Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model.

Diabetes mellitus is a well-known chronic metabolic disease that poses a long-term threat to human health and is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. Type 2 diabetes mellitus (T2DM) typically affects many metabolic pathways, resulting in ß-cell dysfunction, insulin resistance, abnormal blood glucose levels, inflammatory processes, excessive oxidative reactions, and impaired lipid metabolism. It also leads to diabetes-related complications in many organ systems. Antidiabetic drugs have been approved for the treatment of hyperglycemia in T2DM; these are beneficial for glucose metabolism and promote weight loss, but have the risk of side effects, such as nausea or an upset stomach. A wide range of active components, derived from medicinal plants, such as alkaloids, flavonoids, polyphenol, quinones, and terpenoids may act as alternative sources of antidiabetic agents. They are usually attributed to improvements in pancreatic function by increasing insulin secretions or by reducing the intestinal absorption of glucose. Ease of availability, low cost, least undesirable side effects, and powerful pharmacological actions make plant-based preparations the key player of all available treatments. Based on the study of therapeutic reagents in the pathogenesis of humans, we use the appropriate animal models of T2DM to evaluate medicinal plant treatments. Many of the rat models have characteristics similar to those in humans and have the advantages of ease of genetic manipulation, a short breeding span, and access to physiological and invasive testing. In this review, we summarize the pathophysiological status of T2DM rat models and focus on several bioactive compounds from herbal medicine with different functional groups that exhibit therapeutic potential in the T2DM rat models, in turn, may guide future approach in treating diabetes with natural drugs.

Cosmetic and Therapeutic Applications of Fish Oil's Fatty Acids on the Skin.

Fish oil has been broadly reported as a potential supplement to ameliorate the severity of some skin disorders such as photoaging, skin cancer, allergy, dermatitis, cutaneous wounds, and melanogenesis. There has been increasing interest in the relationship of fish oil with skin protection and homeostasis, especially with respect to the omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). The other PUFAs, such as α-linolenic acid (ALA) and linoleic acid (LA), also show a beneficial effect on the skin. The major mechanisms of PUFAs for attenuating cutaneous inflammation are the competition with the inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production. On the other hand, PUFAs in fish oil can be the regulators that affect the synthesis and activity of cytokines for promoting wound healing. A systemic review was conducted to demonstrate the association between fish oil supplementation and the benefits to the skin. The following describes the different cosmetic and therapeutic approaches using fatty acids derived from fish oil, especially ALA, LA, DHA, and EPA. This review summarizes the cutaneous application of fish oil and the related fatty acids in the cell-based, animal-based, and clinical models. The research data relating to fish oil treatment of skin disorders suggest a way forward for generating advances in cosmetic and dermatological uses.

Validation of a new simple scale to measure symptoms in heart failure from traditional Chinese medicine view: a cross-sectional questionnaire study.

BACKGROUND: Current clinical practices used to functionally classify heart failure (HF) are time-consuming, expensive, or require complex calculations. This study aimed to design an inquiry list from the perspective of traditional Chinese medicine (TCM) that could be used in routine clinical practice to resolve these problems. METHODS: The severity of documented HF in 115 patients was classified according to their performance in maximal exercise tests into New York Heart Association (NYHA) functional classification (FC) II or NYHA FC III. Concomitantly, the patients were assessed using the new TCM inquiry list and two validated quality of life questionnaires, namely, the Short Form 36 (SF-36) generic scale and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Factor analysis was applied to extract the core factors from the responses to the items in TCM inquiry list; logistic regression analysis was then used to predict the severity of HF according to the extracted factors. RESULTS: The TCM inquiry list showed moderate levels of correlation with the physical and emotional components of the SF-36 and the MLHFQ, and predicted the functional class of HF patients reliably using logistic regression analysis, with a correct prediction rate with 64.3 %. Factor analysis of the TCM inquiry list extracted five core factors, namely, Qi Depression, Heart Qi Vacuity and Blood Stasis, Heart Blood Vacuity, Dual Qi-Blood Vacuity, and Yang Vacuity, from the list, which aligned with the perspective of TCM as it relates to the pattern of HF. The correct prediction rate rose to 70.4 % when Dual Qi-Blood Vacuity was combined with the MLHFQ. The excessive false-negative rate is a problem associated with the TCM inquiry list. CONCLUSIONS: The TCM inquiry list is a simple scale and similar to patient-reported subjective measures of quality of life in HF, and may help to classify patients into NYHA FC II or NYHA FC III. Factor 4 addresses dizziness, dizzy vision and general weakness, which are critical parameters that distinguish between NYHA FC II and NYHA FC III. Incorporating these three items into the management of HF may help to classify patients from a functional perspective.

Laser-assisted nanocarrier delivery to achieve cutaneous siRNA targeting for attenuating psoriasiform dermatitis.

Psoriasis is an autoimmune skin disorder presenting the excessive expression of interleukin (IL)-6. The topical use of small interfering RNA (siRNA) has been increasingly discovered for treating skin diseases. A delivery system capable of protecting siRNA while facilitating both skin targeting and cellular entrance is critical for the successful medication of topically-applied siRNA. Herein, we developed a delivery system for siRNA based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles and combined this system with an ablative laser to promote skin absorption for topical psoriasis therapy. The siRNA absorption enhancement was compared by two laser modalities: a fractional CO2 laser and a fully-ablative Er:YAG laser. We characterized the effect of the delivery system by the cellular uptake, IL-6 silencing, in vitro skin absorption, cutaneous biodistribution, and in vivo psoriasiform dermatitis in mice. The nanocarriers showed minimal cytotoxicity and facile cellular uptake to knock down the IL-6 expression. The nanoformulation containing a cationic surfactant (Forestall) for ion pairing with siRNA achieved a 66% and 77% IL-6 knockdown efficiency toward keratinocytes and macrophages, respectively. In the Franz cell absorption, the lasers increased the naked siRNA penetration to the receptor compartment by 3.7-5.0-fold but remarkably reduced skin deposition using imiquimod (IMQ)-treated psoriasiform skin as the barrier. The fractional laser facilitated nanoparticle-associated siRNA skin deposition up to 3.3-fold, whereas the transport of the nanocarriers to the receptor was negligible. Qualitatively, the lasers increased nanoparticle delivery in the epidermis with limited effect to elevate the penetration depth. The fractional-mediated nanocarrier delivery dramatically attenuated the erythema and scaly lesions of psoriasiform dermatitis. The histological examination displayed a reduction of epidermal hyperplasia and macrophage infiltration by the combination of laser and nanosystem. The passive and laser-assisted naked siRNA delivery was less effective in mitigating dermatitis. The topical delivery of fractional laser-assisted nanoparticles on mice resulted in a 56% IL-6 knockdown. Our results manifested the benefit of cutaneous siRNA targeting using ablative lasers to deliver nanocarriers for treating psoriatic inflammation.

Facile Biofilm Penetration of Cationic Liposomes Loaded with DNase I/Proteinase K to Eradicate Cutibacterium acnes for Treating Cutaneous and Catheter Infections.

BACKGROUND: The biofilm produced by Cutibacterium acnes is a major infection threat for skin and implanted catheters. Nanoparticles provide a new approach to eradicate biofilms. The present study evaluated the capability of cationic liposomes loaded with DNase I (DNS) and proteinase K (PK) to remove preformed C. acnes biofilms. METHODS: DNS and PK were able to target and disassemble the biofilm by degrading extracellular polymer substances (EPS). Soyaethyl morpholinium ethosulfate (SME) was used to render a positive charge and enhance the antibacterial activity of the liposomes. RESULTS: The cationic liposomes containing enzymes yielded monodisperse nanovesicles ranging between 95 and 150 nm. The entrapment efficiency of the enzymes in the liposomes achieved a value of 67-83%. All liposomal formulations suppressed planktonic C. acnes growth at a minimum inhibitory concentration (MIC) equal to the free SME in the solution. The enzyme in the liposomal form inhibited biofilm growth much better than that in the free form, with the dual enzyme-loaded liposomes demonstrating the greatest inhibition of 54% based on a crystal violet assay. The biofilm-related virulence genes PA380 and PA1035 were downregulated by the combined enzymes in the liposomes but not the individual DNS or PK. Scanning electron microscopy (SEM) and confocal microscopy displayed reduced C. acnes aggregates and biofilm thickness by the liposomal system. The liposomes could penetrate through about 85% of the biofilm thickness. The in vitro pig skin permeation also showed a facile delivery of liposomes into the epidermis, deeper skin strata, and hair follicles. The liposomes exhibited potent activity to eliminate C. acnes colonization in mouse skin and catheters in vivo. The colony-forming units (CFUs) in the catheter treated with the liposomes were reduced by 2 logs compared to the untreated control. CONCLUSION: The data suggested a safe application of the enzyme-loaded cationic liposomes as antibacterial and antibiofilm agents.

Coenzyme Q0 From Antrodia cinnamomea Exhibits Drug-Resistant Bacteria Eradication and Keratinocyte Inflammation Mitigation to Ameliorate Infected Atopic Dermatitis in Mouse.

Atopic dermatitis (AD) is an inflammatory skin disease that is usually accompanied by Staphylococcus aureus infection due to cutaneous barrier-function damage. Benzenoid compounds from Antrodia cinnamomea are known to exhibit antibacterial and anti-inflammatory activities. This study sought to investigate the potential of benzenoids for treating bacteria-infected AD. The compounds were screened against methicillin-resistant S. aureus (MRSA). Coenzyme Q0 (CoQ0), a key ingredient in A. cinnamomea, showed the strongest MRSA growth inhibition. We further tested the inhibitory effect of CoQ0 on planktonic and biofilm MRSA. The work was also performed to explore the potential effectiveness of CoQ0 on AD using activated keratinocytes and in vivo experimental AD mice as the models. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CoQ0 against MRSA were 7.81 µg/ml. CoQ0 was found to eradicate biofilm MRSA efficiently and reduce the biofilm thickness. CoQ0 killed MRSA by inhibiting DNA polymerase and topoisomerases. A proteomic assay showed that CoQ0 also reduced the ribosomal proteins. In the anti-inflammation study, CoQ0 was found to downregulate the expression of interleukin (IL)-6, chemokine (C-C motif) ligand (CCL)5, and CCL17 in HaCaT cells. CoQ0 at 0.5 µg/ml could recover the filaggrin decreased by HaCaT activation to the normal control. We established a bacteria-infected AD-like model in mice using ovalbumin (OVA) and topically applied MRSA. Topical CoQ0 delivery lessened the MRSA presence in the AD-like lesions by >90%. The erythema, barrier function, and epidermal thickness of the AD-like wounds were improved by CoQ0 through the reduction of IL-1ß, IL-4, IL-6, IL-10, interferon (IFN)-γ, and by neutrophil infiltration in the lesional skin. CoQ0 is therefore regarded as effective in mitigating AD symptoms associated with bacterial load.

Analysis of Factors Influencing the Efficiency of Acupuncture in Tinnitus Patients.

An effective acupuncture treatment must comprehend the influence of various factors, but studies in this aspect remain limited. This study aimed to identify relevant factors and search for the best practical method of acupuncture for patients with tinnitus. The study was a retrospective review of patients' data with a prospective design who had subjective idiopathic tinnitus and received acupuncture between May 2012 and August 2017. Patients' demographics, tinnitus characteristics, previous diseases, underlying diseases, oral habits, audiograms, acupuncture sessions, and acupoints were recorded and analyzed. A visual analog scale (VASloudness) was used for measuring the loudness of tinnitus, and the Clinical Global Impression-Improvement scale (CGI-I) was used for assessing the suffering of patients. Good treatment responses in patients were defined as the magnitude of change from the baseline VASloudness for ≥ 30% plus CGI-I ≤ 3 points. In total, 107 patients were enrolled. Most factors were not significantly associated with the treatment effectiveness of acupuncture in tinnitus patients. Only the combination of acupoints and the number of acupuncture sessions reached statistically significant differences. Further analyzing these two factors, we confirmed that the combination of periauricular and distal acupuncture and 17 to 24 acupuncture sessions contributed to a considerably better outcome. This result would serve as a reference for clinical acupuncturists to select an appropriate acupuncture strategy in the treatment of tinnitus.

The atopic dermatitis-like lesion and the associated MRSA infection and barrier dysfunction can be alleviated by 2,4-dimethoxy-6-methylbenzene-1,3-diol from Antrodia camphorata.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease with an associated barrier dysfunction and Staphylococcus aureus infection. The mainstay steroid and calcineurin inhibitor therapy shows some adverse effects. 2,4-Dimethoxy-6-methylbenzene-1,3-diol (DMD) is a benzenoid isolated from Antrodia camphorata. OBJECTIVE: We investigated the inhibitory effect of DMD on methicillin-resistant S. aureus (MRSA), the chemokine production in stimulated keratinocytes, and the AD-like lesion found in ovalbumin (OVA)-sensitized mice. METHODS: The antimicrobial effect and cutaneous barrier function were evaluated using an in vitro culture model and an in vivo mouse model of AD-like skin. RESULTS: DMD exhibited a comparative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against MRSA with nalidixic acid, a conventional antibiotic. The MIC and MBC for DMD was 78.1 and 156.3 µg/ml, respectively. DMD also showed the ability to eliminate the clinical bacteria isolates with resistance to methicillin and vancomycin. The DNA polymerase and gyrase inhibition evoked by DMD for bacterial lethality was proposed. In the activated keratinocytes, DMD stopped the upregulation of chemokines (CCL5 and CCL17) and increased the expression of differentiation proteins (filaggrin, involucrin, and integrin ß-1). Topical application of DMD facilely penetrated into the skin, with AD-like skin displaying 2.5-fold greater permeation than healthy skin. The in vivo assessment using the mouse model with OVA sensitization and MRSA inoculation revealed a reduction of transepidermal water loss (TEWL) and bacterial burden by DMD by about 2- and 100-fold, respectively. Differentiation proteins were also restored after topical DMD delivery. CONCLUSION: Our data demonstrated an advanced concept of AD treatment by combined barrier repair and bacterial eradication with a sole agent for ameliorating the overall complications.

A new grid-scale model simulating the spatiotemporal distribution of PM2.5-PAHs for exposure assessment.

Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Several modeling approaches have been developed for simulating ambient PAHs, but no hourly intra-urban spatial data are currently available. The aim of this study is to develop a new modeling strategy in simulating, on an hourly basis, grid-scale PM2.5-PAH levels. PM and PAHs were collected over a one-year time frame through an established air quality monitoring network within a metropolitan area of Taiwan. Multivariate linear regression models, in combination with correlation analysis and PAH source identification by principal component analysis (PCA), were performed to simulate hourly grid-scale PM2.5-PAH concentrations, taking criteria pollutants and meteorological variables selected as possible predictors. The simulated levels of 72-h personal exposure were found to be significantly (R=0.729**, p<0.01) correlated with those analyzed from portable personal monitors. A geographic information system (GIS) was used to visualize spatially distributed PM2.5-PAH concentrations of the modeling results. This new grid-scale modeling strategy, incorporating the output of simulated data by GIS, provides a useful and versatile tool in personal exposure analysis and in the health risk assessment of air pollution.

In utero exposure to dioxins and polychlorinated biphenyls and its relations to thyroid function and growth hormone in newborns.

The aim of this study is to examine the association between transplacental exposure to dioxins/polychlorinated biphenyls (PCBs) and thyroid and growth hormones in newborns. We recruited 118 pregnant women, between 25 and 34 years of age, at the obstetric clinic. Personal data collected included reproductive and medical histories and physical factors. Clinicians gathered placental and umbilical cord serum upon delivery and carefully scored the 118 newborns, making both structural and functional assessments. We analyzed placentas for 17 polychlorinated dibenzo-p-dioxins and dibenzofurans and 12 dioxin-like PCB congeners with the World Health Organization-defined toxic equivalent factors, and six indicator PCBs by high-resolution gas chromatography and high-resolution mass spectrometry. We analyzed thyroid and growth hormones from cord serum using radioimmunoassay. Insulin-like growth factor (IGF)-1, IGF-binding globulin-3, and thyroxine x thyroid-stimulating hormone (T4 x TSH) were significantly associated with increased placental weight and Quetelet index (in kilograms per square meter; correlation coefficient r = 0.2-0.3; p < 0.05). Multivariate analyses showed independently and significantly decreased free T4 (FT4) x TSH with increasing non-ortho PCBs (r = -0.2; p < 0.05). We suggest that significant FT4 feedback alterations to the hypothalamus result from in utero exposure to non-ortho PCBs. Considering the vast existence of bioaccumulated dioxins and PCBs and the resultant body burden in modern society, we suggest routine screening of both thyroid hormone levels and thyroid function in newborns.

Osteoblastic differentiation of stem cells from human exfoliated deciduous teeth induced by thermosensitive hydrogels with strontium phosphate.

Stem cells from human exfoliated deciduous teeth (SHEDs) are a novel source of multi-potential stem cells for tissue engineering because of their potential to differentiate into multiple cell lineages. Strontium exhibits an important function in bone remodeling because it can simulate bone formation and decrease bone resorption. Hydrogels can mimic the natural cellular environment. The association of hydrogels with cell viability is determined using biological tests, including rheological experiments. In this study, osteogenic differentiation was investigated through SHED encapsulation in hydrogels containing strontium phosphate. Results of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and proliferating cell nuclear antigen (PCNA) immunofluorescence staining indicated that the cells grew well and SHEDs proliferated in the hydrogels. Strontium-loaded chitosan-based hydrogels induced the biomineralization and high expression of alkaline phosphatase. Moreover, the expression levels of bone-related genes, including type-I collagen, Runx2, osteopontin (OP), and osteonectin (ON), were up-regulated during the osteogenic differentiation of SHEDs. This study demonstrated that strontium can be an effective inducer of osteogenesis for SHEDs. Elucidating the function of bioceramics (such as strontium) is useful in designing and developing strategies for bone tissue engineering.

Prevalence of non-insulin-dependent diabetes mellitus and related vascular diseases in southwestern arseniasis-endemic and nonendemic areas in Taiwan.

There is evidence indicating that ingestion of arsenic may predispose the development of diabetes mellitus in arsenic-endemic areas in Taiwan. However, the prevalence of diabetes and related vascular diseases in the entire southwestern arseniasis-endemic and nonendemic areas remains to be elucidated. We used the National Health Insurance Database for 1999-2000 to derive the prevalence of non-insulin-dependent diabetes and related vascular diseases by age and sex among residents in southwestern arseniasis-endemic and nonendemic areas in Taiwan. The study included 66,667 residents living in endemic areas and 639,667 in nonendemic areas, all greater than or equal to 25 years of age. The status of diabetes and vascular diseases was ascertained through disease diagnosis and treatment prescription included in the reimbursement claims of clinics and hospitals. The prevalence of non-insulin-dependent diabetes, age- and gender-adjusted to the general population in Taiwan, was 7.5% (95% confidence interval, 7.4-7.7%) in the arseniasis-endemic areas and 3.5% (3.5-3.6%) in the nonendemic areas. Among both diabetics and nondiabetics, higher prevalence of microvascular and macrovascular diseases was observed in arseniasis-endemic than in the nonendemic areas. Age- and gender-adjusted prevalence of microvascular disease in endemic and nonendemic areas was 20.0% and 6.0%, respectively, for diabetics, and 8.6% and 1.0%, respectively, for nondiabetics. The corresponding prevalence of macrovascular disease was 25.3% and 13.7% for diabetics, and 12.3% and 5.5% for nondiabetics. Arsenic has been suggested to increase the risk of non-insulin-dependent diabetes mellitus and its related micro- and macrovascular diseases.

Infant exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls (PCDD/Fs, PCBs)--correlation between prenatal and postnatal exposure.

Polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are recognized environmental endocrine disruptors, which are environmentally persistent and may bio-accumulate in human bodies. Pregnant and nursing women may pass these pollutants to their babies both trans-placentally and lactationally. We measured and examined correlations of the levels of PCDD/Fs and PCBs in perinatal venous serum, placenta, umbilical-cord serum (representing prenatal exposure), and breast milk (postnatal exposure). Subjects included pregnant women without clinical complication between the ages of 25 and 35, who delivered their babies during 2000.12.01 and 2001.11.30 in central Taiwan. A total of 20 participants were randomly selected from those provided the four biological specimens for analysis of 17 PCDD/Fs, and 12 dioxin-like PCBs and six indicator PCBs using high-resolution gas chromatography/high-resolution mass spectrometry. Higher PCDD/F levels were found in placenta (10.3 TEq-pg/g lipid) and venous serum (9.1 TEq-pg/g lipid) compared to those in breast milk (7.6 TEq-pg/g lipid). Pearson and Spearman correlation analyses showed well association of PCDD/F and PCB levels between different specimens. The total dioxin/PCB level in milk, venous and cord serum can be well predicted by that in placenta through regression functions. This first study of multi-specimen correlation further established rather consistent ratios of these chemical concentrations in various specimens relative to those in venous serum.

SNPs of GSTM1, T1, P1, epoxide hydrolase and DNA repair enzyme XRCC1 and risk of urinary transitional cell carcinoma in southwestern Taiwan.

A hospital-based case-control study was conducted near a former black-foot disease (BFD)-endemic area in southwestern Taiwan to examine the possible risk factors and genetic susceptibility for urinary transitional cell carcinoma (TCC). A total of 221 patients with pathologically confirmed TCC and 223 age-sex-matched control subjects from urology outpatient clinics were recruited between 1998 and 2002. The results showed that residency in the BFD area and consumption of well water for more than 10 years was a strong factor on urinary cancer risk (odds ratio [OR],8.16, 95% confidence interval [CI],3.34-19.90, p<0.0001). Dose response relationship between average arsenic concentration in well water and TCC risk was also observed. Cigarette smoking played a relatively minor role in urinary carcinogenesis in this study. The GSTP1 Ile105Val A-->G polymorphism was significantly associated with cancer risk (A/G+G/G: OR=0.60, 95%CI=0.39-0.94, p=0.02), and the effect of Val105 allele was largely confined to the subjects diagnosed earlier than 55 years old (A/G+G/G: OR,0.29; 95% CI, 0.09-0.87, p=0.03). The results suggest that GSTP1 is a candidate for susceptibility locus and Ile105 allele may predispose individuals to early-onset urinary TCC. The GSTM1 null genotype was associated with tumors of high-invasiveness (OR,2.21; 95% CI, 1.34-4.73) as well as with early-onset TCC risk (OR,2.53; 95% CI, 0.97-6.59). Our preliminary results showed the XRCC1 Arg194Trp were associated with arsenic-related urinary TCC and the interaction between the genotype and the exposure was statistically significant. The modulating effect of the GSTM1, GSTT1, GSTP1 Ile105Val, EPHX Tyr113His and XRCC1 Arg280His on arsenic-related TCC risk was also suggestive. These observations implied that impaired metabolism of carcinogenic exposure as well as impaired DNA repair function play an important role in arsenic-related urinary transitional cell carcinogenesis.

Biomarkers of exposure, effect, and susceptibility of arsenic-induced health hazards in Taiwan.

Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (<1 year) internal dose, skin hyperpigmentation and palmoplantar hyperkeratosis are for long-term (many years) internal dose, and percentage of monomethylarsonic acid in total metabolites of inorganic arsenic in urine may be considered as an exposure marker for biologically effective dose. The biomarkers of early biological effects of ingested inorganic arsenic included blood levels of reactive oxidants and anti-oxidant capacity, genetic expression of inflammatory molecules, as well as cytogenetic changes including sister chromatid exchange, micronuclei, and chromosome aberrations of peripheral lymphocytes. Both mutation type and hot spots of p53 gene were significantly different in arsenic-induced and non-arsenic-induced TCCs. The frequency of chromosomal imbalances analyzed by comparative genomic hybridization and the frequency of loss of heterozygosity were significantly higher in arsenic-induced TCC than non-arsenic-induced TCC at specific sites. Biomarkers of susceptibility to arsenic-induced health hazards included genetic polymorphisms of enzymes involved in xenobiotic metabolism, DNA repair, and oxidative stress, as well as serum level of carotenoids. Gene-gene and gene-environment interactions are involved in arsenic-induced health hazards through toxicological mechanisms including genomic instability and oxidative stress.