Mechanistic Pathways and Molecular Targets of Plant-Derived Anticancer ent-Kaurane Diterpenes.

Since the first discovery in 1961, more than 1300 ent-kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon. Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe the anticancer potential and mechanism of action of ent-kaurane compounds in a series of cancer cell lines. Oridonin is one of the prime anticancer ent-kaurane diterpenoids that is currently in a phase-I clinical trial in China. In this review, we have extensively summarized the anticancer activities of ent-kaurane diterpenoids according to their plant sources, mechanistic pathways, and biological targets. Literature analysis found that anticancer effect of ent-kauranes are mainly mediated through regulation of apoptosis, cell cycle arrest, autophagy, and metastasis. Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4. The most common metastatic target proteins of ent-kauranes are MMP-2, MMP-9, VEGF, and VEGFR whereas LC-II and mTOR are key regulators to induce autophagy.

Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling.

Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/ß-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases.

Flexicaulin A, An ent-Kaurane Diterpenoid, Activates p21 and Inhibits the Proliferation of Colorectal Carcinoma Cells through a Non-Apoptotic Mechanism.

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia), a genus of the Lamiaceae (formerly Labiatae) family, has been reported as a rich source of natural diterpenes. In the current study, we evaluated the in vitro anti-proliferative property of flexicaulin A (FA), an Isodon diterpenoid with an ent-kaurane structure, in human carcinoma cells, by means of cell viability assay, flow cytometric assessment, quantitative polymerase chain reaction array, Western blotting analysis, and staining experiments. Subsequently, we validated the in vivo antitumor efficacy of FA in a xenograft mouse model of colorectal carcinoma. From our experimental results, FA appears to be a potent antitumor molecule, since it significantly attenuated the proliferation of human colorectal carcinoma cells in vitro and restricted the growth of corresponsive xenograft tumors in vivo without causing any adverse effects. Regarding its molecular mechanism, FA considerably elevated the expression level of p21 and induced cell cycle arrest in the human colorectal carcinoma cells. While executing a non-apoptotic mechanism, we believe the antitumor potential of FA opens up new horizons for the therapy of colorectal malignancy.

In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence.

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1-19), including 11 novel ones (5 and 10-19) from another Miliusa plant ( M. balansae), and synthesized additional derivatives to elucidate the structure-activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5-40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1-3 (GI50 0.03-4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

Isolation, evaluation of bioactivity and structure determination of amethinol A, a prototypic amethane diterpene from Isodon amethystoides bearing a six/five/seven-membered carbon-ring system.

We report the isolation of a novel diterpene, designated as `amethane', from Isodon amethystoides (Lamiaceae). The diterpene [amethinol A; systematic name: (4aR,4bR,7R,10aS)-4b,7-dihydroxy-7-isopropyl-1,1-dimethyl-9-oxododecahydrobenzo[a]azulene-4a(2H)-carboxylic acid], possesses a unique skeleton containing a six/five/seven-membered tricyclic system. Intermolecular O-H...O close contacts were found to the carboxyl, carbonyl and hydroxy groups, connecting molecules into a two-dimensional structure. A possible biosynthetic pathway has been proposed. In addition, the compound was evaluated for its biological activities against different disease targets, and was found to significantly attenuate RORγt-dependent autoimmune responses.

Antimalarial Activity of Plant Metabolites.

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Perspectives of Plant Natural Products in Inhibition of Cancer Invasion and Metastasis by Regulating Multiple Signaling Pathways.

BACKGROUND: Metastasis is often derived from increased invasion and migration of tumor cells, and is the most frequent cause of cancer-associated death. Either the prophylactic or therapeutic treatment of metastatic cancer remains very challenging today by virtue of the complex histopathology and genetic or epigenetic variations. Medicinal scientists had discovered many potential anti-invasive and anti-metastatic compounds from plant materials. However, data on currently available plant-based compounds inhibiting cancer invasion and metastasis is relatively scanty and no published article has been found with updated information in this unique and important aspect. METHODS: We obtained relevant information from a structured search of 327 peer-reviewed articles, including both research- and review-based papers, related to the use of plant materials in cancer treatments, particularly for the suppression of invasion and metastasis. RESULTS: We have categorized the plant-based products with anti-invasive or anti-metastatic properties into alkaloids, flavonoids, terpenes, quinones, phenolics, xanthone and sulfur-containing compounds, and complemented with their chemical structures, sources of isolation and biological targets in the present review article. CONCLUSION: We aim to provide readers a convenient way in reviewing the potential anti-invasive and anti-metastatic plant-based products with links to different mechanistic pathways, and to inspire researchers with updated information for the development of new anticancer remedies.

Concise Synthesis of Natural Phenylphenalenone Phytoalexins and a Regioisomer.

Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1), 2-hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are accomplished in 11 or 12 steps. The synthetic strategy features a Friedel-Crafts acylation to construct the 1H-phenalen-1-one tricyclic core followed by a Suzuki cross-coupling to obtain the target compounds.

The Use of Naphthoquinones and Furano-naphthoquinones as Antiinvasive Agents.

BACKGROUND: Cancer is a leading cause of mortality in the world and metastasis is to blame. A number of naphthoquinones (NQs) have shown ability to reduce cancer stemness and metastatic potential. Furano-naphthoquinones (FNQs), which is a class of NQ characterized by the incorporation of an additional furan ring, have demonstrated improved anti-cancer potency as compared to the other classes of NQs. OBJECTIVE: In this study, the natural origins, synthetic routes and derivatives of migrastatic NQs were reviewed. The anti-invasive and anti-metastatic mechanisms of NQs and the more powerful FNQs in targeting cancer were also discussed. METHODS: The articles related to the anti-invasive mechanisms of NQs were comprehensively reviewed. The plant origins, synthetic routes and antitumor effects of more than 360 FNQs were also covered and presented according to their chemical structures. RESULTS: Anti-cancer NQs inhibit cancer invasion by acting on epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and signal transducer and activator of transcription 3 (STAT3) signaling. BBI608, a natural FNQ, has entered phases I and II clinical trials. It has been regarded as a potential candidate for new-generation lead compound acting directly on CSCs to overcome the problem of chemotherapy resistance. Apart from the plant-derived FNQs, there are a number of synthetic FNQs that were found to intervene in cancer invasion and metastasis. CONCLUSION: The anti-invasive mechanisms of NQs have been thoroughly studied. FNQs generally show higher anti-cancer activity than that of NQs. The mechanisms of action of FNQs are worth further investigation.

Design, synthesis and evaluation of novel dihydrostilbene derivatives as potential anti-melanogenic skin-protecting agents.

The stems of Dendrobium orchids (Orchidaceae), also known as Shi Hu, have been used for medicinal purposes for centuries in oriental countries. In fact, the health benefits of Shi Hu have been evidenced by its modern pharmacological actions on conquering oxidative stress in pathological conditions. From the extracts of two commonly used Dendrobium species, we obtained discernible amounts of stilbenoids, explicitly trans-resveratrol (1) and dihydro-resveratrol (2), which are prototypical antioxidants. When applied to cultured melanocytes, these stilbenoids, dihydro-resveratrol (2) in particular, significantly reduced melanin formation via inhibiting tyrosinase activity and expression of tyrosinase-related proteins. By utilizing dihydro-resveratrol (2) as the basic structural unit, we synthesized 11 novel dihydrostilbene derivatives (3-13) in good yields and purity, with manipulative steps. In addition to their anti-melanogenic activity, some of the novel derivatives are indeed potential antioxidants as they quenched intracellular oxidative radicals in a manner more efficient than Trolox, a water-soluble analogue of vitamin E, and thus premeditated beneficial to skin protection.

Resveratrol Ameliorates the Severity of Fibrogenesis in Mice with Experimental Chronic Pancreatitis.

SCOPE: Resveratrol is generally considered beneficial to health-span and longevity since this dietary stilbenoid has been scrutinized for its activating property on the "rescue gene" sirtuin-1 that promotes cellular survival under stress. In addition to its antiaging property, our previous in vitro studies revealed that resveratrol notably inhibits the production of extracellular matrix (ECM) proteins in pancreatic stellate cells (PSCs), the classic effector cells against pancreatic injury. OBJECTIVE: We aim to extrapolate resveratrol intervention to the management of fibrogenesis in mice with chronic pancreatitis. METHODS AND RESULTS: C57/BL6 mice are given repetitive injections of cerulein (50 µg kg-1  h-1 ) for 6 weeks for the induction of chronic pancreatitis. We demonstrate that the oral administration of resveratrol (20 mg kg-1  d-1 ) effectively attenuated PSC activation, ECM deposition, fibrogenesis, and acinar atrophy in the pancreatitic parenchyma of cerulein-induced mice, as the damage index score was improved by 45.5%. The enhanced cell survival and preserved acinar integrity by resveratrol plausibly involves a perpetuated nuclear accumulation of Mist1 and a negative modulation of the Akt and p38 MAPK pathways. CONCLUSION: We suggest that resveratrol is potentially a nutraceutical for the mitigations of pancreatic fibrosis in chronic pancreatitis for which no effective therapeutic measure is currently available.

Efficient Semisynthesis of (-)-Pseudoirroratin A from (-)-Flexicaulin A and Assessment of Their Antitumor Activities.

Accumulating evidence indicates that natural ent-kaurane diterpenoids show great potential for medical treatment of different pathological conditions including cytotoxicity, antibacterial, and anti-inflammatory activity. Among a variety of diterpenoids tested, (-)-pseudoirroratin A displayed a promising antitumor property in vitro and in vivo. However, this diterpenoid could merely be isolated in a limited amount from a rare source of Isodon pseudoirrorata. To overcome such scanty source, we developed a novel, facile, and efficient semisynthetic strategy to prepare (-)-pseudoirroratin A from natural (-)-flexicaulin A, which can be expediently obtained from I. flexicaulis in a great quantity. The three-dimensional structure and the absolute configuration of our synthetic diterpenoid have been determined and confirmed with the X-ray crystallographic analysis. More importantly, we demonstrated for the first time that pseudoirroratin A exerted significant cytotoxicity against human colorectal carcinoma cells via an induction of apoptosis, as well as a remarkable suppression on tumor growth in a colon cancer xenograft mouse model.

Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis.

Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance. In the present study, upon the oral administration of dihydro-resveratrol (10-50 mg/kg), the severity of acute pancreatitis in the cerulein-treated rats was significantly ameliorated as evidenced by decreased α-amylase activities in the plasma and lessened oedema formation in the pancreatic parenchyma. In addition, the generation of intracellular reactive oxidative products, including malondialdehyde and protein carbonyls, was accordingly reduced, so as the production of pro-inflammatory cytokines. While inhibiting the activities of NADPH oxidase and myeloperoxidase, the depletion of glutathione was considerably restored. Importantly, the attenuation of pancreatic oxidative damage by dihydro-resveratrol was associated with a down-regulation of the nuclear factor-kappaB and phosphatidylinositol 3'-kinase-serine/threonine kinase signalling pathways. Furthermore, we demonstrated that the solubility of dihydro-resveratrol was at least 5 times higher than trans-resveratrol whilst exhibiting a much lower cytotoxicity. Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans-resveratrol due to the lack of proper microbial strains.

Dihydro-Resveratrol Ameliorates Lung Injury in Rats with Cerulein-Induced Acute Pancreatitis.

Acute pancreatitis is an inflammatory process originated in the pancreas; however, it often leads to systemic complications that affect distant organs. Acute respiratory distress syndrome is indeed the predominant cause of death in patients with severe acute pancreatitis. In this study, we aimed to delineate the ameliorative effect of dihydro-resveratrol, a prominent analog of trans-resveratrol, against acute pancreatitis-associated lung injury and the underlying molecular actions. Acute pancreatitis was induced in rats with repetitive injections of cerulein (50 µg/kg/h) and a shot of lipopolysaccharide (7.5 mg/kg). By means of histological examination and biochemical assays, the severity of lung injury was assessed in the aspects of tissue damages, myeloperoxidase activity, and levels of pro-inflammatory cytokines. When treated with dihydro-resveratrol, pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening were significantly reduced in rats with acute pancreatitis. In addition, the production of pro-inflammatory cytokines and the activity of myeloperoxidase in pulmonary tissues were notably repressed. Importantly, nuclear factor-kappaB (NF-κB) activation was attenuated. This study is the first to report the oral administration of dihydro-resveratrol ameliorated acute pancreatitis-associated lung injury via an inhibitory modulation of pro-inflammatory response, which was associated with a suppression of the NF-κB signaling pathway.

Qing-dai powder promotes recovery of colitis by inhibiting inflammatory responses of colonic macrophages in dextran sulfate sodium-treated mice.

BACKGROUND: Qing-dai powder (QDP), comprising Indigo naturalis (Qing-dai) and dried alum (Ku-fan), was used in Chinese medicine to treat the conditions associated with mucosal hemorrhage, such as ulcerative colitis (UC). This study aims to investigate the effects and potential mechanism of QDP on dextran sulfate sodium (DSS)-induced acute colitis in mice and to examine the regulatory effects of QDP on macrophages. METHODS: Seven- to eight-week-old male C57BL/6 mice were challenged with 2.0 % DSS in drinking water for 5 days and then the colitic mice were arbitrarily allocated into five groups (n = 10 for each group). QDP (0.77, 1.54 and 3.08 g/kg) and sulfasalazine (SASP) (0.20 g/kg) were orally administered for 7 days. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological signs of damage was analyzed by H&E staining; myeloperoxidase activity was measured by colorimetric method, levels of proinflammatory cytokines were determined by ELISA; changes in macrophages in the colon were analyzed by immunohistochemistry (IHC) and flow cytometry. Lipopolysaccharide (LPS)-induced RAW264.7 cells were treated with or without QDP, then the production of TNF-α and IL-6 were measured by ELISA; and protein molecules such as COX-2, iNOS, IкB-α were determined by Western blot. RESULTS: Oral administration of QDP at dosages of 1.54 and 3.08 g/kg significantly reduced disease activity index on day 12 (P < 0.001 for 1.54 g/kg and P < 0.0008 for 3.08 g/kg), colon shortening (P = 0.012 for 1.54 g/kg, P = 0.001 for 3.08 g/kg), histological damage (P < 0.001 for 1.54 g/kg, P < 0.001 for 3.08 g/kg) and colonic myeloperoxidase activity (P = 0.002 for 1.54 g/kg, P < 0.001 for 3.08 g/kg) of DSS-treated mice. Moreover, QDP treatment (1.54 and 3.08 g/kg) significantly decreased DSS-induced infiltration of macrophages, and production of TNF-α (P = 0.005 for 1.54 g/kg, P = 0.002 for 3.08 g/kg), IL-1ß (P = 0.008 for 1.54 g/kg, P = 0.002 for 3.08 g/kg) and IL-6 (P = 0.011 for 1.54 g/kg, P = 0.004 for 3.08 g/kg) in colonic tissues, and also reduced serum MCP-1 levels (P = 0.001 for 1.54 g/kg, P < 0.001 for 3.08 g/kg). In RAW264.7 cells, QDP significantly suppressed LPS-induced production of TNF-α and IL-6 (Both P < 0.001 for 1.0 µg/mL QDP treatment) and expression levels of COX-2 (P = 0.002 and P = 0.001 for 1 and 3 µg/mL QDP treatment, respectively) and iNOS (P < 0.001 for 3 µg/mL QDP treatment) by inhibiting IкB-α degradation (P = 0.007 and P = 0.004 for 1 and 3 µg/mL QDP treatment, respectively) and NF-кB p65 nuclear translocation. CONCLUSION: QDP suppressed the inflammatory responses of colonic macrophages in DSS-induced UC in mice and LPS-induced RAW264.7 cells.

Eruberin A, a Natural Flavanol Glycoside, Exerts Anti-Fibrotic Action on Pancreatic Stellate Cells.

BACKGROUND: Eruberin A (2, 3-dehydroflavonoid), a flavanol glycoside isolated from Pronephrium penangianum, has been used as a blood-nourishing folk medicine for centuries; however, it indeed possesses a variety of other health-promoting benefits including anti-fibrotic bioactivity. Activation of pancreatic stellate cells (PSCs) is the key initiating step in pancreatic fibrosis, which is a characteristic feature associated with chronic pancreatitis and pancreatic adenocarcinoma. METHODS: The anti-fibrotic effect of eruberin A and the underlying mechanisms of its anti-fibrotic action in LTC-14 cells, which retained essential characteristics and morphological features of primary PSCs, were examined by means of real-time polymerase chain reactions, Western blotting and immunostaining. RESULTS: The application of eruberin A (20 µg/ml) effectively inhibited the expression levels of fibrotic mediators namely alpha-smooth muscle actin, fibronectin and type I-collagen, so as the sonic hedgehog signaling pathway components post transforming growth factor-beta (5 ng/ml) stimulation. Eruberin A treatment also led to a notable decrease in the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT). CONCLUSION: Our results demonstrated that eruberin A significantly suppressed the expression levels of fibrotic mediators in PSCs, and we suggest that its anti-fibrotic mechanism was associated with an attenuation of the PI3K/AKT/NF-κB signaling pathway.

Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells.

BACKGROUND: Pancreatic fibrosis is a prominent histopathological characteristic of chronic pancreatitis and plausibly a dynamic process of transition to the development of pancreatic ductal adenocarcinoma. Conversely, the activation of pancreatic stellate cells (PSCs) has been recently suggested as the key initiating step in pancreatic fibrosis. As natural polyphenols had been largely applied in complementary therapies in the past decade, in this study, we aimed to investigate which groups of phenolic compounds exert promising inhibitory actions on fibrogenesis as there are few effective strategies for the treatment of pancreatic fibrosis to date. METHODS: We examined the anti-fibrotic effects of a variety of herbal constituents using a cellular platform, the LTC-14 cells, which retained essential characteristics and morphologies of primary PSCs, by means of various biochemical assays including cell viability test, real-time polymerase chain reaction and Western blotting analysis. RESULTS: Among a number of commonly used herbal constituents, we found that the application of rhein, emodin, curcumin and resveratrol significantly suppressed the mRNA and protein levels of several fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in LTC-14 cells against transforming growth factor-beta stimulation. Though the values of cytotoxicity varied, the mechanism of the anti-fibrotic action of these four phenolic compounds was principally associated with a decrease in the activation of the nuclear factor-kappaB signaling pathway. CONCLUSIONS: Our findings suggest that the mentioned phenolic compounds may serve as anti-fibrotic agents in PSC-relating disorders and pathologies, particularly pancreatic fibrosis.

Anti-fibrotic effect of trans-resveratrol on pancreatic stellate cells.

Trans-resveratrol, also known as 3,5,4'-trihydroxy-trans-stilbene, is a natural stilbenoid found at high concentration in skins of red grapes and berries. Over the recent years, it has been reported with a variety of beneficial effects such as antioxidant, anti-aging and anti-inflammatory bioactivities; thus often utilized as an active substance in human and veterinary therapeutics. In the current study, we aimed to delineate the mechanism of its anti-fibrotic action by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction and Western blotting analyses in a cellular model, the LTC-14 cells, which retain essential characteristics and morphological features of primary pancreatic stellate cells (PSCs). Our results demonstrated that the application of trans-resveratrol as low as 10 µM notably suppressed the mRNA and protein levels of different fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in the LTC-14 cells stimulated with transforming growth factor-beta, a well recognized pro-fibrotic inducer. Importantly, the mechanism of the anti-fibrotic action of trans-resveratrol was associated with a decrease in nuclear factor-kappaB activation and protein kinase B phosphorylation. In conclusion, our finding suggests that trans-resveratrol may serve as a therapeutic or an adjuvant agent in anti-fibrotic approaches and/or PSC-relating pathologies.

A Chinese medicinal formulation ameliorates dextran sulfate sodium-induced experimental colitis by suppressing the activity of nuclear factor-kappaB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is generally associated with a set of debilitating symptoms including abdominal pain, tenesmus, diarrhea and bloody stool. The standard approaches for treating IBD, which are the application of pharmaceuticals, are often unsatisfactory. IBD patients may suffer from repeated relapses and even exacerbation after taking these medications. Thus, patients are increasingly seeking relief through the use of complementary and alternative medicines. AIM OF STUDY: To provide scientific ground for the mode of actions of a Chinese medicinal formulation-modified ZenWu Decoction (MZWD) in ulcerative colitis. MATERIALS AND METHODS: C57BL6 mice were fed with 3 cycles of 2% dextran sulfate sodium (DSS) in drinking water for the induction of chronic colitis and then given MZWD at 17.47 g/kg/day. Effects of MZWD were evaluated by histopathological and biochemical assays. RESULTS: When MZWD was given, inflammatory responses namely immune-cell infiltration, elevated serum levels of pro-inflammatory cytokines and mucosal lesions were notably suppressed. Further, MZWD treatment attenuated the activation of nuclear factor-kappaB (NF-κB), the vital regulator of inflammatory cascades, while lessening the degradation of I-kappaB-alpha and reducing the activity of protease-activated receptor 2 in DSS-induced colonic tissues. Consequently, diarrhea, bloody stool and colon shortening were reduced whilst mucosal integrity was improved in MZWD-treated colitis mice. CONCLUSIONS: Our findings suggest that MZWD is a potential remedy for treating IBD, and the mechanism of its efficacy is an anti-inflammatory effect associated with the suppression of the NF-κB pathway.

Traditional Chinese medicine formulas for irritable bowel syndrome: from ancient wisdoms to scientific understandings.

Traditional Chinese Medicine (TCM) serves as the most common alternative therapeutic approach for Western medicine and benefits IBS patients globally. Due to the lack of scientific evidence in the past, TCM formulas were not internationally well recognized as promising IBS remedies. In this review, firstly, we present the etiology and therapy of IBS in terms of traditional Chinese medical theory. Secondly, we summarize the clinical randomized controlled trials (RCTs) of TCM formulas for IBS patients that are available in the literature (from 1998 to September 2013), in which 14 RCTs conducted of high quality were discussed in detail. Of the 14 selected trials, 12 of those concluded that TCM formulas provided superior improvement in the global symptoms of IBS patients over the placebo or conventional medicines. As well, all 14 RCTs suggested that TCM formulas have good safety and tolerability. Last but not least, we explore the pharmacological mechanisms of the anti-IBS TCM formulas available in the literature (from 1994 to September, 2013). Collectively, in combating IBS symptoms, most TCM formulas exert multi-targeting actions including the regulation of neurotransmitters and hormones in the enteric nervous system (ENS), modulation of smooth muscle motility in the gastrointestinal (GI) tract, modulation of the hypothalamic-pituitary-adrenal (HPA) axis, attenuation of intestinal inflammation and restoration of intestinal flora, etc. In conclusion, TCM formulas appear to be promising for IBS treatment. This review provides a useful reference for the public in furthering a better understanding and acceptance of TCM formulas as IBS remedies.