This review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis. We retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis. We included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes. There are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk. This review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.

OBJECTIVE—We investigated the phenotypic features of diabetic microvascular complications and their association with a (CA)_n microsatellite and a C/T polymorphism at the 5′ region of the aldose reductase gene (ALR2) in a consecutive cohort of 738 Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS—Of the entire patient cohort, 392 were free of diabetes complications, or uncomplicated, 159 had diabetic nephropathy, 66 had diabetic retinopathy, and 121 had both diabetic nephropathy and retinopathy. Nephropathy was defined as urinary albumin excretion rate (AER) ≥20 μg/min and albumin-to-creatinine ratio ≥3.5 mg/mmol in two urine collections. Retinopathy was defined by the presence of hemorrhages, exudates, laser marks, and fibrous proliferation or by a history of vitrectomy. (CA)_n and C/T polymorphisms were examined by PCR followed by capillary electrophoresis and digestion with BfaI, respectively. RESULTS—In the whole cohort, patients with diabetic retinopathy (n = 187) had higher blood pressure and lower BMI, while those with diabetic nephropathy (n = 280) had higher blood pressure, waist-to-hip ratio, and lipid profile than those without the respective complications. The z+6 carriers of the (CA)_n polymorphism were less common in patients with diabetic retinopathy than those without diabetic retinopathy (n = 551) (4.3 vs. 9.3%, P = 0.04). The CT/TT carriers had a higher AER than the CC carriers (30.2 ×/÷ 7.2 vs. 21.9 ×/÷ 6.9 μg/min, P = 0.03). Further subgroup analysis was performed after excluding uncomplicated patients with <5 years disease duration. The group with both diabetic nephropathy and retinopathy had higher frequencies of the z-2 allele (25.7 vs. 16.9%, P = 0.03) and T allele (26.4 vs. 18.5%, P = 0.04) and a lower frequency of the z+6 allele (1.7 vs. 5.5%, P = 0.054) than the uncomplicated group. Multiple logistic regression analysis confirmed that z-2 carrying (odds ratio 2.6, 95% CI 1.20–5.83, P = 0.02) and CT/TT genotypes (OR 2.5, 95% CI 1.19–5.19, P = 0.02) were independent predictors for both diabetic nephropathy and retinopathy. CONCLUSIONS—Chinese type 2 diabetic patients exhibited phenotypic differences in terms of risk factors for both diabetic nephropathy and diabetic retinopathy. Both the z-2 allele of (CA)_n polymorphism and T allele of ALR2 were independently associated with severe diabetic microvascular complications.

Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1)in vitrostudies using cell line models; (2) serum pharmacology; (3)in vivostudies using animal models; and (4) clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time.In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studiesin vivoshowed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance.

Cadmium (Cd) pollution is a serious global problem, which causes irreversible toxic effects on animals. Freshwater crab, Sinopotamon henanense, is a useful environmental indicator since it is widely distributed in benthic habitats whereby it tends to accumulate Cd and other toxicants. However, its molecular responses to Cd toxicity remain unclear. In this study, we performed transcriptome sequencing and gene expression analyses of its hepatopancreas with and without Cd treatments. A total of 7.78 G clean reads were obtained from the pooled samples and 68,648 unigenes with an average size of 622 bp were assembled, in which 5,436 were metabolism-associated and 2,728 were stimulus response-associated that include 380 immunity-related unigenes. Expression profile analysis demonstrated that most genes involved in macromolecular metabolism, oxidative phosphorylation, detoxification and anti-oxidant defense were up-regulated by Cd exposure, whereas immunity-related genes were down-regulated, except the genes involved in phagocytosis were up-regulated. The current data indicate that Cd exposure alters gene expressions in a concentration-dependent manner. Therefore, our results provide the first comprehensive S.henanense transcriptome dataset, which is useful for biological and ecotoxicological studies on this crab and its related species at molecular level and some key Cd-responsive genes may provide candidate biomarkers for monitoring aquatic pollution by heavy metals.

OBJECTIVE—We examined the prevalence of different forms of diabetes in Hong Kong Chinese patients with familial early-onset type 2 diabetes and compared their clinical features with patients with familial late-onset type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 145 young patients with early-onset diabetes (age and age at diagnosis ≤40 years) and a family history of diabetes were studied. They were screened for mutations in the genes encoding glucokinase, hepatocyte nuclear factor (HNF)-4α, and HNF-1α. The mitochondrial DNA A→G at nucleotide 3243 (mt3243) and amylin S20G mutations were studied, and antibodies to GAD (anti-GADs) were also examined. RESULTS—The prevalence of putative diabetogenic gene mutations and autoimmune markers were 4% for glucokinase, 0% for HNF-4α, 5% for HNF-1α, 3% for mt3243, 2% for amylin S20G, and 4% for anti-GAD. Compared with late-onset patients, the patients with early-onset diabetes had a higher prevalence of a parental history of diabetes and were generally more obese. When classified by obesity indexes (BMI and waist circumference), the obese patients, especially those with early-onset diabetes, had a clustering of cardiovascular risk factors and increased rates of retinopathy and albuminuria. CONCLUSIONS—Genetic factors (up to 14%) and obesity (55%) play more significant roles than autoimmunity (4%) in familial type 2 diabetes in young Chinese patients. The significance of obesity-related genes and other gene-gene and gene-environment interactions in these young patients remains to be determined.

Background/Aims: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Levistolide A (LA), a natural compound isolated from the traditional Chinese herb Ligusticum chuanxiong Hort, is used for treating cancer. In this study, we investigated the anticancer effect of LA in HCT116 and its isogenic p53-/- colon cancer cells, as well as the underlying mechanisms. Methods: MTT assay was used to evaluate the effect of LA on the viability of cancer cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined by flow cytometry. Protein expression was detected by western blotting. Results: The results showed that LA inhibited viability and caused apoptosis of both wild-type and p53-/- HCT116 cells. LA was able to trigger production of ROS and endoplasmic reticulum (ER) stress. Inhibition of ROS using N-acetylcysteine abrogated LA-induced ER stress and apoptosis, as well as the reduction in cancer cell viability. Conclusion: Our results indicate that LA causes apoptosis of colon cancer cells via ROS-mediated ER stress pathway. It will be interesting to develop the natural compound for chemotherapy of cancers such as CRC.