attenuates cerebral ischemic injury. The possible mechanism is that SCED inhibits thrombosis formation, platelet aggregation and activation of PLC/PKC pathway. On this basis, this new extract could be a promising agent to inhibit thrombosis formation and protect against cerebral ischemia injury.

Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it's definite clinical effect and mechanism on colon carcinoma is unclear. AIM OF THE STUDY: To test the hypothesis that the protective effect of danshen on colon cancer and discover the bioactive compounds through in vitro study. MATERIALS AND METHODS: We conducted a nationwide cohort study by using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised patients diagnosed with malignant neoplasm of colon (ICD-9-CM codes:153) in catastrophic illness database between January 1, 2000, and December 31, 2010. We used the Kaplan-Meier method to estimate colon [corrected] cancer cumulative incidences. Next, human colon cancer cells (HCT 116 cells and HT29 cells) were used to investigate the effect of dihydroisotanshinone I (DT) on the proliferation and apoptosis of human colon cancer cells and the underlying mechanism through XTT assay and flow cytometry. The in vivo effect of DT treatment was investigated through a xenograft nude mouse model. RESULTS: In our study, the in vivo protective effect of danshen in the different stage of colon cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro, we found that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the proliferation of colon carcinoma cells, HCT 116 cells and HT-29 cells. Moreover, DT induced apoptosis of colorectal cancer cells. DT also repressed the protein expression of Skp2 (S-Phase Kinase Associated Protein 2) and the mRNA levels of its related gene, Snail1 (Zinc finger protein SNAI1) and RhoA (Ras homolog gene family, member A). In addition, DT also blocked the colon cancer cells recruitment ability of macrophage by decreasing CCL2 secretion in macrophages. DT treatment also significantly inhibited the final tumor volume in a xenograft nude mouse model. CONCLUSION: Danshen has protective effects in colon cancer patients, which could be attributed to DT through blocking the proliferation of colon cancer cells through apoptosis.

Traditional Chinese medicine for pulmonary fibrosis therapy: Progress and future prospects.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulmonary fibrosis (PF) is a chronic, debilitating and often lethal lung disorder. Despite the molecular mechanisms of PF are gradually clear with numerous researchers' efforts, few effective drugs have been developed to reverse human PF or even halt the chronic progression to respiratory failure. Traditional Chinese medicine (TCM), the main component of the medical practice used for more than 5000 years especially in China, often exerts wider action spectrum than previously attempted options in treating human diseases. Recent data have shown the anti-fibrotic benefits of the active ingredients from TCM in this field, which may represent an attractive source of the drug discovery against PF. AIM OF THE REVIEW: This review summarizes the pre-clinical and clinical evidence on the benefits of TCM and their active ingredients, and provides a comprehensive information and reliable basis for the exploration of new treatment strategies of botanical drugs in the therapy of PF. METHODS: The literature information was obtained from the scientific databases on ethnobotany and ethno medicines (up to Aug 2016), mainly from the Pubmed, Web of Science and CNKI databases, and was to identify the experimental studies on the anti-fibrotic role of the active agents from TCM and the involved mechanisms. The search keywords for such work included: "lung fibrosis" or "pulmonary fibrosis", and "traditional Chinese medicine", "extract" or "herb". RESULTS: A number of studies have shown that the active agents of single herbs and TCM formulas, particularly the flavonoids, glycosides and alkaloids, exhibit potential benefits against PF, the mechanisms of which appear to involve the regulation of inflammation, oxidant stress, and pro-fibrotic signaling pathways, etc. Besides, the processing methods for discovering TCM in treating PF were prospectively discussed. CONCLUSION: These research work have shown the therapeutic benefits of TCM in the treatment of PF. However, more continued researches should be undertaken to clarify the unconfirmed chemical composition and regulatory mechanisms, conduct standard clinical trials, and evaluate the possible side effects. The insights provided in present review will be needed for further exploration of botanical drugs in the development of PF therapy.

Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), as the most common type of dementia, has brought a heavy economic burden to healthcare system around the world. However, currently there is still lack of effective treatment for AD patients. Herbal medicines, featured as multiple herbs, ingredients and targets, have accumulated a great deal of valuable experience in treating AD although the exact molecular mechanisms are still unclear. MATERIALS AND METHODS: In this investigation, we proposed a network pharmacology-based method, which combined large-scale text-mining, drug-likeness filtering, target prediction and network analysis to decipher the mechanisms of action for the most widely studied medicinal herbs in AD treatment. RESULTS: The text mining of PubMed resulted in 10 herbs exhibiting significant correlations with AD. Subsequently, after drug-likeness filtering, 1016 compounds were remaining for 10 herbs, followed by structure clustering to sum up chemical scaffolds of herb ingredients. Based on target prediction results performed by our in-house protocol named AlzhCPI, compound-target (C-T) and target-pathway (T-P) networks were constructed to decipher the mechanism of action for anti-AD herbs. CONCLUSIONS: Overall, this approach provided a novel strategy to explore the mechanisms of herbal medicine from a holistic perspective.

Treatment with tanshinone IIA suppresses disruption of the blood-brain barrier and reduces expression of adhesion molecules and chemokines in experimental autoimmune encephalomyelitis.

Tanshinone IIA (TSIIA), one of the major bioactive components of the traditional Chinese herb Salvia miltiorrhiza, has been reported to have both anti-inflammatory and immunoregulatory effects. The effect of treatment with TSIIA in multiple sclerosis, an autoimmune inflammatory neurodegenerative disease, however, remains poorly understood. In the present study, experimental autoimmune encephalomyelitis (EAE), a classical experimental model of MS, was used to investigate the therapeutic effect of TSIIA. TSIIA attenuated motor dysfunction and improved inflammation and demyelination associated with EAE in a dose-dependent manner. TSIIA also significantly reduced the levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule-1 (Iba-1), and protected the integrity of the blood-brain barrier (BBB) by increasing the expression of critical endothelial tight junction (TJ) proteins. TSIIA also inhibited the expression of some adhesion molecules and chemokines, which are considered to be critical for adhesion of immune cells and migration across the BBB. TSIIA was thus shown to be effective in the treatment of EAE through preventing the infiltration of immune cells into the CNS, strengthening the integrity of the BBB and decreasing the numbers of adhesion molecules and chemokines.

Protective effect of Naoxintong against cerebral ischemia reperfusion injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong (NXT), a renowned traditional Chinese medicine in China, has been used for the treatment of acute and chronic cardio-cerebrovascular diseases in clinic for more than 20 years. AIM OF THE STUDY: To evaluate the potential neuroprotective effect of NXT against ischemia reperfusion (I/R) injury in mice and investigate the underlying mechanisms. MATERIALS AND METHODS: Focal cerebral I/R injury in adult male CD-1 mice was induced by transient middle cerebral artery occlusion (tMCAO) for 1h followed by reperfusion for 23h. Mice were randomly divided into five groups: Sham group; tMCAO group; Vehicle group; NXT-treated groups at doses of 0.36g/kg and 0.54g/kg. The effects of NXT on murine neurological function were estimated by neurological defect scores, infarct volume and brain water content at 24h after tMCAO. Immunohistochemistry and Western blot were used to detect the expression of LOX-1, pERK1/2 and NF-κB at 24h after tMCAO. qRT-PCR was used to detect the expression of LOX-1 and NF-κB at 24h after tMCAO. RESULTS: Compared with Vehicle group, 0.54g/kg group of NXT significantly ameliorated neurological outcome, infarction volume and brain water content, decreased the expression of LOX-1, pERK1/2 and NF-κB (P<0.05). CONCLUSION: NXT protected the mice brain against I/R injury, and this protection maybe associated with the down-regulation of LOX-1, pERK1/2 and NF-κB expression.