Effect Of Co-treatment Research Articles

Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment

Despite recent progress, systemic delivery remains the major hurdle for development of safe and effective small inhibitory RNA (siRNA)-based therapeutics. Encapsulation of siRNA into liposomes is a promising option to overcome obstacles such as low stability in serum and inefficient internalization by target cells. However, a major liability of liposomes is the potential to induce an acute inflammatory response, thereby increasing the risk of numerous adverse effects. In this study, we characterized a liposomal siRNA delivery vehicle, LNP201, which is capable of silencing an mRNA target in mouse liver by over 80%. The biodistribution profile, efficacy after single and multiple doses, mechanism of action, and inflammatory toxicity are characterized for LNP201. Furthermore, we demonstrate that the glucocorticoid receptor (GR) agonist dexamethasone (Dex) inhibits LNP201-induced cytokine release, inflammatory gene induction, and mitogen-activated protein kinase (MAPK) phosphorylation in multiple tissues. These data present a possible clinical strategy for increasing the safety profile of siRNA-based drugs while maintaining the potency of gene silencing.

Melatonin Potentiates the Neuroprotective Properties of Resveratrol Against Beta-Amyloid-Induced Neurodegeneration by Modulating AMP-Activated Protein Kinase Pathways

Background and PurposeRecent studies have demonstrated that resveratrol (RSV) reduces the incidence of age-related macular degeneration, Alzheimer's disease (AD), and stroke, while melatonin (MEL) supplementation reduces the progression of the cognitive impairment in AD patients. The purpose of this investigation was to assess whether the co-administration of MEL and RSV exerts synergistic effects on their neuroprotective properties against β-amyloid (Aβ)-induced neuronal death.MethodsThe neuroprotective effects of co-treatment with MEL and RSV on Aβ1-42-induced cell death, was measured by MTT reduction assay. Aβ1-42 caused an increase in intracellular levels of reactive oxygen species (ROS), as assessed by H2-DCF-DA dye, and a reduction of total glutathione (GSH) levels and mitochondrial membrane potential, as assessed using monochlorobimane and rhodamine 123 fluorescence, respectively. Western blotting was used to investigate the intracellular signaling mechanism involved in these synergic effects.ResultsWe treated a murine HT22 hippocampal cell line with MEL or RSV alone or with both simultaneously. MEL and RSV alone significantly attenuated ROS production, mitochondrial membrane-potential disruption and the neurotoxicity induced by Aβ1-42. They also restored the Aβ1-42-induced depletion of GSH, back to within its normal range and prevented the Aβ1-42-induced activation of glycogen synthase kinase 3β (GSK3β). However, co-treatment with MEL and RSV did not exert any significant synergistic effects on either the recovery of the Aβ1-42-induced depletion of GSH or on the inhibition of Aβ1-42-induced GSK3β activation. Aβ1-42 treatment increased AMP-activated protein kinase (AMPK) activity, which is associated with subsequent neuronal death. We demonstrated that MEL and RSV treatment inhibited the phosphorylation of AMPK.ConclusionsTogether, our results suggest that co-administration of MEL and RSV acts as an effective treatment for AD by attenuating Aβ1-42-induced oxidative stress and the AMPK-dependent pathway.

Homocysteine Reduces Sperm Motility via Elevation of Mitochondrial Superoxide Anions in Normal and Subfertile subjects: Potential Effect of Co-treatment with Folic acid

Homocysteine Reduces Sperm Motility via Elevation of Mitochondrial Superoxide Anions in Normal and Subfertile subjects: Potential Effect of Co-treatment with Folic acid

Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers.

Chlorophyll (Chla) and chlorophyllin (CHL) were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans, where CHL reduced excretion of aflatoxin B(1) (AFB(1))-DNA repair products in Chinese unavoidably exposed to dietary AFB(1). However, neither AFB(1) pharmacokinetics nor Chla effects were examined. We conducted an unblinded crossover study to establish AFB(1) pharmacokinetic parameters among four human volunteers, and to explore possible effects of CHL or Chla cotreatment in three of those volunteers. For protocol 1, fasted subjects received an Institutional Review Board-approved dose of 14C-AFB(1) (30 ng, 5 nCi) by capsule with 100 mL water, followed by normal eating and drinking after 2 hours. Blood and cumulative urine samples were collected over 72 hours, and 14C- AFB(1) equivalents were determined by accelerator mass spectrometry. Protocols 2 and 3 were similar except capsules also contained 150 mg of purified Chla or CHL, respectively. Protocols were repeated thrice for each volunteer. The study revealed rapid human AFB(1) uptake (plasma k(a), 5.05 + or - 1.10 h(-1); T(max), 1.0 hour) and urinary elimination (95% complete by 24 hours) kinetics. Chla and CHL treatment each significantly impeded AFB(1) absorption and reduced Cmax and AUCs (plasma and urine) in one or more subjects. These initial results provide AFB(1) pharmacokinetic parameters previously unavailable for humans, and suggest that Chla or CHL co-consumption may limit the bioavailability of ingested aflatoxin in humans, as they do in animal models.

Influence of statin treatment on platelet inhibition by clopidogrel – a randomized comparison of rosuvastatin, atorvastatin and simvastatin co‐treatment

Possible interactions between clopidogrel and atorvastatin, simvastatin or rosuvastatin (a 'non-CYP3A4' metabolized statin) were investigated in a randomized prospective study using sensitive and specific ex vivo platelet function tests. Patients with coronary artery disease participating in a double-blind study comparing lipid-lowering effects of atorvastatin (20-80 mg OD; n = 22) and rosuvastatin (10-40 mg OD; n = 24) were studied before and after 2 weeks treatment with clopidogrel 75 mg OD after completed statin dose titration. In addition, 23 patients were randomized to open-label simvastatin 40 mg OD. Clopidogrel inhibited 10 mumol L(-1) ADP-induced platelet aggregation by 40 +/- 27%, 57 +/- 28% and 51 +/- 29%, respectively, in patients on rosuvastatin, atorvastatin and simvastatin treatment. The other platelet tests yielded similar results. No dose-dependent effects of rosuvastatin or atorvastatin co-treatment on clopidogrel efficacy were observed. Treatment with CYP3A4 metabolized statins, atorvastatin or simvastatin, did not attenuate the platelet inhibitory effect of clopidogrel maintenance treatment compared with the non-CYP3A4 metabolized, rosuvastatin.

P1048 Effect of co-treatment of UIC2 monoclonal antibody and Pgp modulators on 99mTc-MIBI and 18FDG accumulation in multidrug resistant and sensitive human ovarian carcinoma cells

International Journal of Gynecology & ObstetricsVolume 107, Issue S2 p. S706-S707 Poster presentations P1048 Effect of co-treatment of UIC2 monoclonal antibody and Pgp modulators on 99mTc-MIBI and 18FDG accumulation in multidrug resistant and sensitive human ovarian carcinoma cells Z. Krasznai, Z. KrasznaiSearch for more papers by this authorM. Pal, M. PalSearch for more papers by this authorF. Zoltan, F. ZoltanSearch for more papers by this authorT. Agnes, T. AgnesSearch for more papers by this authorS. Gábor, S. GáborSearch for more papers by this authorG. Katalin, G. KatalinSearch for more papers by this authorG. Laszlo, G. LaszloSearch for more papers by this authorH. Zoltan, H. ZoltanSearch for more papers by this author Z. Krasznai, Z. KrasznaiSearch for more papers by this authorM. Pal, M. PalSearch for more papers by this authorF. Zoltan, F. ZoltanSearch for more papers by this authorT. Agnes, T. AgnesSearch for more papers by this authorS. Gábor, S. GáborSearch for more papers by this authorG. Katalin, G. KatalinSearch for more papers by this authorG. Laszlo, G. LaszloSearch for more papers by this authorH. Zoltan, H. ZoltanSearch for more papers by this author First published: 20 November 2009 https://doi.org/10.1016/S0020-7292(09)62534-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume107, IssueS2Abstracts of XIX FIGO World Congress of Gynecology and ObstetricsOctober 2009Pages S706-S707 RelatedInformation

LLL-3, a STAT3 inhibitor, represses BCR-ABL-positive cell proliferation, activates apoptosis and improves the effects of Imatinib mesylate

The chimeric protein BCR-ABL, a constitutively active protein-tyrosine kinase, triggers downstream signalling proteins, such as STAT3, ultimately resulting in the survival of myeloid progenitors in BCR-ABL-positive leukemias. Here, we evaluated the effect of LLL-3, an inhibitor of STAT3 activity, on cell viability and its addictive effects with Imatinib mesylate (IM) treatment in BCR-ABL-positive cells. Viability of cell lines was determined using the WST-1 assay in response to drug treatment, either LLL-3 alone or in conjunction with IM. Annexin V-FITC/PI staining, sub-G1 DNA content and Caspase-3/7 activation assays were performed to evaluate apoptosis. LLL-3 treatment decreased cell viability, triggered apoptosis and activated Caspases-3/7 in K562 cells. LLL-3 increases IM treatment to inhibited cell viability and activation of apoptosis in BCR-ABL-positive cell lines. LLL-3 reduced cell viability and induced apoptosis in K562 cells. Moreover, the observed addictive effects of co-treatment with IM and LLL-3 suggest this combination has therapeutic potential.

Effects of Cotreatment of 12‐O‐tetradecanoylphorbol‐13‐acetate and H2O2 on Apoptotic Regulation via AMP‐Activated Protein Kinase–Cyclooxygenase‐2 Signals

Colorectal cancer displays elevated cyclooxygenase-2 (COX-2) expression, and several studies have suggested that COX-2 expression is associated with parameters of aggressive colon cancer. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and recent studies indicate that AMPK activation strongly suppresses cell proliferation in nonmalignant cells as well as in tumor cells. As a metabolic sensing signal, AMPK is involved in cancer cell apoptosis. In HT-29 colon cancer cells, the regulation of COX-2 expression by treating with TPA (12-O-tetradecanoylphorbol-13-acetate), low-level H(2)O(2), high-level H(2)O(2), and finally the combinations of TPA and low H(2)O(2) or high H(2)O(2) was investigated. We found that COX-2 expression levels with treatment reacted as follows: with TPA alone > TPA and low H(2)O(2) > low H(2)O(2) > high H(2)O(2) > TPA and high H(2)O(2). COX-2 regulation by these agents was accompanied by the alteration of AMPK control. The apoptotic bodies were detected as follows: high level of H(2)O(2) > TPA > low level of H(2)O(2). The present findings suggest that both COX-2 stimulators (TPA and H(2)O(2)) might have differential effects on COX-2 and AMPK regulation and further apoptotic regulation.

Effects of adiponectin and leptin co-treatment on human breast cancer cell growth

Obesity is a risk factor for postmenopausal breast cancer (BC), but the specific mechanisms for this relationship are not well understood. Studies on adipocyte-derived adiponectin and leptin reveal opposing effects on BC cell proliferation in vitro, suggesting they may play a role in BC pathogenesis. In the current study we examined effects on proliferation of five BC cell lines treated with varying adiponectin:leptin (A/L) ratios. A decrease in proliferation was noted for MCF-7 and T47-D cells with increasing ratios (2-500), while an increase was seen in similarly treated MDA-MB-231 and MDA-MB-361 cells. For SK-BR-3 cells, an increase was seen at a ratio of 8. We identified differential effects on some pro-mitogenic, survival and apoptosis-related proteins in MCF-7 and T47-D cells treated at an A/L ratio of 100. Specifically, the AKT and MAPK pathways were not activated in MCF-7 cells, but AKT activation occured within 30 min and MAPK activation was sustained at 48 h in T47-D cells. p53 and Bax were elevated in MCF-7, but were below basal in T47-D cells at 30 min. While co-treatment enhanced apoptosis in MCF-7, similar treatment had the opposite effect in T47-D cells. There were no differences in cell cycle distribution between treated or untreated MCF-7 or T47-D, although T47-D cells had a slightly higher proportion in the G1/G0 phase after co-treatment. The effects of A/L ratio on mediating proliferation may have some specificity since the cell lines exhibited different responses. This may explain previous inconsistencies for the relationship of serum leptin with BC. More studies are needed to better understand the complex interactions that exist between these two adipokines.

Synergistic interaction of proteasome and topoisomerase II inhibition in multiple myeloma

Multiple myeloma is a malignancy of terminally differentiated plasma cells and is incurable in the majority of the patients. Thus, novel effective treatment regimens are urgently needed. In this study, we examined the effects of co-treatment with proteasome-inhibitor bortezomib and topoisomerase II inhibitor etoposide in multiple myeloma cells lines OPM-2, RPMI-S and NCI-H929. Using the median effect method of Chou and Talalay, we evaluated the combination indices (CI) for simultaneous and sequential treatment schedules. In the sequential treatment schedule, we found strong synergistic effects in all three cell lines, even at low single-agent cytotoxicity levels. When cells were treated simultaneously with both drugs, the synergy was present but less pronounced than in the sequential treatment schedule. The synergistic effects observed in the co-treatment schedules were accompanied by an inhibition of anti-apoptotic effects that were induced by etoposide alone. Namely, bortezomib abrogated both etoposide-induced NF–κB activation and etoposide-induced bcl-2 up-regulation. Our data suggest that combining etoposide with bortezomib might be useful for cancer treatment, as bortezomib potentially inhibits counter-regulatory mechanisms of tumor cells, which are induced by topoisomerase II inhibition and which may contribute to acquired chemoresistance.

Effects of anticancer agents and scavengers on CMV-promoter-driven exogenous gene expression in genetically modified cells

This study aimed to investigate whether the levels of rsGFP mRNA and the fluorescence levels of cytomegalovirus (CMV)-promoter-driven rsGFP (red-shifted green fluorescent protein) could be changed by using anticancer agents and also to examine the effects of co-treatment with anticancer agents and scavengers. The pQBI25 vector, which encodes the CMV promoter and the cDNA for rsGFP, was transfected into FR cells (rat skin fibroblast cell line). FR-pQBI25 cells were then exposed to doxorubicin, 5-fluorouracil, methotrexate or paraquat with or without scavengers such as N-acetyl cysteine (NAC) and edaravone for 48 h. The levels of rsGFP mRNA were found to be significantly higher following doxorubicin, 5-fluorouracil and paraquat treatment but were not changed by methotrexate. These levels of rsGFP mRNA were found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone. The fluorescence levels of rsGFP were found to be significantly higher following doxorubicin and paraquat treatment but were not changed by 5-fluorouracil and methotrexate. The levels were also found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone and also after doxorubicin/NAC co-treatment compared with doxorubicin alone. These findings suggest that CMV-promoter-driven exogenous gene expression may be partly regulated by reactive oxygen species.

Effect of organic tomato ( Lycopersicon esculentum ) extract on the genotoxicity of doxorubicin in the Drosophila wing spot test

The consumption of organic tomatoes (ORTs) reduces the risk of harmful effects to humans and the environment caused by exposure to toxic agrochemicals. In this study, we used the somatic mutation and recombination test (SMART) of wing spots in Drosophila melanogaster to evaluate the genotoxicity of ORT and the effect of cotreatment with ORT on the genotoxicity of Doxorubicin® (DXR, a cancer chemotherapeutic agent) that is mediated by free radical formation. Standard (ST) cross larvae were treated chronically with solutions containing 25%, 50% or 100% of an aqueous extract of ORT, in the absence and presence of DXR (0.125 mg/mL), and the number of mutant spots on the wings of emergent flies was counted. ORT alone was not genotoxic but enhanced the toxicity of DXR when administered concomitantly with DXR. The ORT-enhanced frequency of spots induced by DXR may have resulted from the interaction of ORT with the enzymatic systems that catalyze the metabolic detoxification of this drug.

Nucleotide Oligomerization Domain-2 (NOD2)-Induced Uveitis: Dependence on IFN-γ

Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-gamma, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis. Mice deficient in IFN-gamma, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-gamma. IFN-gamma production in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy. NOD2 activation resulted in the production of IFN-gamma within the eye. Deficiency in IFN-gamma diminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-gamma markedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-gamma to enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-gamma and MDP cotreatment on adhering and infiltrating cells. IFN-gamma was identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-gamma in vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-gamma may occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.

The interaction of butyrate with TNF-α during differentiation and apoptosis of colon epithelial cells: Role of NF-κB activation

We demonstrated that TNF-α suppressed differentiation and potentiated cell death induced by butyrate (NaBt) in both adenocarcinoma HT-29 and fetal FHC human colon cells in vitro. Since TNF-α is a typical activator of NF-κB pathway, we studied the role of NF-κB activation in cell differentiation and death during the TNF-α and NaBt co-treatment. TNF-α induced rapid NF-κB activation in both HT-29 and FHC cell lines and this effect was differently modulated by NaBt in these two cell lines. In HT-29 cells, NaBt potentiated NF-κB activity induced by TNF-α after 4 h treatment. However, this initial potentiation of NF-κB activity was not observed in FHC cells. During additional time of TNF-α and NaBt co-treatment, NaBt decreased the TNF-α-mediated NF-κB activity in both cell types. We also detected a different response of HT-29 and FHC cells after the pre-treatment with the NF-κB inhibitor parthenolide. Our results indicated that NaBt-mediated differentiation and apoptosis of colon epithelial cells can be modulated by TNF-α. Furthermore, we found significant differences in the mechanism of the NaBt and TNF-α co-treatment effects between cells of non-cancer and cancer origin, suggesting that the NF-κB pathway may be more effectively involved in these processes in cancer cells.

Renin Inhibitor Aliskiren Improves Impaired Nitric Oxide Bioavailability and Protects Against Atherosclerotic Changes

We investigated whether aliskiren, a direct renin inhibitor, improves NO bioavailability and protects against spontaneous atherosclerotic changes. We also examined the effects of cotreatment with aliskiren and valsartan, an angiotensin II receptor blocker, on the above-mentioned outcomes. Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), aliskiren, valsartan, or aliskiren plus valsartan for 8 weeks. Then, acetylcholine-induced NO production was measured as a surrogate index of endothelium protective function, and both superoxide and vascular peroxynitrite were measured. Tetrahydrobiopterin in aortic segments was assessed by high-performance liquid chromatography with fluorescence detection. Plaque area was quantified by histology. Increase in plasma NO concentration in response to intra-aortic acetylcholine infusion was significantly greater in all of the test groups than in controls. Aliskiren+valsartan cotreatment increased acetylcholine-induced NO by 6.2 nmol/L, which was significantly higher than that with either aliskiren or valsartan alone. Vascular superoxide and peroxynitrite levels were both significantly higher in controls and significantly lower in the aliskiren+valsartan group than in the aliskiren or valsartan group. The highest tetrahydrobiopterin levels were observed after aliskiren+valsartan cotreatment. Histology of the thoracic aorta revealed that the plaque area was significantly decreased with combination therapy compared with monotherapy. Treatment with a direct renin inhibitor has protective effects on endothelial function and atherosclerotic changes. Furthermore, cotreatment with a direct renin inhibitor and an angiotensin II receptor blocker has additive protective effects on both.

A Small Molecule Inhibitor of Isoprenylcysteine Carboxymethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells

A number of proteins involved in cell growth control, including members of the Ras family of GTPases, are modified at their C terminus by a three-step posttranslational process termed prenylation. The enzyme isoprenylcysteine carboxylmethyl-transferase (Icmt) catalyzes the last step in this process, and genetic and pharmacological suppression of Icmt activity significantly impacts on cell growth and oncogenesis. Screening of a diverse chemical library led to the identification of a specific small molecule inhibitor of Icmt, cysmethynil, that inhibited growth factor signaling and tumorigenesis in an in vitro cancer cell model (Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., and Casey, P. J. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 4336-4341). To further evaluate the mechanisms through which this Icmt inhibitor impacts on cancer cells, we developed both in vitro and in vivo models utilizing PC3 prostate cancer cells. Treatment of these cells with cysmethynil resulted in both an accumulation of cells in the G(1) phase and cell death. Treatment of mice harboring PC3 cell-derived xenograft tumors with cysmethynil resulted in markedly reduced tumor size. Analysis of cell death pathways unexpectedly showed minimal impact of cysmethynil treatment on apoptosis; rather, drug treatment significantly enhanced autophagy and autophagic cell death. Cysmethynil-treated cells displayed reduced mammalian target of rapamycin (mTOR) signaling, providing a potential mechanism for the excessive autophagy as well as G(1) cell cycle arrest observed. These results identify a novel mechanism for the antitumor activity of Icmt inhibition. Further, the dual effects of cell death and cell cycle arrest by cysmethynil treatment strengthen the rationale for targeting Icmt in cancer chemotherapy.

Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model

Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar disorder, and have been shown to have neuroprotective properties in vivo and in vitro. A recent study demonstrated that combined treatment with lithium and VPA elicits synergistic neuroprotective effects against glutamate excitotoxicity in cultured brain neurons, and the synergy involves potentiated inhibition of glycogen synthase kinase-3 (GSK-3) activity through enhanced GSK-3 serine phosphorylation [Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576–2588]. We therefore investigated the effects of lithium and VPA cotreatment on the disease symptom onset, survival time and neurological deficits in cooper zinc superoxide dismutase (SOD1) G93A mutant mice, a commonly used mouse model of amyotrophic lateral sclerosis (ALS). The G93A ALS mice received twice daily i.p. injections with LiCl (60 mg/kg), VPA (300 mg/kg) or lithium plus VPA, starting from the 30 th day after birth and continuing until death. We found that combined treatment with lithium and VPA produced a greater and more consistent effect in delaying the onset of disease symptoms, prolonging the lifespan and decreasing the neurological deficit scores, compared with the results of monotreatment with lithium or VPA. Moreover, lithium in conjunction with VPA was more effective than lithium or VPA alone in enhancing the immunostaining of phospho-GSK-3β Ser9 in brain and lumbar spinal cord sections. To our knowledge, this is the first demonstration of enhanced neuroprotection by a combinatorial approach using mood stabilizers in a mouse ALS model. Our results suggest that clinical trials using lithium and VPA in combination for ALS patients are a rational strategy.

Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials.

Despite lacking evidence for its safety and efficacy, antipsychotic cotreatment is common in schizophrenia. To evaluate therapeutic and adverse effects of antipsychotic cotreatment vs monotherapy in schizophrenia. Cochrane Schizophrenia Group register and hand searches of relevant journals/conference proceedings. Randomized controlled trials comparing antipsychotic monotherapy to cotreatment with a second antipsychotic. Two authors independently extracted data. For homogenous dichotomous data, we calculated random effects, relative risk (RR), 95% confidence intervals (CIs), and numbers needed to treat (NNT). For continuous data, weighted mean differences were calculated. In 19 studies (1229 patients) with 28 monotherapy and 19 cotreatment arms, antipsychotic cotreatment was superior to monotherapy regarding 2 a priori defined coprimary outcomes: less study-specific defined inefficacy (N = 22, n = 1202, RR = 0.76, CI = 0.63-0.90, P = .002, NNT = 7, CI = 4-17, P = .0008, I(2) = 78.9%) and all-cause discontinuation (N = 20, n = 1052, RR = 0.65, CI = 0.54-0.78, P < .00001). Results were consistent using Clinical Global Impressions thresholds of less than much (P = .006) and less than minimally (P = .01) improved. Specific psychopathology and adverse event data were insufficient to yield meaningful results. In sensitivity analyses, 5 efficacy moderators emerged: concurrent polypharmacy initiation, clozapine combinations, trial duration >10 weeks, Chinese trials, and second-generation + first-generation antipsychotics. In a meta-regression, similar dose combinations, second-generation + first-generation antipsychotics and concurrent polypharmacy initiation remained significant. In certain clinical situations, antipsychotic cotreatment may be superior to monotherapy. However, the database is subject to possible publication bias and too heterogeneous to derive firm clinical recommendations, underscoring the need for future research.

Inhibitory effects of a dietary phytochemical 3,3′-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats

3,3′-Diindolylmethane (DIM), derived from indole-3-carbinol (I3C), is used as a dietary supplement for its putative anticancer effects that include suppression of mammary tumor growth in female rats. The mechanism of action DIM may involve its interaction(s) with hepatic cytochromes P450 (CYPs) catalyzing oxidations of 17β-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague–Dawley rats was primarily a competitive inhibitor of β-naphthoflavone (β-NF)- or I3C-induced CYP1A1 probe activity, and a potent mixed or uncompetitive inhibitor of phenobarbital (PB)-induced CYP2B1 or CYP2B2 probe activity, respectively. Microsomal metabolites of DIM were tentatively identified as two mono-hydroxy isomers of DIM, each formed preferentially by CYP1A1- or CYP2B1/2-catalyzed reaction. Evaluation of the effects of co-treatment of rats with PB and DIM by a full factorial ANOVA showed that DIM decreased the PB-induced CYP2B1 and CYP2B2 mRNA expression levels, and the rates of 2- and 4-hydroxylation of E2, and total E2 metabolite formation. The results suggest that interactions of DIM, and/or its mono-hydroxy metabolites, with CYP2B1 and CYP2B2 found to occur in hepatic microsomes upon addition of DIM or co-treatment of rats with DIM affect the rates of relevant oxidations of E2, and potentially protect against estrogen-dependent tumorigenesis.

Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: The mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1

The intrinsic or acquired resistance to multiple drugs (MDR) of cancer cells remains one of the main obstacles for chemotherapy. Development of small molecule targeting to hypoxia inducible factor-1 (HIF-1) has been recently proposed as strategy for treatments of drug-resistant solid tumors. In the present study, emodin, proven as a reactive oxygen species (ROS) generator by our previous work, was applied in combination with cisplatin and other chemotherapeutic drugs in the multidrug resistant prostate carcinoma cell line DU-145 and normal human dermal fibroblasts. Results showed that emodin/cisplatin co-treatment remarkably elevated ROS level and enhanced chemosensitivity in DU-145 cells, compared with cisplatin-only treatment, but exerted little effect on non-tumor cells. The effect of co-treatment on MDR1 gene and its upstream regulator HIF-1 was then investigated in DU-145. Co-treatment down-regulated MDR1 expression and promoted drug retention, and meanwhile suppressed transactivation of HIF-1 in response to hypoxia without changing expression of HIF-1α. The experiments on tumor-bearing mice showed that co-treatment inhibited the tumor growth in vivo, owing to oxidative stress and MDR1 down-regulation within tumors. HIF-1 transactivation and clonegenisis were suppressed in cells isolated from the tumors. Finally, examinations for the body weight, the organ histology and the antioxidant capacity of serum suggested that no systemic toxicity related to co-treatment was discernable. In conclusions, emodin, as a novel small inhibitor of HIF-1, may be recognized an effective adjunctive to improve efficacy of cytotoxic drugs in prostate cancer cells with over-activated HIF-1 and potent MDR.