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The effect of fermented soy (FSWW08) on blood hematology and cachexia in cancer patients
Abstract
Abstract In cancer patients, appetite and immune status are significantly weakened. Two experimental fermented formulations without (group A, named as FSWW08) and with (group B, FSWW08) an extract from yam root were investigated against a placebo formulation with casein (group C) in a clinical study conducted in six cancer hospitals where cancer patients underwent radio or chemotherapy (patients undergoing radiation therapy n=78, patients undergoing chemotherapy n=184, total 262). IgG and IgA were increased by formulation A in patients despite receiving radio- or chemotherapy. Group A experienced statistically significant increases in lymphocyte transformation rates, whereas group B and group C did not. Formulations A and B either inhibited or lessened statistically significant decreases in white blood counts, whereas the placebo group experienced substantial decreases. Hemoglobin and platelet decreases were inhibited in group A, although not statistically significantly. Patients in group A received no blood transfusions, whereas many patients from the placebo group received blood transfusions. Appetite loss was reduced in group A from 57.9% to 13.3% and in group B from 70% to 35.8%. In the placebo group, an increase in appetite loss was detected under chemo and radiation therapy from 41.8% to 70.9%.
... This paper therefore systematically investigates the effect of fermented soy bean formulation on cancer cells in vitro, as was shown by others also, in vivo in CTC extracted from blood from cancer patients, which has not been shown before. We detected and reported earlier that the effectiveness of chemotherapy was increased by fermented soy formulation, side effects were reduced, and survival increased [39,40]. This study investigates in vitro whether a combination of the classic cytotoxic compound doxorubicin may be combined with fermented soy bean and counterbalance some of the side effects of classical chemotherapy on the genetic level. ...
... The study protocol was reviewed by a local institutional review board (IRB) to protect the rights of patients, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup and was published previously [24,39,40]. All patients had to sign an Informed Consent Form after the physician explained the study and he read the informed consent form where the study goal was outlined in a written form, in which the study was outlined and participation was voluntarily and it was explained individually to all patients that they could leave the study at any time even without explanation. ...
... All in vitro procedures determining the gene expression determination have been described before [24,39,40,44], however a more thorough investigation and discussion about in vitro and in vivo comparison and DNA repair is missing. Investigations of the human breast cancer cell line BT-474 were conducted, which were purchased from the German National Resource ...
Introduction: It was suggested that specific plants may reduce cancer's resistance to chemotherapy. Resistance inhibits apoptosis, as well as other fundamental anti-cancer protective mechanisms. Soy bean has been found to reduce cellular stress and repair DNA damage caused by drought or parasites, and can transfer this defense mechanism to other plant species as well. The aim of this study is therefore to conduct a systematic comparison of the effect of soy bean formulation (FSWW08) on gene expression in in vitro human breast cancer cell line, and in in vivo in blood circulating tumor cells (CTC), after oral consumption of FSWW08 by patients suffering from breast-, ovarian-, and prostate cancer. Method: In vitro gene expressions studies were conducted with the human breast cancer cell line BT-474 that was exposed to doxorubicin or FSWW08, either alone or in combination. Ovarian-, prostate-, and breast cancer patients received FSWW08 for 30 days. CTC were extracted from their blood according to an established protocol. Gene expression evaluations were conducted before and after treatment. Results: In vitro, the multi-drug resistance (MDR) protein was reduced by FSWW08, but was increased by doxorubicin. The combination of FSWW08 and doxorubicin, however, showed a protective effect against the increase of MDR in physiologic concentrations, increased, however, also in high experimental concentrations of both agents. The expression of several cancer-related protective genes, such as tumor suppressor factors p21, p38 and p53, was improved by FSWW08 in vitro and in vivo, which helped cell differentiation and new tissue formation. Additionally, the BAX/Bcl2 ratio was improved, in vitro, as well as gene expression of estrogen receptor beta, NF-κB, MAP kinase, c-JUN, and matrix metalloproteinase 9, together with an increase of VEGF expression in vivo in CTC.
Public health interest in vaccinations and immune protection has increased with the COVID-19 pandemic. Dairy products are an important source of protein and other nutrients, and there are unresolved research questions regarding the potential health impact of dairy products on the enhancement of immune response. A systematic literature review was conducted to synthesize the published literature reporting the effects of dairy interventions on: 1) the vaccine-specific immune response and 2) immunoglobulins in the absence of vaccination. To assess study validity and quality, we used the Academy of Nutrition and Dietetics Quality Criteria Checklist. Sixty-one studies (59 clinical trials, 1 cohort, 1 cross-sectional survey) were included, spanning 1983-2017. Ten trials evaluated the effect of dairy intervention on vaccine-specific IgG, IgA, IgM, vaccine-specific antibody titers, seroprotection rates, or seroconversion rates. Of these, 7 reported significant increases with dairy interventions for post-vaccine tetanus antibodies, mean change in tetanus antibody level, total antibody titers to flagellin from Salmonella Adelaide, mean antibody titers to influenza B, influenza-specific IgA and IgG levels, and seroconversion or seroprotection rates for influenza A and B. Fifty-six studies evaluated dairy’s effects on immunoglobulins without vaccinations. The results were heterogenous, with some studies reporting significant enhancement of immunoglobulins (IgA, IgE, or IgG), while others observed no differences between groups. Clinical relevance of the immunoglobulin changes was not investigated in these studies. Dairy products and their components could enhance the efficacy of vaccines. This review highlights the evidence gaps and provides a potential roadmap for additional research.
Under FSWW08, mental stress and anxiety was reduced, accompanied by a normal sleeping pattern at night and increased energy levels, which caused increased physical activity. Patient reported improved breathing, documented by stable FVW. The patient exhibited a normalization of blood pressure (from pre diagnosed ALS and no consumption of FSWW08, similarly in the off phase, when FSWW08 was not taken) from 170/100 mm HG to 120/80 mm HG under FSWW08 consumption) within seven days, blood lipids were normalized (cholesterol, triglycerides, HDL, LDL). It is reported in the literature that unfavorable blood lipids are related to severity of ALS in Japanese and Western patients. This is the first time stabilization of ALS has been observed accompanied by improvements in blood lipids in patients. This single report corroborates studies conducted with FSWW08 in other diseases including cancer, severe mental diseases (PTSD and Schizophrenia) and severe virus infections. The FDA has granted a general unspecific Health Claim that soy improves blood lipids like cholesterol and triglycerides. This is the first time a fermented soy formulation, FSWW08, has prevent progression of ALS over a two years period and normalized blood lipids. The special fermentation of FSWW08 causes an increase in immunity, cellular stress reduction and blood lipids. Larger clinical trials in ALS patients with FSWW08 are now warranted to investigating whether these results can be confirmed, and whether FSWW08 increases survival, as well as whether blood lipids are a prognostic marker of ALS.
Emergence of drug resistance has brought major problems in chemotherapy. Using nutrients in combination with chemotherapy could be beneficial for improvement of sensitivity of tumors to drug resistance. Soybean-derived isoflavones have been suggested as chemopreventive agents for certain types of cancer, particularly breast cancer. In this study, the synergistic effects of soy isoflavone extract in combination with docetaxel in murine 4T1 breast tumor model were investigated.
In this study, mice were divided into 4 groups (15 mice per group) of control, the dietary Soy Isoflavone Extract (SIE, 100 mg/kg diet), the Docetaxel (DOCE, 10 mg/kg) injection and the combination of dietary soy isoflavone extract and intravenous docetaxel injection (DOCE+SIE). After 3 injections of docetaxel (once a week), 7 mice were sacrificed to analyze MKI67 gene and protein expressions and the rest were monitored for diet consumption, tumor growth and survival rates.
In DOCE+SIE group, diet consumption was significantly higher than DOCE group. While lifespan showed a trend towards improvement in DOCE+SIE group, no significant difference was observed among the 4 studied groups. Tumor volume was not significantly affected in treated groups. A lower but not significant MKI67 protein expression was detected in western blot in DOCE+SIE group. The mRNA expression was not significantly different among groups.
The results suggest that the combination of soy isoflavone as an adjunct to docetaxel chemotherapy can be effective in improving diet consumption in breast cancer.
Kachexie ist eine Begleiterkrankung von Krebs, Aids oder rheumatoider Arthritis. Andere Symptome dieser Erkrankungen sind Depression sowie chronische Erschöpfung. Für alle diese Begleiterkrankungen, die die Lebensqualität der schwererkrankten Patienten negativ beeinflussen, wird eine Erhöhung von Entzündungsmediatoren (z.B. IL-6 und TNF-α) verantwortlich gemacht. Für Krebs wird eine Erniedrigung der Apoptose, ausgelöst durch eine Erhöhung von NFκB verantwortlich gemacht. Eine Gabe eines fermentierten Soja-Produktes, das in den USA seit 10 Jahren zur Verbesserung der Lebensqualität von Krebspatienten eingesetzt wird, wurde in einer prospektiven Studie untersucht: Für je 5 Patienten, die unter Prostata-, Ovar- oder Brustkrebs litten, konnte eine signifikante Verminderung von Kachexie, Stress und Depression festgestellt werden. Gleichzeitig konnte man für Prostata- und Ovarkrebs-Patienten eine Erhöhung der Genexpression apoptotischer Marker disseminierter Tumorzellen feststellen. Zusätzlich wurde eine starke Erhöhung der Genexpression des Tumorsuppressorgens p21 festgestellt. Auch wenn die prospektive Studie präliminär ist und die Anzahl der untersuchten Patienten zu klein, so widerspricht sie nicht unserer Annahme, dass es einen direkten Zusammenhang zwischen Krebs und Begleiterkrankungen, besonders der Kachexie, gibt.
Cancer initiating cells have been described to be the only cell population with tumorigenic capacity in glioblastoma multiforme, one of the most aggressive and untreatable cancers. Recent work from our group described that NFκB pathway was activated in glioblastoma initiating cells undergoing differentiation, and that blockade of this activation promoted senescence of differentiating cells. NFκB activation in cancer may be the result of either exposure to proinflammatory stimuli in the tumor microenvironment or upregulation of the signaling pathway by upstream regulators. Appropriate control of NFκB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NFκB related tumors, including glioblastoma. Here, we summarize the current knowledge of the relevance of NFκB in cancer and its possible role as a target of therapeutic intervention..
Dioscorealide B is an active compound from the rhizome of Dioscorea membranacea Pierre which locally known as "Hua-Khao-Yen". This medicinal plant has long been used in the anticancer prescription of Thai traditional medicine.
To examine the cytotoxic effect and mechanism of Dioscorealide B in human breast carcinoma cells.
Dioscorealide B was isolated from the rhizome of Hua KhaoYen (Dioscorea membranacea).The cytotoxicity of Dioscorealide B was evaluated in two human breast cancer cell lines, MCF-7 and MDA-MB 468 by Sulphorhodamine B (SRB) assay. RT-PCR and Caspase-Glo assay were used to further elucidate its cytotoxic mechanism.
Dioscorealide B showed cytotoxic effect on MCF-7 (IC50 = 2.76 microM) and MDA-MB 468 (IC50 = 9.93 microM). The mRNA level for p53, p21 and Bax were increased while Bcl-2 was decreased after the treatment. MCF-7 treated with Dioscorealide B showed the induction of apoptosis via the activation of caspase-9 and -7.
The results suggested that the mechanisms of Dioscorealide B might be involved in p53 and the intrinsic apoptotic pathway.
NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.
We have used in vitro and mouse xenograft models to examine the interaction between breast cancer stem cells (CSC) and bone marrow-derived mesenchymal stem cells (MSC). We show that both of these cell populations are organized in a cellular hierarchy in which primitive aldehyde dehydrogenase expressing mesenchymal cells regulate breast CSCs through cytokine loops involving IL6 and CXCL7. In NOD/SCID mice, labeled MSCs introduced into the tibia traffic to sites of growing breast tumor xenografts where they accelerated tumor growth by increasing the breast CSC population. With immunochemistry, we identified MSC-CSC niches in these tumor xenografts as well as in frozen sections from primary human breast cancers. Bone marrow-derived MSCs may accelerate human breast tumor growth by generating cytokine networks that regulate the CSC population.
In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry.
Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM).
Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4-hydroxylation pathway EM were 16% higher (P(trend) = 0.02) and 19% higher (P(trend) = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (P(trend) < 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States).
Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk.
Dendritic cells (DCs) in lymphoid tissue arise from precursors that also produce monocytes and plasmacytoid DCs (pDCs). Where
DC and monocyte lineage commitment occurs and the nature of the DC precursor that migrates from the bone marrow to peripheral
lymphoid organs are unknown. We show that DC development progresses from the macrophage and DC precursor to common DC precursors
that give rise to pDCs and classical spleen DCs (cDCs), but not monocytes, and finally to committed precursors of cDCs (pre-cDCs).
Pre-cDCs enter lymph nodes through and migrate along high endothelial venules and later disperse and integrate into the DC
network. Further cDC development involves cell division, which is controlled in part by regulatory T cells and fms-like tyrosine
kinase receptor-3.
This report illustrates that the beta-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis.
Tumours contain immune cells and a network of pro- and anti-inflammatory cytokines, which collaborate in the development and progression of cancer. Cytokine profiles might prove to be prognostic. The systemic effects of pro-inflammatory cytokines are associated with fatigue, depression and cognitive impairment, and can affect quality of life before, during and after treatment. In people with advanced cancer, pro-inflammatory cytokines are additionally associated with anorexia and cachexia, pain, toxicity of treatment and resistance to treatment. However, physical activity might modify cytokine levels and decrease fatigue in patients with cancer, and might also improve their prognosis.
Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention
Information on the urinary excretion of dehydroepiandrosterone (DHEA) and its direct metabolites is scarce for healthy subjects during growth. We used gas chromatography-mass spectrometry urinary steroid profiling to noninvasively study adrenarchal metabolome in 400 healthy subjects, aged 3-18 yr. Urinary 24-h excretion rates of DHEA did not increase significantly before age 7-8 yr. However, DHEA together with its 16alpha-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 3beta,16alpha,17beta-androstenetriol (DHEA&M), as well as the DHEA metabolite, 5-androstene-3beta,17beta-diol (ADIOL), and the sum of major urinary androgen metabolites (C19) rose consistently from the youngest to the oldest age group. The significant increases (P < 0.01) observed for 24-h excretion rates of C19, ADIOL, and DHEA&M were 2- to 4-fold in boys and girls between age 3 and 8 yr. DHEA&M, for example, rose from about 20 to 80 microg/d (P < 0.0001) during this period. Until the age of 16 yr, DHEA&M excretion also increased to nearly 1000 microg/d. Patterns of steroidogenic enzyme activities were assessed (from definite ratios of urinary steroid metabolites) for 21-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and 5alpha-reductase. Our results indicate for healthy boys and girls that adrenarche is a gradual process starting much earlier than hitherto believed. Efficient metabolism of DHEA, especially to 16-hydroxylated steroids, may explain the almost constant levels seen for this steroid until age 7-8 yr. The established reference values for DHEA, DHEA&M, ADIOL, C19 (including androsterone and etiocholanolone), and urinary parameters of steroidogenic enzyme activities could be useful to identify nutritional, environmental, and pathophysiological interrelations with the progressive maturational process of adrenarche. Our data may also be used as reference data for the diagnosis of steroid-related disorders.
The immune system is increasingly found to be involved in the development of several chronic illnesses, for which allopathic medicine has provided limited tools for treatment and especially prevention. In that context, it appears worthwhile to target the immune system in order to modulate the risk of certain chronic illnesses. Meanwhile, natural health products (NHPs) are generating renewed interest, particularly in the prevention and treatment of several chronic diseases. Over 20 scientists from fields related to immune function and NHPs were thus convened to establish the state of knowledge on these subjects and to explore future research directions. This review summarizes the result of discussions held during the symposium. It thus seeks to be thought provoking rather than to comprehensively cover such broad areas of research. Notably, a brief overview of the immune system is presented, including potentially useful targets and strategies to keep it in an equilibrated state, in order to prevent certain disorders. The pertinence and limitations of targeting the immune system to prevent chronic diseases is also discussed. The paper then discusses the usefulness and limitations of current experimental tools available to study the immune modulating effects of NHPs. Finally, a concise review of some of the most studied NHPs showing promising immunomodulatory activity is given, and avenues for future research are described.
New cancer therapeutic strategies must be investigated that enhance prostate cancer treatment while minimizing associated toxicities. We have previously shown that genistein, the major isoflavone found in soy, enhanced prostate cancer radiotherapy in vitro and in vivo. In this study, we investigated the cellular and molecular interaction between genistein and radiation using PC-3 human prostate cancer cells.
Tumor cell survival and progression was determined by clonogenic analysis, flow cytometry, EMSA analysis of NF-kappaB, and western blot analysis of cyclin B1, p21WAF1/Cip1, and cleaved PARP protein.
Genistein combined with radiation caused greater inhibition in PC-3 colony formation compared to genistein or radiation alone. Treatment sequence of genistein followed by radiation and continuous exposure to genistein showed optimal effect. Cell cycle analysis demonstrated a significant dose- and time-dependent G2/M arrest induced by genistein and radiation that correlated with increased p21WAF1/Cip1 and decreased cyclin B1 expression. NF-kappaB activity was significantly decreased by genistein, yet increased by radiation. Radiation-induced activation of NF-kappaB activity was strongly inhibited by genistein pre-treatment. A significant and striking increase in cleaved PARP protein was measured following combined genistein and radiation treatment, indicating increased apoptosis.
A mechanism of increased cell death by genistein and radiation is proposed to occur via inhibition of NF-kappaB, leading to altered expression of regulatory cell cycle proteins such as cyclin B and/or p21WAF1/Cip1, thus promoting G2/M arrest and increased radiosensitivity. These findings support the important and novel strategy of combining genistein with radiation for the treatment of prostate cancer.
The fact that auxin induces root formation has been known for more than half a century. However, despite the recent progress
in this field, neither the molecular processes in which the auxin-responsive genes leading to root formation nor the interactions
between phytohormones and other bioactive molecules during the commitment phase of root formation are well understood. Here
the effect of biomolecules such as cytokinin, glutathione, and flavonoids, as well as the expression of several transcription
factors in in vitro root formation in model legume Medicago truncatula are presented. It was demonstrated that auxin NAA (1-naphthaleneacetic acid) pretreatment for 7 d can irreversibly interrupt
somatic embryo formation, whilst both reduced and oxidized forms of glutathione enhance root formation via a mechanism independent
of ethylene perception, as determined by analysis of the ethylene-insensitive skl mutant. It was also shown that quercetin and the well-known auxin transport inhibitor NPA (N-1-naphthylphthalamic acid), which has a similar structure to quercetin, and isoflavonoids formononetin and genistein caused
severe reduction in root formation. Also, the relative expression of several transcription factors was analysed in 1-week-old
NAA-treated explants (stem cell niche formation stage), in NAA- and BAP-treated explants (no root formation), and in the roots
of germinated seeds. The results showed, for the first time in a legume, that the transcription factors homeodomain WOX5 and the AP2-domain containing PLETHORA1 and 2, BABY BOOM1 were strongly induced by auxin addition, while cytokinin addition dramatically reduced their expression, indicating a role
for these genes in the formation of root stem cell niches.
We previously showed that genistein, the major bioactive component of soy isoflavones, acts as a radiosensitizer and potentiates prostate tumor cell killing by radiation in vitro and in animal tumor models in vivo. However, when given alone in vivo, pure genistein promoted increased lymph node metastasis, which was not observed with a soy isoflavone mixture consisting of genistein, daidzein, and glycitein. In this study, we show that soy inhibit tumor cell growth and potentiates radiation-induced cell killing in vitro like pure genistein. In an orthotopic model, combining soy isoflavones with tumor irradiation inhibited prostate tumor growth. To determine the molecular mechanisms by which soy isoflavones potentiate radiotherapy, we investigated apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) and nuclear factor kappaB (NF-kappaB), two signaling molecules involved in survival pathways. Soy isoflavones decreased APE1/Ref-1 expression in vitro, whereas radiation up-regulated it. Pretreatment with soy isoflavones followed by radiation inhibited APE1/Ref-1 expression. APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-kappaB mediated by soy isoflavones and radiation, thus promoting cell killing. In vivo treatment of prostate tumors with soy isoflavones and radiation down-regulated APE1/Ref-1 protein expression and NF-kappaB activity, confirming the molecular alterations observed in vitro. The down-regulation of APE1/Ref-1 and NF-kappaB by isoflavones, in vitro and in vivo, supports our hypothesis that these markers represent biological targets of isoflavones. Indeed, a 2-fold increase in APE1/Ref-1 expression, obtained by cDNA transfection, resulted in a 2-fold increase in NF-kappaB DNA-binding activity, and both of which were down-regulated by soy isoflavones, confirming the cross-talk between these molecules and, in turn, causing radiosensitization.
The development of an effective pharmacological countermeasure is needed to reduce the morbidity and mortality in military and civilian populations associated with possible exposure to ionizing radiation. Previous studies in mice have shown that a single subcutaneous (sc) injection of the natural steroid androst-5-ene-3beta,17beta-diol (5-androstenediol, 5-AED), 24-48 h prior to a lethal dose of whole-body (60)Co gamma radiation, stimulated hematopoiesis and enhanced survival. These effects are consistent with our previous observation of 5-AED-induced elevations in circulating G-CSF in normal and irradiated mice. The purpose of this study was to obtain data on the pharmacokinetics of 5-AED after sc and buccal administration to mice, and to determine whether cytokine genes are induced by sc 5-AED in hematopoietic tissues (bone marrow, spleen). We studied effects on serum cytokines and chemokines, and also analyzed the pharmacokinetics of 5-AED after sc administration and compared it with buccal delivery. 5-AED was administered 24 h before irradiation or sham-irradiation. Cytokine mRNAs were quantified by quantitative real-time PCR (QRT-PCR), and cytokine levels in serum by multiplex Luminex. 5-AED administration was associated with elevation of message for GM-CSF, IL-2, IL-3, IL-6, and IL-10 in spleen, and GM-CSF and IL-2 in bone marrow. Irradiation enhanced G-CSF, GM-CSF, IFN-gamma, TPO, IL-2, IL-3, IL-6, IL-10, and IL-12 in spleen, and GM-CSF, IFN-gamma, TPO, IL-3, and IL-10 in bone marrow. Serum levels of G-CSF were significantly elevated in 5-AED-treated mice 4 h after irradiation or sham-irradiation. Serum macrophage inflammatory protein-1gamma (MIP-1gamma) was significantly elevated 4 h after irradiation in 5-AED-treated mice. Plasma 5-AED peaked 2 h after sc injection (30 mg/kg), and remained significantly above control after 4 days, but not 8 days. The time course of plasma 5-AED after buccal delivery (60 mg/kg) was similar, but levels were significantly lower compared to sc delivery. Plasma 5-AED 24 h after administration was not significantly different between sc and buccal delivery. However, in contrast to many studies showing enhanced survival after sc administration of 5-AED, we found no effect on survival of buccal 5-AED. The results suggest that radioprotection is not dependent on the 5-AED concentration at the time of irradiation, but rather on events triggered during the first few hours after administration. The current results suggest that further studies are warranted to directly test the roles of cytokines in the radioprotective effects of 5-AED.
The effects of genistein on 30-day survival and delayed lung injury were examined in C57BL/6J female mice. A single subcutaneous injection of vehicle (PEG-400) or genistein (200 mg/kg) was administered 24 h before total body irradiation (7.75 Gy (60)Co, 0.6 Gy/min). Experimental groups were: No treatment + Sham (NC), Vehicle + Sham (VC), Genistein + Sham (GC), Radiation only (NR), Vehicle + Radiation (VR), Genistein + Radiation (GR). Thirty-day survivals after 7.75 Gy were: NR 23%, VR 53%, and GR 92%, indicating significant protection from acute radiation injury by genistein. Genistein also mitigated radiation-induced weight loss on days 13-28 postirradiation. First generation lung fibroblasts were analyzed for micronuclei 24 h postirradiation. Fibroblasts from the lungs of GR-treated mice had significantly reduced micronuclei compared with NR mice. Collagen deposition was examined by histochemical staining. At 90 days postirradiation one half of the untreated and vehicle irradiated mice had focal distributions of small collagen-rich plaques in the lungs, whereas all of the genistein-treated animals had morphologically normal lungs. Radiation reduced the expression of COX-2, transforming growth factor-beta receptor (TGFbetaR) I and II at 90 days after irradiation. Genistein prevented the reduction in TGFbetaRI. However, by 180 days postirradiation, these proteins normalized in all groups. These results demonstrate that genistein protects against acute radiation-induced mortality in female mice and that GR-treated mice have reduced lung damage compared to NR or VR. These data suggest that genistein is protective against a range of radiation injuries.
Transforming growth factor beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is a key mediator of proinflammatory and stress signals. Activation of TAK1 by proinflammatory cytokines and T and B cell receptors induces the nuclear localization of nuclear factor kappaB (NF-kappaB) and the activation of c-Jun N-terminal kinase (JNK)/AP1 and P38, which play important roles in mediating inflammation, immune responses, T and B cell activation, and epithelial cell survival. Here, we report that TAK1 is critical for the survival of both hematopoietic cells and hepatocytes. Deletion of TAK1 results in bone marrow (BM) and liver failure in mice due to the massive apoptotic death of hematopoietic cells and hepatocytes. Hematopoietic stem cells and progenitors were among those hematopoietic cells affected by TAK1 deletion-induced cell death. This apoptotic cell death is autonomous, as demonstrated by reciprocal BM transplantation. Deletion of TAK1 resulted in the inactivation of both JNK and NF-kappaB signaling, as well as the down-regulation of expression of prosurvival genes.
Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.
Many cancer patients do not die due to impaired organ functions, but as a result of reduced general conditions, such as cachexia, sarcopenia, depression, infections, or stress. Reduced general health may be caused by immune modifying cytokines released from the tumor into the body. Improvement of immunity would not only reduce cancer side effects through inhibiting cytokine release from the tumor into the blood, but also, according to a new hypothesis, modify the cancer stem cells (CSC) in the tumor, which are believed to drive cancer growth and metastasis. We reported previously several investigations with a dietary fermented soy formulation (FSWW08) in cancer patients, where we saw a) strong reduction of cancer symptoms, b) broken resistance to chemotherapy, and c) a strong reduction of chemotherapy's toxic side effects, when taken in combination. This publication reports two new findings from a pilot study with postsurgical, treatment resistant patients conducted over four years. First, neither treatment resistance nor side effects were observed. Second, more patients have survived than expected. The improved health and immunity is detected together with increased CSC differentiation, suggesting lower aggressiveness, which was corroborated by increased gene expressions, particularly of steroidal hormones, MAPkinase, NF-κB, and tumor suppressor factor p53, a typical marker of "stemness" or cell differentiation. Although limited by its small, homogenous sample size, the results of this pilot study illustrate the relationship between CSCs differentiation, and the clinical symptoms of immunity, which influence survival outcomes and raise the clinical potential of measuring CSCs in ovarian, prostate, and breast cancers. The improved survival rates are also seen in larger cohort studies, which show similar gene expression profiles, which were induced by FSWW08 in the treatment resistant cancer patients in this study.
A clinical study was conducted to determine steroidal hormone cascade in the blood to relate them to mental performance with the Clinician-Administered PTSD scale (CAPS), serum lipid concentrations, and steroidal hormones, particularly cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), and pregnenolone, in treatment-resistant male veterans with combat-related chronic posttraumatic stress disorder (PTSD) before and after consumption of a special fermented soy formulation (FSWW08). Admitted veterans in the study were resistant to conventional psychological and pharmacological therapies.
Ten treatment-resistant soldiers with combat-related PTSD (according to the
FSWW08 increased blood levels of steroids, such as testosterone, estradiol, and particularly the adrenal hormones cortisol and androstenediol. Decreased steroidal hormones from the upper part of the hormone cascade, such as cholesterol, DHEA, and pregnenolone were experienced. The arteriosclerotic risk was reduced (cholesterol, 280±35 to 205±22 mmol/L, p
The rhizome of Dioscorea birmanica Prain & Burkill was commonly used by Thai folk doctors to treat cancer patients. The previous report was found that its extract exhibit high cytotoxic against lung cancer cells. Thus, the objective of this research was to investigate the cytotoxic activity against lung cancer cells using Dioscorea birmanica Prain & Burkill extract and an isolated cytotoxic compound therein. The ethanolic extract of Dioscorea birmanica Prain & Burkill showed cytotoxic activity against two types of lung cancer cell lines (CORL23 and A549) and against normal lung cells (MRC5) (IC50=8.7, 7.5 and 94.8µg/ml respectively) in the sulphorhodamine B assay [1,2]. Bioassay guided fractionation was used to isolate the cytotoxic saponin diosgenin-3-O-α-l-rhamnosyl (1 → 2)-β-d-glucopyranoside or Prosapogenin A of dioscin (DBS1). DBS1 showed high cytotoxic activity against two types of lung cancer cells; CORL23 and A 549 (IC50=1.8., 1.8µg/ml respectively) but less cytotoxic activity against normal lung cells MRC5 (IC50=37.1µg/ml). These results can support using this plant to treat cancer by Thai folk doctors. Acknowledgements: Thammasart University for financial support References: 1. Tharat, A. et al. (2004)J. of Ethnopharmacology 90:33–38. 2. Skehan P. et al.(1990)J.Natl. Cancer Inst. 82(13): 1107–12.
Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/−cells, and robust levels in NF1−/−cells. A 17β-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1−/− malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatet hormonal influence. Developmental Dynamics 237:513–524, 2008. © 2008 Wiley-Liss, Inc.
Deltonin is an active component purified from Dioscorea zingiberensis WRIGHT (DZW), and has shown anticancer effects. However, its mechanism of action remains elusive. In the present study, we investigated the effect of Deltonin on a panel of cancer cell lines and analyzed its mechanism in C26 cells, a murine colon carcinoma cell. Our results showed that Deltonin markedly inhibited the growth of all examined cancer cell lines. Deltonin induced dose- and time-dependent apoptosis in C26 cells. The event of apoptosis was accompanied by the release of cytochrome c, depolarization of mitochondrial membrane potential, and dose- and time-dependent reactive oxygen species (ROS) generation. Deltonin also increased the expression of Bax, decreased the expression of B-cell lymphoma/lewkmia-2 (Bcl-2), and induced the activation of caspase 9, caspase 3 and poly(ADP-ribose) polymerase (PARP). Furthermore, Deltonin decreased Akt and extracellular signal-regulated kinase-1/2 (ERK(1/2)) activity. These results demonstrate that Deltonin mediates the growth inhibition of cancer cells through multiple targets, which include the generation of reactive oxygen species (ROS), mitochondrial apoptosis and the inhibition of the mitogen-activated protein kinase (MAPK) and Akt signaling pathways, suggesting Deltonin is a potent cancer preventive and therapeutic agent.
The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.
To investigate the cytotoxic activity against lung cancer cells of Dioscorea birmanica Prain & Burkill extract and its compounds.
Cytotoxic activity was tested against two types of lung cancer cell line (A549 and CORL-23), one type of normal lung cell (MRC-5) by sulforhodamine B assay. Bioassay guide fractionation was used for isolating cytotoxic compounds. The structure elucidation of active ingredients was proven by spectrophotometry technique.
The results found that the ethanolic extract of Dioscorea birmanica Prain & Burkill (DBE) showed high cytotoxic activity against lung cancer cells; A 549 and COR-L23 (IC50 = 7.45 +/- 0.31, 8.71 +/- 0.29 microg/ml, respectively) but no cytotoxic activity against normal cancer cells MRC-5 (IC50 = 94.76 +/- 1.25 micro/ml). Six fractions from DBE were isolated by vaccuum liquid chromatography with ordering polarity of solvent and were coded as DB1-DB6, respectively. The fraction DB5 showed high cytotoxic against A 549 and COR-L23 (IC50 = 6.14 +/- 0.08 and 16.44 +/- 1.23 microg/ml, respectively) but less toxic to normal cell. Diosgenin-3-O-alpha-L-rhamnosyl (1-->2)-beta-D-glucopyranoside or Prosapogenin A of dioscin (DBS1) was isolated from DB5 fraction and had highest cytotoxic activity against those two types of lung cancer cells (IC50 = 1.81 +/- 0.03, 1.84 +/- 0.05 microg/ml), respectively) but less cytotoxic against normal lung cells MRC-5 (IC50 = 37.09 +/- 0.67 microg/ml).
The steroid saponin from Dioscorea birmanica showed cytotoxic activity against human lung cancer cells but less toxic against normal lung cells.
Two new steroidal saponins, diosbulbisides D (1) and E (2), along with five known saponins (3- 7) were isolated from the rhizomes of Dioscorea bulbifera L. Their structures were elucidated on the basis of spectral data. Compounds 6 and 7, two 3- O-trisaccharides of diosgenin spirostanes, showed moderate cytotoxic activity against human hepatocellular carcinoma cells, with IC₅₀ values of 3.89 µM and 7.47 µM on SMMC7721, and 10.87 µM and 19.10 µM on Bel-7402 cell lines, respectively.
The amount of soy products consumed in Japan is much greater than that in Western countries. Recent evidence indicates that soy isoflavones play a beneficial role in obesity, cancer, osteoporosis, and cardiovascular disease. The soybean isoflavone genistein is present at high levels in soy products. Genistein is structurally similar to 17beta-estradiol (E2), and genistein has been suggested to be act as E2 or an antagonist against E2. Genistein suppresses antigen-specific immune response in vivo and lymphocyte proliferation response in vitro. However, genistein enhances the cytotoxic response mediated by NK and cytotoxic T cells and the cytokine production from T cells. Thus, the effect of genistein on immunity is immune cell-dependent. Due to its unique effect on immune function, genistein has been used for the treatment of the diseases in animal models and it has been found that genistein inhibits allergic inflammatory responses. In this review, we summarize current studies related to the effect of isoflavone genistein on the immune system.
To estimate the effect of independent practice association (IPA) model HMOs and the Kaiser Foundation Health Plan's group model on inpatient utilization of Medicare beneficiaries in the last 2 years of life, compared with traditional fee-for-service (FFS) coverage.
Data from the Centers for Medicare & Medicaid Services were linked to inpatient discharge data from the California Office of Statewide Health Planning and Development for 1991-2001. A sample of aged Medicare beneficiaries who died between January 1998 and June 2001 and were continuously enrolled during the 2 years before death in (1) FFS (n = 234,498), (2) an IPA (n = 109,577), or (3) Kaiser (n = 29,434) were selected.
The probability of at least 1 hospitalization, number of inpatient days given at least 1 hospitalization, and total inpatient days per year in the last 2 years of life were estimated for each subgroup. A 2-part regression model, which adjusted for age, sex, Medicaid status, race, ethnicity, and chronic condition associated with the last hospitalization, was applied to determine the HMO-FFS difference in inpatient utilization during the last 2 years of life.
During their last 2 years of life, decedents in IPAs and Kaiser used approximately 34% and 51% fewer inpatient days, respectively, than decedents in FFS.
Medicare beneficiaries who died while enrolled in an HMO, particularly Kaiser, had many fewer hospital days during the 2 years before death than beneficiaries who died with FFS coverage.
Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. The anticarcinogenic protease inhibitors are extremely potent agents with the ability to prevent cancer, with some unique characteristics as anticarcinogenic agents. The anticarcinogenic protease inhibitors have the ability to irreversibly suppress the carcinogenic process. They do not have to be continuously present to suppress carcinogenesis. They can be effective when applied in both in vivo and in vitro carcinogenesis assay systems at long time periods after carcinogen exposure, and are effective as anticarcinogenic agents at extremely low molar concentrations. While several different types of protease inhibitors can prevent the carcinogenic process, the most potent of the anticarcinogenic protease inhibitors on a molar basis are those with the ability to inhibit chymotrypsin or chymotrypsin-like proteases. The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is a potent chymotrypsin inhibitor that has been extensively studied for its ability to prevent carcinogenesis in many different model systems. Much of this review is focused on the characteristics of BBI as the anticarcinogenic protease inhibitor, as this is the protease inhibitor that has risen to the human trial stage as a human cancer chemopreventive agent. Part of this review hypothesizes that the Bowman-Birk family of protease inhibitors plays a role in plants similar to that of alpha1-antichymotrypsin in people. Both BBI and alpha1-antichymotrypsin are potent inhibitors of chymotrypsin and chymotrypsin-like enzymes, are highly anti-inflammatory, and are thought to play important roles in the defense of their respective organisms. It is believed that BBI will be shown to play a major role in the prevention and/or treatment of several different diseases, in addition to cancer.
Cachexia represents the clinical consequence of a chronic, systemic inflammatory response, and its manifestations differ considerably from those of starvation. Although cachexia is classically associated with chronic infections and malignant conditions, some of its elements have been identified in a wide variety of chronic diseases and in aging persons. Cachexia has repeatedly been associated with adverse clinical outcomes. The changes seen in cachexia are multidimensional and highly coordinated. Most obvious is a redistribution of the body's protein content, with preferential depletion of skeletal muscle and an increase in the synthesis of proteins involved in the response to tissue injury-the so-called acute-phase response. The physiologic, metabolic, and behavioral changes of cachexia are tightly regulated by cytokines, which signal the synthesis of acute-phase proteins as well as changes in intermediary metabolism that provide substrate and energy. The metabolic adaptations, notably the increase in the rate of protein degradation, limit the ability of hypercaloric feeding to reverse the depletion of lean mass. Recent studies have demonstrated the ability of anabolic and anticatabolic agents to mitigate the loss of skeletal muscle and to improve clinical outcomes in selected circumstances. Preclinical initiatives target the cytokine regulation of protein metabolism. It should be stressed that metabolic manipulation in cachexia could have positive or negative clinical effects, which must be distinguished through appropriate clinical trials.
Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table (Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.
In most cells, the NF-kappaB transcription factor is sequestered in the cytoplasm by interaction with inhibitory proteins, the IkappaBs. Here, we show that combined IkappaBalpha/IkappaBepsilon deficiency in mice leads to neonatal death, elevated kappaB binding activity, overexpression of NF-kappaB target genes, and disruption of lymphocyte production. In IkappaBalpha/IkappaBepsilon-deficient fetuses, B220+IgM+ B cells and single-positive T cells die by apoptosis. In adults, IkappaBalpha-/-IkappaBepsilon-/- reconstituted chimeras exhibit a nearly complete absence of T and B cells that is not rescued by cotransfer with wild-type bone marrow. These findings demonstrate that IkappaBs tightly control NF-kappaB activity in vivo and that increased NF-kappaB activity intrinsically impairs lymphocyte survival. Because reduction or rise of NF-kappaB activity leads to similar dysfunction, they also reveal that only a narrow window of NF-kappaB activity is tolerated by lymphocytes.
Since it is known that androstenediol (ADIOL) has potent immunoregulatory effects, changes in ADIOL levels during and after pregnancy might affect the maternal immune system. We examined serum concentrations of ADIOL and androstenediol 3-sulfate (ADIOLS) together with IFN-gamma and IL-4 production levels during pregnancy and after delivery up to 10-11 months postpartum. The subjects were 73 normal pregnant, 76 normal postpartum, and 28 normal non-pregnant women. ADIOL and ADIOLS were measured using EIA and GC/MS, respectively. The cytokine levels in the supernatant of whole-blood cultures stimulated with phorbol 12-myristate 13-acetate and ionomycin were measured using ELISA. ADIOL levels significantly decreased compared to non-pregnant levels in the first trimester (P < 0.05) and were reversed in the third trimester (P < 0.05). After pregnancy, ADIOL levels gradually declined, and a significant decrease was observed at 10-11 months postpartum (P < 0.05). ADIOLS levels were significantly lower in the third trimester (P < 0.05) and significantly higher at the first month postpartum (P < 0.001) compared to non-pregnant women. IFN-gamma and IL-4 levels decreased during pregnancy and subsequently increased postpartum. On the other hand, we found significant negative correlations between ADIOL concentrations and production levels of IFN-gamma (P < 0.05) or IL-4 (P < 0.05). These findings suggest that ADIOL may be involved in modifying the maternal immune response during and after pregnancy.
Radiation protection from death and stimulating hematopoietic recovery by oral administrations of genistein, 160 mg/kg b.w., once daily for seven consecutive days before whole-body gamma-rays irradiation, were confirmed by tests with adult male BALB/c mice. Moreover, the protective action of genistein was compared to that of diethylstilbestrol (DES). Based on the studies of survival, behavior of hematograms, endogenous hematopoietic spleen colony formation (endoCFUs), and numbers of nucleated cell, granulocyte-macrophage colony forming units (CFU-GM) in bone marrow following irradiation, it was demonstrated that genistein was an effective radioprotector. The survival of irradiated mice protected by genistein was significantly increased and statistically higher than that of mice pre-treated with DES. Stimulated recovery of leukocytes, erythrocytes, lymphocytes and thrombocytes were observed in mice pre-treated with genistein or DES, however, the effects of genistein on promoting recovery of bone marrow nucleated cells, leukocytes and lymphocytes were significantly higher than those of DES. Enhanced endoCFUs, numbers of bone marrow nucleated cells and CFU-GM were also found in mice pre-treated with genistein as well as DES. Meanwhile, endoCFU numbers in mice pre-treated with genistein was 3.47-fold higher than that in the irradiated control group, although no significant difference was found between genistein administration and DES administration. It could be deduced that the radioprotective action against death is induced by a possible process of enhanced regeneration of the hematopoietic stem cells due to not only strengthened radioresistance and increased numbers of remained hematopoietic cells, but also enhanced post-irradiation repair or promoted proliferation of the hematopoietic stem cells. These effects of genistein may have some therapeutic implications for radiation-induced injuries.
Although androstenediol (adiol or 5-androstene-3beta,17beta-diol), a metabolite of dehydroepiandrosterone (DHEA), has protective effects following trauma-hemorrhage (T-H), it remains unknown whether administration of adiol has any salutary effects on the inflammatory response and outcome following a combined insult of T-H and sepsis. Male rats underwent T-H shock [mean arterial pressure (MAP) 40 mmHg for 90 min] followed by resuscitation. Adiol (1 mg/kg body wt) or vehicle was administered at the end of resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) at 20 h after T-H or sham operation. Five hours after CLP, plasma and tissue samples were analyzed for cytokines (IL-6 and IL-10), MPO, neutrophil chemotactic factor (CINC-3), and liver injury (alanine aminotransferase and lactate dehydrogenase). In another group of rats, the gangrenous cecum was removed at 10 h after CLP, the cavity was irrigated with warm saline and closed in layers, and mortality was recorded over 10 days. T-H followed by CLP produced a significant elevation in plasma IL-6 and IL-10 levels, enhanced neutrophil cell activation, and resulted in liver injury. Adiol administration prevented the increase in cytokine production, neutrophil cell activation, and attenuated liver injury. Moreover, rats subjected to the combined insult, receiving vehicle or adiol, had a 50% and 6% mortality, respectively. Since adiol administration suppresses proinflammatory cytokines, reduces liver damage, and decreases mortality after the combined insult of T-H and sepsis, this agent appears to be a novel adjunct to fluid resuscitation for decreasing T-H-induced septic complications and mortality.
5-Androstenediol (5-AED) stimulates hematopoiesis and enhances survival in animals exposed to ionizing radiation (IR), suggesting that this steroid may act on hematopoietic progenitor cells. We used gamma-irradiated primary human CD34(+) hematopoietic progenitor cells to show that 5-AED protects hematopoietic cells from IR damage, as shown by enhanced cell survival, clonogenicity, proliferation, and differentiation. Unlike in tumor cells, IR did not induce nuclear factor-kappaB (NFkappaB) activation in primary progenitors. However, IR stimulated IkappaB(beta) release from NFkappaB/IkappaB complexes and caused NFkappaB1 (p50) degradation. 5-AED stabilized NFkappaB1 in irradiated cells and induced NFkappaB gene expression and NFkappaB activation (DNA binding). 5-AED stimulated interleukin-6 and granulocyte colony-stimulating factor (G-CSF) secretion. The survival-enhancing effects of 5-AED on clonogenic cells were abrogated by small interfering RNA inhibition of NFkappaB gene expression and by neutralization of G-CSF with antibody. The effects of 5-AED on survival and G-CSF secretion were blocked by the NFkappaB inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). 5-AED had no effect on accumulation of the proapoptotic factor p53 after IR, as determined by Western blot. The results indicate that NFkappaB1 degradation after IR may be responsible for the radiation sensitivity of CD34+ cells compared with tumor cells. 5-AED exerts survival-enhancing effects on irradiated human hematopoietic progenitor cells via induction, stabilization, and activation of NFkappaB, which results in increased secretion of hematopoietic growth factor G-CSF.
Nuclear factor-kappaB pathway plays important roles in the control of cell proliferation, differentiation, apoptosis, inflammation, stress response, cell signaling transduction, and other physiological processes. Because the disorder of these physiological processes has been linked with the onset of cancers, NF-kappaB has been described as a major culprit in cancer. Experimental in vitro and in vivo studies have shown that down-regulation of NF-kappaB activity by natural and synthetic NF-kappaB inhibitors suppresses the development of carcinogen-induced tumors, inhibits the growth of cancer cells, and induces apoptosis with alternation of gene expression which is critical for the control of carcinogenesis and cancer cell survival. Moreover, recent studies indicate that the effects of conventional cancer therapeutics could be enhanced by natural and synthetic NF-kappaB inhibitors, suggesting that down-regulation of NF-kappaB could sensitize cancer cells to conventional therapeutics. Therefore, targeting NF-kappaB is a novel preventive and therapeutic strategy against human cancers. In this brief review article, we will summarize the state of our knowledge for the role of NF-kappaB in relation to cancer prevention and therapy.
Objective:
In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF).
Methods:
All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients.
Results:
By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes.
Conclusion:
The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.
A benign human plexiform neurofibroma cell. Note the extensive tubulin networks (red), which become disrupted after addition of 2ME2, an estrogen metabolite implicated in tumor toxicity. The green staining represents S100 staining, indicating the Schwann Cell origin of the tumor cells. Blue is DAPI nuclear staining. See Roth et al., Developmental Dynamics 237:513-524, 2008. (c) 2008 Wiley-Liss, Inc.
Malignant effusions offer a unique opportunity for the study of interactions between the human immune system and cancer. We have recently demonstrated that malignant effusions are characterized by an accumulation of T cells expressing chemokine receptors such as CCR4, which is commonly found on Th2 cells. In contrast, effector T cells expressing chemokine receptors typical for Th1 cells, such as CCR5, showed a diminished homing into malignant effusions.
We analyzed concentrations of 12 different cytokines and 9 chemokines within malignant and nonmalignant effusions and investigated cytokine expression by effusion-infiltrating leukocytes.
We observed that concentrations of the immunoregulatory cytokine TGF-beta(1) and of angiogenic factors VEGF and IL-8 were markedly increased within effusions caused by malignancies. However, we did not observe signs of a typical Th1 or Th2 milieu. Analyzing concentrations of 9 different chemokines, we found elevated concentrations of the chemokines MDC, eotaxin, I-TAC, and MCP-1 in malignant effusions. Interestingly, tumor-infiltrating leukocytes themselves seemed to contribute strongly to the creation of a distinct cytokine/chemokine pattern within cancer-related effusions. Additional analyses suggested that this cytokine/chemokine milieu might support an enrichment of immunosuppressive leukocytes.
The local cytokine and chemokine milieu within malignant effusions seems to promote angiogenesis and to block an efficient immune-mediated antitumor response. An elimination of such tumor-promoting influences will be necessary in order to transform local immunotolerance into clinically relevant immune recognition of tumors causing malignant effusions.
AR agents inhibitors
- Kennedy
Physiologischer Einfluss adrenaler Androgene und Glucocorticoide auf den Unterarmknochen im Wachstumsalter bei gesunden Kindern Dissertation Available athttp www diss fu berlin de
- Boye
Medicare HMO impact on utilization at the end of life
- K Fonkych
- O Leary
- J F Melnick
- G A Keeler
Physiologischer Einfluss adrenaler Androgene und Glucocorticoide auf den Unterarmknochen im Wachstumsalter bei gesunden Kindern
- K R Boye