As Well as Physiological States, Pathological States and Therapeutical Problems May Be a Gushing Spring for Biological Theory - and Conversely

New class of therapies, including bipolar therapies (BPT) and paradoxical unipolar therapies (PUT) were firstly proposed in relation to a clinical insight and to some results of biological investigations, then they gave rise to mathematical modeling which brought a justification of these therapies, at least from a theoretical point of view. After recalling the mathematical model for the regulation of agonistic antagonistic couples, and reporting the fundamental types of control simulation by means of it, we point out the validity of therapeutical applications inferred from this model. These therapy modalities, including BPT and PUT, now concern the following diseases: astrocytomas, epilepsia and trials on multiple sclerosis. Even if such attempts are in their early stage, noticeably for the last case where biological changes have mainly been studied, it seems that a large span of treatments is open to BPT and PUT. Improvement of these techniques in the future depends, in our opinion, on a parallel working on the dynamics of the mathematical model and the dynamics, perceived by clinical insight and confirmed by biological investigations, of the body reactions to such strategies. Justification of BPT and PUT was given, by resorting to the notion of pathological homeostasis which, too often, intervenes in order to nullify the effects of unilateral (not paradoxical) therapies. This research has elicited some therapies which use two agents with antagonistic effects or only an agent with effects similar to the agent already in excess in the body - in both cases at nearly physiological doses.     

Ginseng increases intestinal elimination of albendazole sulfoxide in the rat

Herbal products show potential drug interactions, some of them with adverse effects. The main aim of this work was to study the effect of Panax ginseng on the intestinal elimination of the benzimidazole derivative albendazole sulfoxide (ABZSO). An upper small intestine segment was isolated and perfused in situ with saline, while ABZSO solution (10 mg/kg i.v.) was administered intravenously. Blood samples and intestinal secretion were collected over 60 min and analysed by HPLC. The intestinal clearance of ABZSO was 0.106+/-0.010 ml/min. Systemic co-administration of ginseng (10 mg/kg i.v.) increased significantly (P<0.05) the clearance of ABZSO (0.132+/-0.005 ml/min). The increase in ABZSO elimination could be the result of the effect of ginseng on metabolic pathways. These results highlight the interactions between herbal products (sometimes dietary constituents) and drugs such as benzimidazoles, since ginseng modifies the luminal clearance of this anthelminthic drug and could potentially interfere with drugs that undergo the same intestinal processes.     

Utilization of the Soft Agar Colony Formation Assay to Identify Inhibitors of Tumorigenicity in Breast Cancer Cells

Given the inherent difficulties in investigating the mechanisms of tumor progression in vivo, cell-based assays such as the soft agar colony formation assay (hereafter called soft agar assay), which measures the ability of cells to proliferate in semi-solid matrices, remain a hallmark of cancer research. A key advantage of this technique over conventional 2D monolayer or 3D spheroid cell culture assays is the close mimicry of the 3D cellular environment to that seen in vivo. Importantly, the soft agar assay also provides an ideal tool to rigorously test the effects of novel compounds or treatment conditions on cell proliferation and migration. Additionally, this assay enables the quantitative assessment of cell transformation potential within the context of genetic perturbations. We recently identified peptidylarginine deiminase 2 (PADI2) as a potential breast cancer biomarker and therapeutic target. Here we highlight the utility of the soft agar assay for preclinical anti-cancer studies by testing the effects of the PADI inhibitor, BB-Cl-amidine (BB-CLA), on the tumorigenicity of human ductal carcinoma in situ (MCF10DCIS) cells.     

Cancer stem cell plasticity and tumor hierarchy

The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.     

The presence of natural human antibodies reactive against pharmacologically active pectic polysaccharides from herbal medicines

Direct ELISA was performed using normal human sera and human colostrum, to analyse the presence of antibodies which react with pharmacologically active pectic polysaccharides isolated from plants used in traditional Japanese herbal (Kampo) medicine. All sera and colostrum were shown to contain IgM, IgG, IgA and secretory IgA class antibodies which react with the active pectic polysaccharides to different degrees. The reacting IgG antibody in normal human serum recognized the ramified regions (rhamnogalacturonan core with carbohydrate side-chains) of the pharmacologically active pectic polysaccharides as the active sites for complement-activating activity. Correlation analysis indicated that a significant and positive correlation was observed between reactivity with the reacting antibody of IgG class and the degree of complement-activating activity of the active polysaccharides.The reacting IgG class antibody, which was purified from normal human serum by affinity chromatography on bupleuran 2IIc (a pharmacologically active pectic polysaccharide from the roots of Bupleurum falcatum)-immobilized Sepharose, showed cross-reactivity not only with some other pharmacologically active pectic polysaccharides from other medicinal herbs but also with autoantigens such as single-strand DNA, myosin and tublin from mammals.     

Effect of herbal melanin on IL-8: a possible role of Toll-like receptor 4 (TLR4)

The production of IL-8 can be induced by LPS via TLR4 signaling pathway. In this study, we tested the effect of a herbal melanin (HM) extract, from black cumin seeds (Nigella sativa L.), on IL-8 production. We used HM and LPS in parallel to induce IL-8 production by THP-I, PBMCs, and TLR4-transfected HEK293 cells. Both HM and LPS induced IL-8 mRNA expression and protein production in THP-1 and PBMCs. On applying similar treatment to HEK293 cells that express TLR4, MD2, and CD14, both HM and LPS significantly induced IL-8 protein production. We have also demonstrated that HM and LPS had identical effects in terms of IL-8 stimulation by HEK293 transfected with either TLR4 or MD2-CD14. Melanin extracted from N. sativa L. mimics the action of LPS in the induction of IL-8 by PBMC and the other used cell lines. Our results suggest that HM may share a signaling pathway with LPS that involves TLR4.     

Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Microsomal triglyceride transfer protein (Mtp) inhibitors represent a novel therapeutic approach to lower circulating LDL cholesterol, although therapeutic development has been hindered by the observed increase in hepatic triglycerides and liver steatosis following treatment. Here, we used small interfering RNAs (siRNA) targeting Mtp to achieve target-specific silencing to study this phenomenon and to determine to what extent liver steatosis is induced by changes in Mtp expression. We observed that Mtp silencing led to a decrease in many genes involved in hepatic triglyceride synthesis. Given the role of diacylglycerol O-acyltransferase 2 (Dgat2) in regulating hepatic triglyceride synthesis, we then evaluated whether target-specific silencing of both Dgat2 and Mtp were sufficient to attenuate Mtp silencing-induced liver steatosis. We showed that the simultaneous inhibition of Dgat2 and Mtp led to a decrease in plasma cholesterol and a reduction in the accumulation of hepatic triglycerides caused by the inhibition of Mtp. Collectively, these findings provide a proof-of-principle for a triglyceride synthesis/Mtp inhibitor combination and represent a potentially novel approach for therapeutic development in which targeting multiple pathways can achieve the desired response.     

蜈龙抗癌颗粒对小鼠移植性肿瘤的治疗实验

目的　观察新药“蜈龙抗癌颗粒”对四种小鼠移植性肿瘤的治疗效果 ,初步探讨该制剂对小鼠的毒副作用。方法　在小鼠急性毒性试验的基础上 ,选择三个剂量对小鼠移植性肿瘤Lewis肺癌、P388白血病、S1 80 肉瘤和H2 2 肝癌进行治疗实验 ,同时检查一批治疗Lewis肺癌实验小鼠的 15项血液学指标和脾脏、胸腺的相对重量。结果与结论　“蜈龙抗癌颗粒”在生药剂量为每日每公斤体重 10、2 5、4 0g(Lewis肺癌、P388白血病 )和每日每公斤体重 15、30、5 0g(S1 80 肉瘤和H2 2 肝癌 )时 ,对小鼠移植性肿瘤有肯定的治疗效果 ,并呈良好的量效关系 ,对小鼠Lewis肺癌的治疗效果最明显。该制剂大剂量时可能对小鼠的造血系统和免疫系统有明显影响。     

Neural regeneration by regionally induced stem cells within poststroke brains: Novel therapy perspectives for stroke patients

Ischemic stroke is a critical disease which causes serious neurological functional loss such as paresis. Hope for novel therapies is based on the increasing evidence of the presence of stem cell populations in the central nervous system(CNS) and the development of stem-cell-based therapies for stroke patients. Although mesenchymal stem cells(MSCs) represented initially a promising cell source,only a few transplanted MSCs were present near the injured areas of the CNS.Thus, regional stem cells that are present and/or induced in the CNS may be ideal when considering a treatment following ischemic stroke. In this context, we have recently showed that injury/ischemia-induced neural stem/progenitor cells(i NSPCs) and injury/ischemia-induced multipotent stem cells(i SCs) are present within post-stroke human brains and post-stroke mouse brains. This indicates that i NSPCs/i SCs could be developed for clinical applications treating patients with stroke. The present study introduces the traits of mouse and human i NSPCs,with a focus on the future perspective for CNS regenerative therapies using novel i NSPCs/i SCs.     

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

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