Influence of 3,3'-diindolylmethane on expression of inflammatory cytokines in periodontal ligament cells induced by lipopolysaccharide / 上海交通大学学报（医学版）

Objective: To investigate the effect of 3,3'-diindolylmethane (DIM) on the expression of inflammatory cytokines in human periodontal ligament cells (hPDLCs) induced by lipopolysaccharide (LPS) and to study the related mechanism. Methods: hPDLCs were isolated and cultured, and CCK-8 method was used to detect the effect of DIM on the proliferation of hPDLCs. hPDLCs were randomly divided into 4 groups: blank group (without LPS and DIM), LPS group (10 μg/mL LPS), 10 μg/mL LPS+6.25 μg/mL DIM, 10 μg/mL LPS+12.50 μg/mL DIM. The cells of all groups were cultured for 12 h. The protein levels of TNF-α, IL-1β and IL-6 in supernatant were detected by enzyme linked immunosorbent assay. The change of mitogenactivated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways were detected by Western blotting. Results: The cell viability was not affected when the DIM concentration was less than 50 μmol/L (P>0.05). DIM at 6.25 and 12.50 μg/mL reduced the LPS-induced expression of TNF-α, IL-1β and IL-6 at protein levels (P<0.05). DIM inhibited the activation of the NF-κB signaling pathway. Conclusion: DIM can reduce the LPS-induced inflammatory cytokine expression in hPDLCs via restraining the activation of the NF-κB signaling pathway.

Treatment with Phytoestrogens Reversed Triclosan and Bisphenol A-Induced Anti-Apoptosis in Breast Cancer Cells

Triclosan (TCS) and bisphenol A (BPA) are endocrine-disrupting chemicals that interfere with the hormone or endocrine system and may cause cancer. Kaempferol (Kaem) and 3,3′-diindolylmethane (DIM) are phytoestrogens that play chemopreventive roles in the inhibition of carcinogenesis and cancer progression. In this study, the influence of TCS, BPA, Kaem, and DIM on proliferation and apoptotic abilities of VM7Luc4E2 breast cancer cells were examined. MTT assay revealed that TCS (0.1–10 μM), BPA (0.1–10 μM) and E2 (0.01–0.0001 μM) induced significant cell proliferation of VM7Luc4E2 cells, which was restored to the control (0.1% DMSO) by co-treatment with Kaem (30 μM) or DIM (15 μM). Reactive oxygen species (ROS) production assays showed that TCS and BPA inhibited ROS production of VM7Luc4E2 cells similar to E2, but that co-treatment with Kaem or DIM on VM7Luc4E2 cells induced increased ROS production. Based on these results, the effects of TCS, BPA, Kaem, and DIM on protein expression of apoptosis and ROS production-related markers such as Bax and Bcl-xl, as well as endoplasmic reticulum (ER) stress-related markers such as eIF2α and CHOP were investigated by Western blot assay. The results revealed that TCS, and BPA induced anti-apoptosis by reducing ROS production and ER stress. However, Kaem and DIM effectively inhibited TCS and BPA-induced anti-apoptotic processes in VM7Luc4E2 cells. Overall, TCS and BPA were revealed to be distinct xenoestrogens that enhanced proliferation and anti-apoptosis, while Kaem and DIM were identified as natural chemopreventive compounds that effectively inhibited breast cancer cell proliferation and increased anti-apoptosis induced by TCS and BPA.

Influence of 3,3'-diindolylmethane on expression of inflammatory cytokines in periodontal ligament cells induced by lipopolysaccharide / 上海交通大学学报（医学版）

Objective·To investigate the effect of 3,3'-diindolylmethane (DIM) on the expression of inflammatory cytokines in human periodontal ligament cells (hPDLCs) induced by lipopolysaccharide (LPS) and to study the related mechanism.Methyls· hPDLCs were isolated and cultured,and CCK-8 method was used to detect the effect of DIM on the proliferation of hPDLCs.hPDLCs were randomly divided into 4 groups:blank group (without LPS and DIM),LPS group (10 μg/mL LPS),10 μg/mL LPS+6.25 μg/mL DIM,10 μg/mL LPS+12.50 μg/mL DIM.The cells of all groups were cultured for 12 h.The protein levels of TNF-α,IL-1β and IL-6 in supernatant were detected by enzyme linked immunosorbent assay.The change of mitogenactivated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways were detected by Western blotting.Results· The cell viability was not affected when the DIM concentration was less than 50 μmol/L (P＞0.05).DIM at 6.25 and 12.50 μg/mL reduced the LPS-induced expression of TNF-α,IL-1β and IL-6 at protein levels (P＜0.05).DIM inhibited the activation of the NF-κB signaling pathway.Conclusion· DIM can reduce the LPS-induced inflammatory cytokine expression in hPDLCs via restraining the activation of the NF-κB signaling pathway.

Protective effects of 3,3′-diindolylmethane on radiation damage of hematopoietic system in mice / 天津医药

Objective To investigate the protective effect of 3,3′-diindolylmethane (DIM) on radiation-induced injury in mouse hematopoietic system. Methods Thirty C57BL/6 mice were randomly divided into control group, 2 Gy irradiation group and 2 Gy irradiation+DIM group (n=10 for each group). Mice of control group received sham irradiation, and the other two groups accepted 2 Gy 137Cs γ-ray total body irradiation. Mice in 2 Gy irradiation +DIM group were intraperitoneally injected 75 mg/kg DIM 30 min before irradiation. Mice of other two groups were treated with reference solution. After 7 d and 15 d of 2 Gy irradiation, the peripheral blood samples were collected to count the number of bone marrow nuclear cells (BMNCs). The level of reactive oxygen species(ROS) was measured by DCFH-DA. The levels of colony forming units-granulocyte-macrophage (CFU-GM) were also detected. Results The numbers of white blood cell (WBC), platelet count (PLT), BMNCs and CFU-GM were significantly decreased and the ROS level of bone marrow cells increased significantly in the irradiated group than those of control group (P<0.05). Compared to 2 Gy irradiation group, the numbers of WBC, PLT, BMNCs and CFU-GM were significantly increased in 2 Gy irradiation +DIM group, and the level of ROS was decreased significantly (P<0.05). Conclusion DIM has a protective effect on hematopoietic cells following radiation-induced injury, which may be related with the decreased ROS level.

In silico analysis of indole-3-carbinol and its metabolite DIM as EGFR tyrosine kinase inhibitors in platinum resistant ovarian cancer vis a vis ADME/T property analysis.

Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family, which is deregulated and over expressed in platinum resistant ovarian cancer. Thus, targeting EGFR receptor along with platinum drugs is one of the major strategies to increase the platinum drug sensitivity. That‟s why, in this study, we aimed to investigate the inhibitory activity and binding site analysis of indole-3-carbinol and its active metabolite 3,3'-diindolylmethane by using molecular simulation studies, also metabolic profile had been investigated by SOM prediction. The 3,3'-diindolylmethane showed significant inhibitory activity and binding energy comparing to indole-3-carbinol, also it processed lower toxicity and will undergo aromatic hydroxylation due its high intrinsic activity and Fe accessibility. Though our research study supports previous reports of EGFR inhibition, further in vivo study is necessary for validation of toxicological and pharmacokinetic study. However, the current work tries to address most of the variables in the dynamic drug design process by In silico study in order to boost the potentiality of the selected molecule to serve as good leads in terms of optimum pharmacokinetic and toxicological attributes.

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103+ Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103+ DCs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3'-diindolylmethane (DIM) inhibited the development of CD103+ DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103+ DCs to induce Foxp3+ Tregs.

Modulation of signal transduction pathways by natural compounds in cancer / 中国天然药物

Cancer is generally regarded as the result of abnormal growth of cells. According to World Health Organization, cancer is the leading cause of mortality worldwide. Mother nature provides a large source of bioactive compounds with excellent therapeutic efficacy. Numerous phytochemicals from nature have been investigated for anticancer properties. In this review article, we discuss several natural compounds, which have shown anti-cancer activity. Natural compounds induce cell cycle arrest, activate intrinsic and extrinsic apoptosis pathways, generate Reactive Oxygen Species (ROS), and down-regulate activated signaling pathways, resulting in inhibition of cell proliferation, progression and metastasis of cancer. Several preclinical studies have suggested that natural compounds can also increase the sensitivity of resistant cancers to available chemotherapy agents. Furthermore, combining FDA approved anti-cancer drugs with natural compounds results in improved efficacy. On the basis of these exciting outcomes of natural compounds against several cancer types, several agents have already advanced to clinical trials. In conclusion, preclinical results and clinical outcomes against cancer suggest promising anticancer efficacy of agents from natural sources.

Prevention and treatment of restenosis after PTA operation in rabbit artery by 3,3'-diindolylmethane / 中国病理生理杂志

0.05).The intimal thickness was decreased in high-dose DIM group compared with model group and low-dose DIM group(P