Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice.

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.

Pharmacological Activity of Eriodictyol: The Major Natural Polyphenolic Flavanone.

Eriodictyol is a flavonoid that belongs to a subclass of flavanones and is widespread in citrus fruits, vegetables, and medicinally important plants. Eriodictyol has been anticipated to explain the method of its activity via multiple cellular signaling cascades. Eriodictyol is an effective natural drug source to maintain higher health standards due to its excellent therapeutic roles in neuroprotection, cardioprotective activity, hepatoprotective activity, antidiabetes and obesity, and skin protection and having highly analgesic, antioxidant, and anti-inflammatory effects, antipyretic and antinociceptive actions, antitumor activity, and much more. This review aims to highlight the modes of action of eriodictyol against various diseases via multiple cellular signaling pathways.

Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1α nuclear translocation.

The aim of this study was to evaluate the pharmacological effects of CPT on CT26 colon cancer cells in vivo and in vitro, and to reveal the potential mechanism. CPT suppressed the proliferation and growth of CT26 colon cancer in vitro and in vivo. CPT inhibited the invasion of CT26 cells in vitro, and decreased the protein expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 but increased those of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 in vitro and in vivo. It also inhibited tumor cell-induced angiogenesis of endothelial cells in vitro and rat aortic ring angiogenesis ex vivo, and possibly by suppressing angiogenesis-associated factors. CPT suppressed the expressions of inflammatory factors in vivo and in vitro. Mechanism studies showed that CPT inhibited the PI3K/AKT/mTOR signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR. Moreover, CPT significantly suppressed the nuclear expression but increased the cytosolic expression of hypoxia inducible factor-1α (HIF-1α). Collectively, CPT inhibited the growth, invasion, inflammation and angiogenesis in CT26 colon cancer, and at least partly, by regulating the PI3K/Akt/mTOR signaling and the nuclear translocation of HIF-1α.

Stachydrine ameliorates carbon tetrachloride-induced hepatic fibrosis by inhibiting inflammation, oxidative stress and regulating MMPs/TIMPs system in rats.

Inflammation and oxidative stress are two crucial factors mediating liver fibrosis. Stachydrine (STA) is a naturally occurring compound extracted from a medicinal plant Leonuru heterophyllus, which can inhibit the proliferation and induce the apoptosis of breast cancer cells, relieve high glucose-induced endothelial cell senescence and isoproterenol-induced cardiac hypertrophy, and exert antitumor effects. However, its roles in hepatic fibrosis remain largely unknown. We aimed to evaluate the effect of STA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats and to elucidate the possible mechanisms. STA alleviated the pathological changes caused by CCl4 injection in livers compared to the normal liver. Hematoxylin-eosin staining further showed that STA treatment remarkably improved the liver histology, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. STA reduced the liver/body weight ratio and the serum levels of aminotransferase, aspartate aminotransferase and alkaline phosphatase. It also significantly decreased collagen deposition and hydroxyproline level. Both mRNA and protein levels of α-SMA, α1(I)-procollagen and fibronectin were decreased by STA compared to those of the model group. STA significantly inhibited the expressions of inflammatory factors interleukin-6 (IL-6), IL-8, IL-1ß, tumor necrosis factor-α, inducible nitric oxide synthase and cyclooxygenase-2. It suppressed oxidative stress by decreasing malondialdehyde level as well as increasing glutathione level and enzymatic activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. STA also significantly increased the protein expressions of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 but decreased those of matrix metalloproteinase-2 (MMP-2) and MMP-9, indicating excessive basement membrane in the fibrotic liver. Collectively, STA has potent protective effects on the liver, with therapeutic implication for liver fibrosis.

Suppressive role of diallyl trisulfide in the activated platelet-mediated hematogenous metastasis of MDA-MB-231 human breast cancer cells.

Accumulating evidence has indicated that garlic consumption may reduce the risk of developing several types of cancer, and extensive studies have revealed the effects of its bioactive component, diallyl trisulfide (DATS), on the proliferation and apoptosis of tumor cells. The present study was undertaken to examine whether DATS affects hematogenous metastasis. In view of the dynamic crosstalk interplayed by tumor cells and platelets in hematogenous metastasis, we attempted to demonstrate the role of DATS in the metastatic behavior of MDA-MB-231 human breast cancer cells, which were co-incubated with activated platelets. Indeed, our data indicated that DATS significantly blocked platelet activation and aggregation induced by platelet-activating factor (PAF), and decreased the production of thromboxane B2 (TXB2). It was also found that DATS suppressed the migration and invasion of MDA-MB-231 cells in the presence of platelets activated by PAF in vitro in a dose-dependent manner. Furthermore, our results revealed thaat the release of activated TGF-ß1 in the platelet-tumor cell system was markedly attenuated by DATS. Therefore, our findings strongly suggest that the diverse pharmacological activities of DATS are at least partially reflected by the interruption of the activated platelets-mediated metastasis of breast cancer cells.

Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple-Negative Breast Cancer (TNBC) via Suppressing MMP2/9 by Blocking NF-κB and ERK/MAPK Signaling Pathways.

BACKGROUND: Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated. METHODS AND RESULTS: MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK. CONCLUSION: DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.

[Synthesis of 2-hydroxyl-5-butyramidobenzoic acid and its effect on acetic acid-induced colitis in rats].

OBJECTIVE: To study the method for synthesis of 2-hydroxyl-5- butyramidobenzoic acid and test its effect on acetic acid-induced colitis in rats. METHODS: 2-hydroxyl-5-butyramidobenzoic acid was synthesized from 5-aminosalicylic acid and butyric acid by amidation, esterification and hydrolization. The effect of 2-hydroxyl-5-butyramidobenzoic acid on acetic acid enema-induced colitis in rats was investigated. RESULTS: The structure of 2-hydroxyl-5-butyramidobenzoic acid was identified by IR and 1H-NMR. After treatment with acetic acid, the colon mucosal damage index (CMDI), fecal occult blood (OB) test, and activity of myelperoxidase (MPO) increased significantly in the rats as compared to the control levels. 2-hydroxyl-5- butyramidobenzoic acid obviously reduced the CMDI and OB, and reduced the level of MPO in the rats with colitis. CONCLUSION: The synthesis of 2-hydroxyl-5-butyramidobenzoic acid requires only mild conditions with simple procedures, and the synthesized 2-hydroxyl-5-butyramidobenzoic acid shows obvious therapeutic effects on mucosal damage of in rats with acetic acid-induced colitis.