Plasmon-activated water as a therapeutic strategy in Alzheimer's disease by altering gut microbiota.

Gut microbiota (GM) are involved in the pathophysiology of Alzheimer's disease (AD) and might correlate to the machinery of the gut-brain axis. Alteration of the GM profiles becomes a potential therapy strategy in AD. Here, we found that plasmon-activated water (PAW) therapy altered GM profile and reduced AD symptoms in APPswe/PS1dE9 transgenic mice (AD mice). GM profile showed the difference between AD and WT mice. PAW therapy in AD mice altered GM profile and fecal microbiota transplantation (FMT) reproduced GM profile in AD mice. PAW therapy and FMT in AD mice reduced cognitive decline and amyloid accumulation by novel object recognition (NOR) test and amyloid PET imaging. Immunofluorescent staining and western blot analysis of ß-amyloid (Aß) and phosphorylated (p)-tau in the brain of AD mice were reduced in PAW therapy and FMT. The inflammatory markers, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α and pro-inflammatory indicator of arginase-1/CD86 ratio were also reduced. Furthermore, immunohistochemistry (IHC) analysis of occludin and claudin-5 in the intestine and AXL in the brain were increased to correlate with the abundant GM in PAW therapy and FMT. Our results showed the machinery of gut-brain axis, and PAW might be a potential therapeutic strategy in AD.

HCH6-1, an antagonist of formyl peptide receptor-1, exerts anti-neuroinflammatory and neuroprotective effects in cellular and animal models of Parkinson's disease.

Microglial activation-induced neuroinflammation contributes to onset and progression of sporadic and hereditary Parkinson's disease (PD). Activated microglia secrete pro-inflammatory and neurotoxic IL-1ß, IL-6 and TNF-α, which subsequently promote neurodegeneration. Formyl peptide receptor-1 (FPR1) of CNS microglia functions as pattern recognition receptor and is activated by N-formylated peptides, leading to microglial activation, induction of inflammatory responses and resulting neurotoxicity. In this study, it was hypothesized that FPR1 activation of microglia causes loss of dopaminergic neurons by activating inflammasome and upregulating IL-1ß, IL-6 or TNF-α and that FPR1 antagonist HCH6-1 exerts neuroprotective effect on dopaminergic neurons. FPR1 agonist fMLF induced activation of microglia cells by causing activation of NLRP3 inflammasome and upregulation and secretion of IL-1ß, IL-6 or TNF-α. Conditioned medium (CM) of fMLF-treated microglia cells, which contains neurotoxic IL-1ß, IL-6 and TNF-α, caused apoptotic death of differentiated SH-SY5Y dopaminergic neurons by inducing mitochondrial oxidative stress and activating pro-apoptotic signaling. FPR1 antagonist HCH6-1 prevented fMLF-induced activation of inflammasome and upregulation of pro-inflammatory cytokines in microglia cells. HCH6-1 co-treatment reversed CM of fMLF-treated microglia-induced apoptotic death of dopaminergic neurons. FPR1 antagonist HCH6-1 inhibited rotenone-induced upregulation of microglial marker Iba-1 protein level, cell death of dopaminergic neurons and motor impairment in zebrafish. HCH6-1 ameliorated rotenone-induced microglial activation, upregulation of FPR1 mRNA, activation of NLRP3 inflammasome, cell death of SN dopaminergic neurons and PD motor deficit in mice. Our results suggest that FPR1 antagonist HCH6-1 possesses anti-neuroinflammatory and neuroprotective effects on dopaminergic neurons by inhibiting microglial activation and upregulation of inflammasome activity and pro-inflammatory cytokines.

Real-world treatment pattern and prognostic factors of stage IV lung squamous cell carcinoma patients.

Lung squamous cell carcinoma (LUSC) represents a minor proportion of nonsmall cell lung cancer (NSCLC) harboring a poor prognosis. Herein, retrospective medical record research was performed to investigate real-world treatment patterns and identify the prognostic factors among LUSC patients. A total of 173 patients with a median age of 68 years were enrolled for analysis. Males were predominant (n = 143, 83%) and current or ex-smokers contributed to 78% of the entire cohort. Pleura and lung were the most common metastatic sites, whereas brain metastasis was only 7%. After diagnosis, however, only 107 patients (62%) had received first-line chemotherapy. In the chemotherapy cohort, median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.1 months, respectively. After multivariable analysis, bone metastasis and the use of first-line single-agent chemotherapy independently predicted shorter PFS. For baseline characteristics, male sex, metastasis to lung, pleura, liver, and bone independently predicted worse OS. Regarding the treatment pattern, patients who had undergone standard first-line doublet therapy and employed targeted therapies after disease progression linked to longer OS. In the real world, even those who underwent chemotherapy still had poor outcome. The findings may help clinicians to orchestrate the treatment strategies for LUSC patients and provide further direction of large-scale studies.

Transferring Plasmon Effect on a Biological System: Expression of Biological Polymers in Chronic Rejection and Inflammatory Rat Model.

The plasmon-activated water (PAW) that reduces hydrogen bonds is made of deionized reverse osmosis water (ROW). However, compared with ROW, PAW has a significantly higher diffusion coefficient and electron transfer rate constant in electrochemical reactions. PAW has a boiling point of97 °C and specific heat of0.94; the energy of PAW is also 1121 J/mol higher than ordinary water. The greater the force of hydrogen bonds between H2O, the larger the volume of the H2O cluster, and the easier it is to lose the original characteristics. The hydrogen bonding force of PAW is weak, so the volume of its cluster is small, and it exists in a state very close to a single H2O. PAW has a high permeability and diffusion rate, which can improve the needs of biological applications and meet the dependence of biological organisms on H2O when performing physiological functions. PAW can successfully remove free radicals, and efficiently reduce lipopolysaccharide (LPS)-induced monocytes to release nitric oxide. PAW can induce expression of the antioxidant gene Nrf2 in human gingival fibroblasts, lower amyloid burden in mice with Alzheimer's disease, and decrease metastasis in mice grafted with Lewis lung carcinoma cells. Because the transferring plasmon effect may improve the abnormality of physiological activity in a biological system, we aimed to evaluate the influence of PAW on orthotopic allograft transplantation (OAT)-induced vasculopathy in this study. Here, we demonstrated that daily intake of PAW lowered the progression of vasculopathy in OAT-recipient ACI/NKyo rats by inhibiting collagen accumulation, proliferation of smooth muscle cells and fibroblasts, and T lymphocyte infiltration in the vessel wall. The results showed reduced T and B lymphocytes, plasma cells, and macrophage activation in the spleen of the OAT-recipient ACI/NKyo rats that were administered PAW. In contrast to the control group, the OAT-recipient ACI/NKyo rats that were administered PAW exhibited higher mobilization and levels of circulating endothelial progenitor cells associated with vessel repair. We use the transferring plasmon effect to adjust and maintain the biochemical properties of water, and to meet the biochemical demand of organisms. Therefore, this study highlights the therapeutic roles of PAW and provides more biomedical applicability for the transferring plasmon effect.

Effects of biochar content on gas diffusion coefficient of soil with different compactness and air contents.

Biochar has been found to be a potentially suitable amendment for landfill cover material and agricultural soil. The addition of biochar can improve the physical (e.g., adsorption capacity) and hydrological properties (e.g., water/gas permeability) of soil. However, no experimental study is available about the effect of biochar content (BC) on the gas diffusion coefficient (DP) of soil. The present study investigated the effect of BC on DP under different degree of compaction (DOC; 85%, 90%, and 95%) and soil air contents (SAC; 5%, 10%, and 15%). It was found that DOC and BC had negligible effects on DP when SAC was low (~ 5%). In contrast, when the SAC was relatively high (~ 15%), soil with DOC of 85% had the largest DP for BC ranging from 0 to 15% (w/w). Only when the SAC was large (~ 15%), the addition of biochar generally increased DP.

Modulation effect of tea consumption on gut microbiota.

Tea is one of the most popular beverages in the world and possesses a wide range of beneficial effects for human health. The modulation of tea on gut microbiota has gained much interest in recent years. The present study discussed the modulation effect of various types of tea on gut microbiota, which plays crucial roles in human health, as investigated by in vitro animal and human studies. The currently available findings from a total of 23 studies support the modulation effects of tea liquid, tea extract, and its major active components, including polyphenols, polysaccharides, and teasaponin, on gut microbiota. Overall, tea possesses prebiotic-like effect and can alleviate the gut microbiota dysbiosis induced by high-fat diet in gut microbiota, despite the detailed bacterial taxa may alter depending on the types of tea supplemented. Current evidence implies that the modulation effect on gut microbiota may be an important action mechanism underlying the beneficial effect of tea consumption in daily life and also the great potential of strategically chosen tea extract to develop functional foods.

Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer.

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family (RASSF1), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

Systemic lupus erythematosus and thyroid disease - Experience in a single medical center in Taiwan.

BACKGROUND: To investigate the association of systemic lupus erythematosus (SLE) with thyroid diseases in a medical center in central Taiwan. METHODS: This is a retrospective cohort of 2796 SLE patients in a tertiary referral medical center from 2000 to 2013. We screened SLE by catastrophic illness registration from national insurance bureau; and thyroid diseases by ICD 9 codes, then confirmed by thyroid function test, auto-antibody, medical and/or surgical intervention. We compared the rate of hyperthyroidism, hypothyroidism and autoimmune thyroid disease (AITD) in SLE patients and the 11,184 match controls. We calculated the rate of these thyroid diseases and positive antibodies to thyroglobulin (ATGAb), thyroid peroxidase (TPOAb) in SLE patients grouped by the presence of overlap syndrome and anti-dsDNA antibody. We also compared the association of thyroid diseases to severe SLE conditions, including renal, central nervous system (CNS) involvement, and thrombocytopenia. RESULTS: Compared to the matched controls, the cumulative incidence of thyroid disease, including hyperthyroidism, hypothyroidism and AITD, were all higher in SLE patients (p < 0.0001). The average age of SLE patients with thyroid diseases patients were older than those without thyroid diseases (p = 0.002). Those had euthyroid AITD were younger than other patients with thyroid diseases (p = 0.02). Up to 30.3% SLE patients had overlap syndrome and had higher relative risk of thyroid diseases than those without overlap syndrome, in terms of hypothyroidism and AITD, but not hyperthyroidism. SLE patients with thyroid diseases also carry higher risk for severe complications such as renal involvement (p = 0.024) central nervous system involvement (p < 0.0001). CONCLUSION: SLE patients had significantly higher rate of hyperthyroidism, hypothyroidism, and AITD than the matched control. Among lupus patients, the risks of thyroid diseases are even higher in the presence of overlap syndrome. SLE patients with thyroid diseases had higher risk of renal and CNS involvement.

Therapeutics for Inflammatory-Related Diseases Based on Plasmon-Activated Water: A Review.

It is recognized that the properties of liquid water can be markedly different from those of bulk one when it is in contact with hydrophobic surfaces or is confined in nano-environments. Because our knowledge regarding water structure on the molecular level of dynamic equilibrium within a picosecond time scale is far from completeness all of water's conventionally known properties are based on inert "bulk liquid water" with a tetrahedral hydrogen-bonded structure. Actually, the strength of water's hydrogen bonds (HBs) decides its properties and activities. In this review, an innovative idea on preparation of metastable plasmon-activated water (PAW) with intrinsically reduced HBs, by letting deionized (DI) water flow through gold-supported nanoparticles (AuNPs) under resonant illumination at room temperature, is reported. Compared to DI water, the created stable PAW can scavenge free hydroxyl and 2,2-diphenyl-1-picrylhydrazyl radicals and effectively reduce NO release from lipopolysaccharide-induced inflammatory cells. Moreover, PAW can dramatically induce a major antioxidative Nrf2 gene in human gingival fibroblasts. This further confirms its cellular antioxidative and anti-inflammatory properties. In addition, innovatively therapeutic strategy of daily drinking PAW on inflammatory-related diseases based on animal disease models is demonstrated, examples being chronic kidney disease (CKD), chronic sleep deprivation (CSD), and lung cancer.

Innovatively Therapeutic Strategy on Lung Cancer by Daily Drinking Antioxidative Plasmon-Induced Activated Water.

Many human diseases are inflammation-related, such as cancer and those associated with aging. Previous studies demonstrated that plasmon-induced activated (PIA) water with electron-doping character, created from hot electron transfer via decay of excited Au nanoparticles (NPs) under resonant illumination, owns reduced hydrogen-bonded networks and physchemically antioxidative properties. In this study, it is demonstrated PIA water dramatically induced a major antioxidative Nrf2 gene in human gingival fibroblasts which further confirms its cellular antioxidative and anti-inflammatory properties. Furthermore, mice implanted with mouse Lewis lung carcinoma (LLC-1) cells drinking PIA water alone or together with cisplatin treatment showed improved survival time compared to mice which consumed only deionized (DI) water. With the combination of PIA water and cisplatin administration, the survival time of LLC-1-implanted mice markedly increased to 8.01 ± 0.77 days compared to 6.38 ± 0.61 days of mice given cisplatin and normal drinking DI water. This survival time of 8.01 ± 0.77 days compared to 4.62 ± 0.71 days of mice just given normal drinking water is statistically significant (p = 0.009). Also, the gross observations and eosin staining results suggested that LLC-1-implanted mice drinking PIA water tended to exhibit less metastasis than mice given only DI water.

Parthenolide promotes apoptotic cell death and inhibits the migration and invasion of SW620 cells.

BACKGROUND/AIMS: Parthenolide (PT), a principle component derived from feverfew (Tanacetum parthenium), is a promising anticancer agent and has been shown to promote apoptotic cell death in various cancer cells. In this study, we focused on its functional role in apoptosis, migration, and invasion of human colorectal cancer (CRC) cells. METHODS: SW620 cells were employed as representative human CRC cells. We performed the MTT assay and cell cycle analysis to measure apoptotic cell death. The wound healing, Transwell migration, and Matrigel invasion assays were performed to investigate the effect of PT on cell migration/invasion. Western blotting was used to establish the signaling pathway of apoptosis and cell migration/invasion. RESULTS: PT exerts antiproliferative effect and induces apoptotic cell death of SW620 cells. In addition, PT prevents cell migration and invasion in a dose-dependent manner. Moreover, PT markedly suppressed migration/invasion-related protein expression, including E-cadherin, ß-catenin, vimentin, Snail, cyclooxygenase-2, matrix metalloproteinase-2 (MMP-2), and MMP-9 in SW620 cells. PT also inhibited the expression of antiapoptotic proteins (Bcl-2 and Bcl-xL) and activated apoptosis terminal factor (caspase-3) in a dose-dependent manner. CONCLUSIONS: Our results suggest that PT is a potential novel therapeutic agent for aggressive CRC treatment.

Efficient Generation of Chemically Induced Mesenchymal Stem Cells from Human Dermal Fibroblasts.

Human mesenchymal stromal/stem cells (MSCs) are multipotent and currently undergoing hundreds of clinical trials for disease treatments. To date, no studies have generated induced MSCs from skin fibroblasts with chemicals or growth factors. Here, we established the first chemical method to convert primary human dermal fibroblasts into multipotent, induced MSC-like cells (iMSCs). The conversion method uses a defined cocktail of small molecules and growth factors, and it can achieve efficient conversion with an average rate of 38% in 6 days. The iMSCs have much higher clonogenicity than fibroblasts, and they can be maintained and expanded in regular MSC medium for at least 8 passages and further differentiated into osteoblasts, adipocytes, and chondrocytes. Moreover, the iMSCs can suppress LPS-mediated acute lung injury as effectively as bone marrow-derived mesenchymal stem cells. This finding may greatly benefit stem cell biology, cell therapy, and regenerative medicine.

Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-κB Activation.

Balsalazide is a colon-specific prodrug of 5-aminosalicylate that is associated with a reduced risk of colon cancer in patients with ulcerative colitis. Parthenolide, a strong NF-κB inhibitor, has recently been demonstrated to be a promising therapeutic agent, promoting apoptosis of cancer cells. In the current study, the antitumor effect of balsalazide combined with parthenolide in human colorectal cancer cells and colitis-associated colon cancers (CAC) was investigated. The results demonstrate that the combination of balsalazide and parthenolide markedly suppress proliferation, nuclear translocation of NF-κB, IκB-α phosphorylation, NF-κB DNA binding, and expression of NF-κB targets. Apoptosis via NF-κB signaling was confirmed by detecting expression of caspases, p53 and PARP. Moreover, treatment of a CAC murine model with parthenolide and balsalazide together resulted in significant recovery of body weight and improvement in histologic severity. Administration of parthenolide and balsalazide to CAC mice also suppressed carcinogenesis as demonstrated by uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) using micro-PET/CT scans. These results demonstrate that parthenolide potentiates the efficacy of balsalazide through synergistic inhibition of NF-κB activation and the combination of dual agents prevents colon carcinogenesis from chronic inflammation. IMPLICATIONS: This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141-51. ©2016 AACR.

MicroRNA-9 suppresses cell migration and invasion through downregulation of TM4SF1 in colorectal cancer.

Transmembrane-4-L6 family 1 (TM4SF1) is upregulated in colorectal carcinoma (CRC). However, the mechanism leading to inhibition of the TM4SF1 is not known. In the present study, we investigated the regulation of TM4SF1 and function of microRNAs (miRNAs) in CRC invasion and metastasis. We analyzed 60 colon cancers and paired normal specimens for TM4SF1 and miRNA-9 (miR-9) expression using quantitative real-time PCR. A bioinformatics analysis identified a putative miR-9 binding site within the 3'-UTR of TM4SF1. We also found that TM4SF1 was upregulated in CRC tissues and CRC cell lines. The expression of TM4SF1 was positively correlated with clinical advanced stage and lymph node metastasis. Moreover, a luciferase assay revealed that miR-9 directly targeted 3'-UTR-TM4SF1. Overexpression of miR-9 inhibited expression of TM4SF1 mRNA and protein, wound healing, transwell migration and invasion of SW480 cells, whereas, overexpression of anti-miR-9 and siRNA-TM4SF1 inversely regulated the TM4SF1 mRNA and protein level in HCT116 cells. Furthermore, miR-9 suppressed not only TM4SF1 expression but also MMP-2, MMP-9 and VEGF expression. In clinical specimens, miR-9 was generally down-regulated in CRC and inversely correlated with TM4SF1 expression. These results suggest that miR-9 functions as a tumor-suppressor in CRC, and that its suppressive effects mediate invasion and metastasis by inhibition of TM4SF1 expression. Our results also indicate that miR-9 might be a novel target for the treatment of CRC invasion and metastasis.

Assessment of complications due to intratympanic injections.

OBJECTIVE: The purpose of the study is to report and to analyze the complications following intratympanic injections (ITI) of steroids. The occurrence rate of complications at different ITI sites, four quadrants of eardrum, was also compared. METHODS: A retrospective clinical review in a medical center. Each patient received ITI twice in a week for 2-3 consecutive weeks as a salvage therapy for sudden sensorineural hearing loss. Post-injection complications, especially transient dizziness and vertigo, were recorded. Patients with acute or chronic vertigo episodes in 1 month were excluded. RESULTS: A total of 59 patients with sudden sensorineural hearing loss and a total of 278 times of ITI were performed in 1 year. The post-injection complications included pain, tongue numbness, transient dizziness, vertigo, tinnitus, and a small persistent perforation. There was no significant difference in the occurrence of these complications between the injections sites on the 4 quadrants of the tympanic membrane. However, there was statistical significance in the post-injection vertiginous episode after IT injections to posterior-inferior quadrant (Q3) and posterior-superior quadrant (Q4) compared to anterior-superior quadrant (Q1) and anterior-inferior quadrant (Q2) (P = 0.0113). CONCLUSION: IT injection is recommended to be applied to the Q2 since the Q1 and Q4 injections are more likely to induce the adverse effect of tongue numbness, while the Q3 and Q4 areas are more likely to induce post-injection vertigo.

Effective Energy Transfer via Plasmon-Activated High-Energy Water Promotes Its Fundamental Activities of Solubility, Ionic Conductivity, and Extraction at Room Temperature.

Water is a ubiquitous solvent in biological, physical, and chemical processes. Unique properties of water result from water's tetrahedral hydrogen-bonded (HB) network (THBN). The original THBN is destroyed when water is confined in a nanosized environment or localized at interfaces, resulting in corresponding changes in HB-dependent properties. In this work, we present an innovative idea to validate the reserve energy of high-energy water and applications of high-energy water to promote water's fundamental activities of solubility, ionic conductivity, and extraction at room temperature. High-energy water with reduced HBs was created by utilizing hot electrons with energies from the decay of surface plasmon excited at gold (Au) nanoparticles (NPs). Compared to conventional deionized (DI) water, solubilities of alkali metal-chloride salts in high-energy water were significantly increased, especially for salts that release heat when dissolved. The ionic conductivity of NaCl in high-energy water was also markedly higher, especially when the electrolyte's concentration was extremely low. In addition, antioxidative components, such as polyphenols and 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (THSG) from teas, and Polygonum multiflorum (PM), could more effectively be extracted using high-energy water. These results demonstrate that high-energy water has emerged as a promising innovative solvent for promoting water's fundamental activities via effective energy transfer.

Parthenolide induces apoptosis in colitis-associated colon cancer, inhibiting NF-κB signaling.

Recently, the nuclear factor (NF)-κB inhibitor parthenolide (PT) was identified as a promising anticancer agent for the promotion of cancer cell apoptosis. Additionally, our previous study demonstrated that PT administration suppresses tumor growth in a xenograft model of colorectal cancer cells via regulation of the B-cell lymphoma-2 (Bcl-2) family. However, the role of PT in the development of colitis-associated colon cancer (CAC) is poorly understood. Therefore, the aim of the present study was to investigate the effects of PT administration on CAC using a murine model. Azoxymethane (AOM) and dextran sulfate sodium (DSS) were administered to induce experimental CAC in the following three groups of treated mice: i) AOM and DSS plus vehicle; ii) AOM, DSS and 2 mg/kg PT; and iii) AOM, DSS and 4 mg/kg PT. It was demonstrated that the histological acuteness of AOM/DSS-induced CAC was significantly reduced following the administration of PT, resulting in decreased NF-κB p65 expression levels via a blockade of phosphorylation and subsequent degradation of inhibitor of κB-α (IκBα). Furthermore, PT administration appeared to enhance the process of carcinogenesis via the downregulation of the antiapoptotic proteins Bcl-2 and Bcl-extra large, mediated by inhibition of NF-κB activation. Apoptosis and caspase-3 expression were markedly increased in the PT-treated group. These findings indicate that PT inhibits IκBα phosphorylation and NF-κB activation, resulting in the initiation of apoptosis and the eventual suppression of CAC development. The beneficial effects of PT treatment observed in the experimental CAC model indicate the potential chemopreventive and therapeutic role of PT in CAC.

Balsalazide Potentiates Parthenolide-Mediated Inhibition of Nuclear Factor-κB Signaling in HCT116 Human Colorectal Cancer Cells.

BACKGROUND/AIMS: Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. Balsalazide can reduce inflammatory responses via several mechanisms, including inhibition of nuclear factor-κB (NF-κB) activity. Parthenolide (PT) inhibits NF-κB and exerts promising anticancer effects by promoting apoptosis. The present investigated the antitumor effects of balsalazide, combined with PT, on NF-κB in a representative human colorectal carcinoma cell line, HCT116. METHODS: We counted cells and conducted annexin-V assays and cell cycle analysis to measure apoptotic cell death. Western blotting was used investigate the levels of proteins involved in apoptosis. RESULTS: PT and balsalazide produced synergistic anti-proliferative effects and induced apoptotic cell death. The combination of balsalazide and PT markedly suppressed nuclear translocation of the NF-κB p65 subunit and the phosphorylation of inhibitor of NF-κB. Moreover, PT and balsalazide dramatically enhanced NF-κB p65 phosphorylation. Apoptosis, through the mitochondrial pathway, was confirmed by detecting effects on Bcl-2 family members, cytochrome c release, and activation of caspase-3 and -8. CONCLUSIONS: Combination treatment with PT and balsalazide may offer an effective strategy for the induction of apoptosis in HCT116 cells.

Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL-induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells.