Genetic susceptibility in pneumoconiosis in China: a systematic review.

OBJECTIVE: Pneumoconiosis, encompassing coal workers' pneumoconiosis (CWP), silicosis and asbestosis, is one of the most common occupational diseases in China. Previous studies revealed significant associations between genetic variations and pneumoconiosis risk among individuals in different countries. With the known variability of genetic makeup between ethnicities, susceptibility to pneumoconiosis due to genetic differences is likely to be ethnicity-specific. The present review aimed at providing a comprehensive overview on the association between genetic polymorphisms and susceptibility of pneumoconiosis, specifically among people in China. METHODS: The literature search was performed in seven English and Chinese databases using keywords related to the review aim. An appraisal of the methodological quality of the included studies was conducted using the assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. RESULTS: Forty-five studies were included in this review. Genotypes of specific genes which are associated with the risk of CWP, silicosis and asbestosis were reported. Our findings showed that genes encoding inflammatory cytokines have been examined extensively, and they demonstrated an association between these genes and pneumoconiosis risk. Gene-environment interactions in pneumoconiosis susceptibility were also reported by a number of studies. CONCLUSIONS: This review summarised the evidence demonstrating the association between genetic polymorphisms and pneumoconiosis susceptibility among people in China, and that various genotypes could modify their risk to develop pneumoconiosis. The findings prompt that identification of individuals at high pneumoconiosis risk through genetic screening and strategies limiting their exposure to dust could be a potential strategy for the control of this occupational disease in China.

Association between genetic polymorphisms in cytochrome P450 enzymes and survivals in women with breast cancer receiving adjuvant endocrine therapy: a systematic review and meta-analysis.

Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

Association of early-life gut microbiome and lifestyle factors in the development of eczema in Hong Kong infants.

Childhood eczema is common but its prevalence is variable in different regions of the world. In this study, we explore the associations of various risk factors such as the microbiome, environment, lifestyle, diet and maternal stress with the development of eczema among infants in Hong Kong. Upon enrolment in the study, the infants' parents provided demographic data by self-reporting. At enrolment and 1 year after birth, the infants' allergic conditions, lifestyles and dietary factors and the degree of maternal stress were assessed using various questionnaires. The infants' gut microbiomes were analysed by 16S RNA sequencing, and the longitudinal changes in various bacterial strains were compared between control and eczema-affected groups. Multivariate analyses (after adjustment for other significant factors) revealed that the changes in the abundance of Hungatella hathewayi in the gut were significantly associated with the development of eczema (p = 0.005). In conclusion, the increased abundance of Hungatella hathewayi was associated with an increased risk of developing eczema by 1 year of age. This study thus explored the potential risk factors for the development of eczema in Hong Kong infants, and sheds light on the possible association between early-life gut microbiome and other environmental factors.

Health in Action: Evaluation of a Participatory Grant-Making Project in East Harlem.

Decision-making processes that include resident input have been shown to be effective in addressing community needs. However, few examples discuss the role of a local health department in leading a participatory decision-making process. In 2016, the New York City Department of Health and Mental Hygiene implemented a participatory grant-making process to allocate grant funds to community organizations in East Harlem. Findings from the evaluation suggest that a participatory grant-making process can be an effective way to include community member as decision makers. It can also build capacity among organizations and foster meaningful community engagement with a local health department.

Adapted Feeding Utensils for People With Parkinson's-Related or Essential Tremor.

OBJECTIVE: Our objective was to evaluate the effectiveness of four adapted feeding utensils with participants with essential tremor (ET) or tremor related to Parkinson's disease (PD). METHOD: Participants performed a simulated feeding task under five conditions: (1) standard spoon (control condition), (2) weighted spoon with standard handle, (3) weighted spoon with built-up handle, (4) swivel spoon, and (5) Liftware Steady™ spoon, a product using active tremor cancellation technology. Participants rated each adapted utensil in comparison with the standard spoon regarding performance, ease of use, speed, neatness, and aesthetics. RESULTS: Participants preferred the Liftware Steady spoon and weighted spoon with standard handle. Friedman's test did not reveal statistically significant differences in ratings between the two preferred utensils. CONCLUSION: Participants had varied reactions to the different adaptive utensils and gave different reasons for preferences. These findings support the need for people with tremor related to ET or PD to have access to trial use of all four devices assessed in this study.

Novel Kunitz-like Peptides Discovered in the Zoanthid Palythoa caribaeorum through Transcriptome Sequencing.

Palythoa caribaeorum (class Anthozoa) is a zoanthid that together jellyfishes, hydra, and sea anemones, which are venomous and predatory, belongs to the Phyllum Cnidaria. The distinguished feature in these marine animals is the cnidocytes in the body tissues, responsible for toxin production and injection that are used majorly for prey capture and defense. With exception for other anthozoans, the toxin cocktails of zoanthids have been scarcely studied and are poorly known. Here, on the basis of the analysis of P. caribaeorum transcriptome, numerous predicted venom-featured polypeptides were identified including allergens, neurotoxins, membrane-active, and Kunitz-like peptides (PcKuz). The three predicted PcKuz isotoxins (1-3) were selected for functional studies. Through computational processing comprising structural phylogenetic analysis, molecular docking, and dynamics simulation, PcKuz3 was shown to be a potential voltage gated potassium-channel inhibitor. PcKuz3 fitted well as new functional Kunitz-type toxins with strong antilocomotor activity as in vivo assessed in zebrafish larvae, with weak inhibitory effect toward proteases, as evaluated in vitro. Notably, PcKuz3 can suppress, at low concentration, the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish, which indicated PcKuz3 may have a neuroprotective effect. Taken together, PcKuz3 figures as a novel neurotoxin structure, which differs from known homologous peptides expressed in sea anemone. Moreover, the novel PcKuz3 provides an insightful hint for biodrug development for prospective neurodegenerative disease treatment.

Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis.

Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFκB p65 cascade was performed by Western blot. The secretion of cytokines IL-1ß, IL-6, IL-10 and TNFα was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFκB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1ß, IL-6, IL-10 and TNFα was induced by silica exposure and the induction of IL-1ß, IL-6 and TNFα was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFκB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis.

Evaluation in zebrafish model of the toxicity of rhodamine B-conjugated crotamine, a peptide potentially useful for diagnostics and therapeutics.

Crotamine is defensin-like cationic peptide from rattlesnake venom that possesses anticancer, antimicrobial, and antifungal properties. Despite these promising biological activities, toxicity is a major concern associated with the development of venom-derived peptides as therapeutic agents. In the present study, we used zebrafish as a system model to evaluate the toxicity of rhodamine B-conjugated (RhoB) crotamine derivative. The lethal toxic concentration of RhoB-crotamine was as low as 4 µM, which effectively kill zebrafish larvae in less than 10 min. With non-lethal concentrations (<1 µM), crotamine caused malformation in zebrafish embryos, delayed or completely halted hatching, adversely affected embryonic developmental programming, decreased the cardiac functions, and attenuated the swimming distance of zebrafish. The RhoB-crotamine translocated across vitelline membrane and accumulated in zebrafish yolk sac. These results demonstrate the sensitive responsivity of zebrafish to trial crotamine analogues for the development of novel therapeutic peptides with improved safety, bioavailability, and efficacy profiles.

Profiling of the silica-induced molecular events in lung epithelial cells using the RNA-Seq approach.

Silicosis is a prolonged, irreversible and incurable occupational disease, and there is a significant number of newly diagnosed cases every year in Hong Kong. Due to the long latency of the disease, the diagnosis can be missed until detailed clinical examination at a later stage. For a better control of this deadly disease, detailing the pro-inflammatory and fibrotic events in the macrophage would be instrumental in understanding the pathogenesis of the disease and essential for the significant biomarkers discovery. In this in vitro study, human cell line model A549 lung epithelial cells were used. The immediate molecular events underneath the activation of quartz silica polymorphs were followed in a time course of 0, 0.5, 2, 8, 16 and 24 h. The transcriptome library was prepared and subjected to RNA-Seq analysis. Data analysis was performed by pathway analysis tools and verified by real-time PCR. The results showed that triggered genes were mainly found in the immune response and inflammatory pathways. An interesting finding was the association of the DNA-binding protein inhibitor (ID) family in the silica exposure to lung cells. The linkage of ID1, ID2 and ID3 to cancer may rationalize themselves to be the markers indicating an early response of silicosis. However, further studies are required to consolidate the roles of these genes in silicosis. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluating Efficacy and Safety of Combination Medication of Atorvastatin and a Herbal Formula Containing Salvia miltiorrhiza and Pueraria lobata on Hyperlipidemia.

Despite being a potent hypolipidemic drug, atorvastatin (AS) possesses certain adverse effects. Using AS and an herbal formula (Danshen and Gegen, DG) in combination may achieve potentiated hypolipidemic effects and also reduce its adverse effects. Hence, this study aimed to investigate the efficacy and safety of an AS and DG combination on high-fat diet-induced hyperlipidemia. Treatment outcomes were assessed by measuring parameters including body weight, adipose tissue, liver, total cholesterol, triglyceride, and low-density and high-density lipoprotein cholesterol. Measurements of adverse effects were achieved by determining aspartate aminotransferase (AST), alanine transaminase (ALT), and creatine kinase (CK). Danshen and Gegen, as well as AS alone, reduced body weight, adipose tissue, liver weight, liver fat vacuoles, total liver lipids, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in high-fat diet-fed mice but increased AST, ALT, and CK. A combination of AS and DG was able to enhance reduced effects on the aforementioned parameters in relation to hyperlipidemia over AS or DG alone. It also reduced the elevation of AST, ALT, and CK induced than by AS or DG alone. Results demonstrated that an AS and DG combination resulted in stronger hypolipidemic effects than with AS or DG alone. Additionally, DG might attenuate adverse effects of AS on the liver and skeletal muscle. Copyright © 2017 John Wiley & Sons, Ltd.

Rhodamine B-conjugated encrypted vipericidin nonapeptide is a potent toxin to zebrafish and associated with in vitro cytotoxicity.

BACKGROUND: Animal venoms contain a diverse array of proteins and enzymes that are toxic toward various physiological systems. However, there are also some practical medicinal uses for these toxins including use as anti-bacterial and anti-tumor agents. METHODS: In this study, we identified a nine-residue cryptic oligopeptide, KRFKKFFKK (EVP50) that is repeatedly encoded in tandem within vipericidin sequences. RESULTS: EVP50 displayed in vivo potent lethal toxicity to zebrafish larvae (LD50=6 µM) when the peptide's N-terminus was chemically conjugated to rhodamine B (RhoB). In vitro, RhoB-conjugated EVP50 (RhoB-EVP50) exhibited a concentration-dependent cytotoxic effect toward MCF-7 and MDA-MB-231 breast cancer cells. In MCF-7 cells, the RhoB-EVP50 nonapeptide accumulated inside the cells within minutes. In the cytoplasm, the RhoB-EVP50 induced extracellular calcium influx and intracellular calcium release. Membrane budding was also observed after incubation with micromolar concentrations of the fluorescent EVP50 conjugate. CONCLUSIONS: The conjugate's interference with calcium homeostasis, its intracellular accumulation and its induced membrane dysfunction (budding and vacuolization) seem to act in concert to disrupt the cell circuitry. Contrastively, unconjugated EVP50 peptide did not display neither toxic nor cytotoxic activities in our in vivo and in vitro models. GENERAL SIGNIFICANCE: The synergic mechanism of toxicity was restricted to the structurally modified encrypted vipericidin nonapeptide.

A Novel Danshensu Derivative Prevents Cardiac Dysfunction and Improves the Chemotherapeutic Efficacy of Doxorubicin in Breast Cancer Cells.

Doxorubicin (Dox) is an anthracycline antibiotic widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. We have previously shown that a Danshensu (DSS) derivative, ADTM, displayed strong cardioprotective effects. With improved chemical stability and activity, a novel DSS derivative, D006, based on the structure of ADTM, was synthesized. In the present study, the protective effects of D006, indexed by attenuation of the cardiotoxicity induced by Dox as well as chemosensitizing effects that increase the antitumor activity of Dox, were investigated. Our results showed that D006 was more potent than either parental compound, or their use in combination, in ameliorating Dox-induced toxicity in H9c2 cells. In our zebrafish model, D006, but not DSS, alone significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment of H9c2 cells. D006 promoted the expression of HO-1 protein in a time-dependent manner while the HO-1 inhibitor, Znpp, reversed the protective effects of D006. In human breast tumor MCF-7 cells, D006 enhanced Dox-induced cytotoxicity by increasing apoptosis. In conclusion, our results indicate that a new DSS derivative exhibits promising protective effects against Dox-induced cardiotoxicity both in vivo and in vitro, an effect at least partially mediated by induction of HO-1 expression and the activation of mitochondrial biogenesis. Meanwhile, D006 also potentiated the anti-cancer effects of Dox in breast tumor cells.

Complexation of clofazimine by macrocyclic cucurbit[7]uril reduced its cardiotoxicity without affecting the antimycobacterial efficacy.

Cucurbit[7]uril (CB[7]) has recently attracted increasing attention in pharmaceutical sciences due to its great potential in improving the physicochemical properties and bioactivity of drug molecules. Herein, we have investigated the influence of CB[7]'s complexation on the solubility, antimycobacterial activity, and cardiotoxicity of a model anti-tuberculosis drug, clofazimine (CFZ), that has poor water-solubility and inherent cardiotoxicity. In our study, CFZ was found to be complexed by CB[7], in a 1 : 1 binding mode with a relatively strong binding affinity (in the order of magnitude of 10(4)-10(5) M(-1)), as determined by the phase solubility method via HPLC-UV analysis and (1)H NMR titration, as well as UV-visible spectroscopic titration, and further confirmed by electrospray ionization mass spectrometry (ESI-MS). Upon complexation, the solubility of virtually insoluble CFZ was significantly increased, reaching a concentration of up to approximately 0.53-fold of the maximum solubility of CB[7]. The inherent cardiotoxicity of CFZ was dramatically reduced to almost nil in the presence of CB[7]. Importantly, on the other hand, such a supramolecular complexation of the drug did not compromise its therapeutic efficacy, as shown by the antimycobacterial activities examined against Mycobacterium smegmatis, demonstrating the significant potential of CB[7] as a functional pharmaceutical excipient.

The antigluconeogenic activity of cucurbitacins from Momordica charantia.

Five new cucurbitacins, kuguacins II-VI (1-5), along with five known analogues (6-10), were obtained from the fruit of Momordica charantia. Structures of the new compounds were elucidated as 5ß,19-epoxycucurbit-23-en-7-on-3ß,25-diol (1), 5ß,19-epoxycucurbit-7,23-dion-3ß,25-diol (2), 5ß,19-epoxycucurbit-6-en-19,23-dion-3ß,25-diol (3), 5ß,19-epoxy-23,24,25,26,27-pentanorcucurbit-6-en-7,19-dion-3ß,22-diol (4), and cucurbit-5-en-7,23-dion-3ß,19,25-triol (5) by extensive spectroscopic and single-crystal X-ray diffraction analyses. Some cucurbitane compounds from this species were screened for their potential antidiabetic properties in terms of antigluconeogenic activity. As a result, compounds 1, 10, 11, and 12 (at 25-100 µM) showed concentration-dependent inhibition on glucose production from liver cells. In addition, compounds 11 and 12 (at 100 µM) showed around 20-30 % inhibition on PEPCK activity.

Antidiabetic Effect of Schisandrae Chinensis Fructus Involves Inhibition of the Sodium Glucose Cotransporter.

Preclinical Research Schisandrae Chinensis Fructus (SCF), the fruit of Schisandra chinensis (Turcz.) Baill. (family Schisandraceae) is traditionally used as a tonic and antidiabetic agent in Asia. In this study, SCF was investigated for its effects on sodium glucose cotransporters 1 and 2 (SGLT 1 and 2) expressed in a COS-7 cell line for its specificity in inhibiting SGLT2, which is a novel mechanism to screen for potential antidiabetic agents. Using a bioassay-guided fractionation, we then tried to isolate and identify the active fraction(s)/component(s). The ethanol extract of SCF at a concentration of 1 mg/mL significantly inhibited 89% of SGLT1 and 73% of SGLT2 activities in a [14 C]-α-methyl-d-glucopyranoside ([14 C]-AMG) uptake assay. Fractionation of the ethanol extract yielded nine fractions, of which F8, at a concentration of 1 mg/mL, was specific in inhibiting SGLT 2 (42% inhibition, P < 0.001), without inhibiting SGLT 1. Using LC/MS-MS, three compounds, deoxyschisandrin, schisandrin B (γ-schisandrin) and schisandrin were identified in F8 and their amounts quantified. However, subsequent evaluation in the [14 C]-AMG uptake assay showed that these three compounds failed to inhibit SGLT 2 activity indicating that the SGLT active component(s) from SCF have yet to be identified. Drug Dev Res 76 : 1-8, 2015.

Anti-inflammatory activities of an active fraction isolated from the root of Astragalus membranaceus in RAW 264.7 macrophages.

The root of Astragalus membranaceus (AR), which has been widely used in Traditional Chinese herbal formulae for treating foot ulcer, was found to exhibit anti-inflammatory property, but its molecular mechanism still remains unknown. We previously identified the anti-inflammatory sub-fraction using bioassay-guided fractionation. The objective of the present study was to investigate the anti-inflammatory mechanism of the major active fraction (MAF) (0.039 to 0.156 mg/mL) using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. MAF was shown to inhibit LPS-induced mRNA and protein expression of inducible nitric oxide synthase by 54.7% and 65.1%, respectively. Additionally, MAF down-regulated the protein expression of cyclooxygenase-2 and MAPK regulator by 45.0% to 74.6%, as well as the reduction of DNA binding activity of nuclear factor kappa B (NFκB) by 66.5%. It also attenuated the production of prostaglandin E2 , interleukin-1 beta (IL-1ß), IL-6 and tumor necrosis factor alpha by 21.2% to 86.2%. Furthermore, the chemical constituents of MAF were identified. A total of 13 known chemical compounds were found in MAF, including five isoflavonoids and eight saponins. In conclusion, a bioactive fraction of AR was identified which possessed anti-inflammatory property by reducing the release of inflammatory mediators and inactivation of NFκB through MAPK signalling pathway.

Structural Variations Identified in Patients with Autism Spectrum Disorder (ASD) in the Chinese Population: A Systematic Review of Case-Control Studies.

Autistic spectrum disorder (ASD) is a neurodevelopmental disability characterised by the impairment of social interaction and communication ability. The alarming increase in its prevalence in children urged researchers to obtain a better understanding of the causes of this disease. Genetic factors are considered to be crucial, as ASD has a tendency to run in families. In recent years, with technological advances, the importance of structural variations (SVs) in ASD began to emerge. Most of these studies, however, focus on the Caucasian population. As a populated ethnicity, ASD shall be a significant health issue in China. This systematic review aims to summarise current case-control studies of SVs associated with ASD in the Chinese population. A list of genes identified in the nine included studies is provided. It also reveals that similar research focusing on other genetic backgrounds is demanded to manifest the disease etiology in different ethnic groups, and assist the development of accurate ethnic-oriented genetic diagnosis.

Isolation of anti-inflammatory fractions and compounds from the root of Astragalus membranaceus.

Foot ulceration, if not treated properly, will eventually result in amputation. Inflammation may impede the wound healing process if not properly controlled. The root of Astragalus membranaceus (AR) is one of the Chinese herbs commonly found in Chinese herbal formulae used for treating foot ulcer. In this study, we aimed to identify the active fractions and/or compounds from AR aqueous extract, which are responsible for the anti-inflammatory effect using in vitro bioassay-guided fractionation. The anti-inflammatory effect was monitored by the inhibition of nitric oxide (NO) released from lipopolysaccharide-stimulated mouse macrophage RAW 264.7 cells after treated with AR aqueous extract or its fractions and isolated components. Two major active fractions (P2-3-2-2-2 and P2-3-2-2-3) were found to significantly inhibit NO production at 0.156 mg/mL (p < 0.01). In addition, three chemical components (formononetin, calycosin and astragaloside IV) were successfully isolated from P2-3-2-2-3. Only formononetin could significantly inhibit NO production (p < 0.01), whereas the other two components had no significant effects at concentrations ranging from 0.039 to 0.156 mg/mL. In conclusion, two major anti-inflammatory active fractions that may enhance wound healing were identified, and formononetin was one of the active ingredients in the active fractions.

Antiproliferative effect of pheophorbide a-mediated photodynamic therapy and its synergistic effect with doxorubicin on multiple drug-resistant uterine sarcoma cell MES-SA/Dx5.

Prolonged cancer chemotherapy is associated with the development of multidrug resistance (MDR), which is a major cause of treatment failure. Photodynamic therapy (PDT) has been applied as anticancer therapy and a means of circumventing MDR. The antiproliferative effect of pheophorbide a-mediated photodynamic therapy (Pa-PDT) has been demonstrated in several human cancer cell lines, including the uterine sarcoma cell line, MES-SA. This study set out to evaluate, first, the therapeutic potential of Pa-PDT on MES-SA/Dx5 uterine sarcoma cells and, subsequently, the effectiveness of combination therapy using Pa-PDT with doxorubicin (Dox). Our results showed that Pa-PDT was able to circumvent MDR in the P-glycoprotein (P-gp) overexpressing human uterine sarcoma cell line, MES-SA/Dx5. Intracellular accumulation of Pa and Pa-PDT-induced cell death was not abrogated by MDR phenotype, when compared to the parental cell line, MES-SA. Combined therapy using Pa-PDT and Dox, a common chemotherapeutic drug, was found to be synergistic in the cell line, MES-SA/Dx5. Both activity and expression of MDR1 and P-gp were reduced by Pa-PDT treatment and such reductions were attenuated by α-tocopherol, the scavenger of reactive oxygen species (ROS), suggesting that the effect of Pa-PDT was mediated by the generation of intracellular ROS. In conclusion, our findings demonstrated the therapeutic potential of Pa-PDT alone or in combination with Dox in combating multidrug-resistant malignancies.

Epigenetic loss of CDH1 correlates with multidrug resistance in human hepatocellular carcinoma cells.

Promoter CpG hypermethylation of tumor suppressor genes is an essential step in cancer progression but little is known about its effect on cancer multidrug resistance. In this study, we showed that CDH1 promoter was hypermethylated in drug resistance of a doxorubicin-induced multidrug resistant hepatocellular carcinoma cell line R-HepG2. Transfection of CDH1 cDNA into R-HepG2 cells led to increased amount of doxorubicin uptake, decreased cell viability, decreased P-glycoprotein expression and increased apoptotic population of cells exposed to doxorubicin. Proto-oncogene tyrosine-protein kinase FYN was over-expressed in R-HepG2 cells which displayed a negative correlation with the expression of CDH1. FYN was knocked down in R-HepG2 cells, leading to less drug resistance by increased cell viability, increased doxorubicin uptake and attenuated P-glycoprotein expression. Our findings identified epigenetic silencing of CDH1 in cancer cells might be a new molecular event of multidrug resistance.