Ding Zhi Fang

Improved Efficacy and Reduced Toxicity of Doxorubicin Encapsulated in Sulfatide-Containing Nanoliposome in a Glioma Model

As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatide-containing nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5∶1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drugs principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

Enhanced Antitumor Efficacy and Reduced Systemic Toxicity of Sulfatide-Containing Nanoliposomal Doxorubicin in a Xenograft Model of Colorectal Cancer

Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX), a sulfatide-containing liposome (SCL) encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX) using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

TaqIB polymorphism in the CETP gene modulates the impact of HC/LF diet on the HDL profile in healthy Chinese young adults

The aim of this study was to investigate the interactions of genetic variants in the genes of cholesterol ester transfer protein (CETP) and low-density lipoprotein receptor (LDLR) with high carbohydrate and low fat (HC/LF) diet on lipid profiles in a young and healthy Chinese Han population. Fifty-six healthy subjects (22.89±1.80 years) were given washout diets of 31% fat and 54% carbohydrate for 7 days, followed by HC/LF diets of 15% fat and 70% carbohydrate for 6 days, with no total energy restriction. Serum lipid profiles at baseline, after washout and following HC/LF diets, as well as CETP and LDLR polymorphisms were analyzed. Carriers of B2 allele of CETP TaqIB polymorphism had significantly higher levels of high density lipoprotein cholesterol (HDL-C) and apo A-I in the whole study population after the diet intervention. Notably, males with CETP TaqIB B1B1 experienced significantly increased HDL-C and apo A-I after HC/LF diet. Regarding the LDLR Pvu II polymorphism, both P1P1 subjects and P2 carriers experienced decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels after HC/LF diet with no statistically significant differences between the genotypes. Our results demonstrate that the elevated HDL-C levels after HC/LF diet in healthy Chinese Han youth are associated with CETP TaqI B2 allele while males with B1B1 genotype are more susceptible to the influence of HC/LF diet on their HDL-C levels. The decreased TC and LDL-C levels after HC/LF diet are not associated with LDLR Pvu II polymorphism.

Reduced severity of posttraumatic stress disorder associated with Val allele of Val66Met polymorphism at brain-derived neurotrophic factor gene among Chinese adolescents after Wenchuan earthquake

The aim of the present study was to longitudinally investigate the association of BDNF Val66Met with PTSD symptoms in Chinese Han adolescents who experienced the 2008 Wenchuan earthquake. Variants of BDNF Val66Met were identified by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. PTSD symptoms were assessed by the PTSD Checklist-Civilian Version (PCL-C) among high school students at 6, 12, and 18 months after the earthquake. No differences of PTSD prevalence and PCL-C scores were found between the Val/Val homozygotes and the Met allele carriers at 6, 12, and 18 months after the earthquake regardless of gender. Decreased PTSD prevalence was observed at 12 and 18 months when compared with that at 6 months after the earthquake regardless of gender and the genotype. Meanwhile, PCL-C scores were decreased consecutively in the female subjects regardless of the genotypes. However, the scores at 18 months were lower when compared with those at 12 months in the male Val/Val homozygotes, but not in the male Met allele carriers. In addition, differences were found for the predictors of PCL-C scores and PTSD prevalence between the Val/Val homozygotes and the Met allele carriers during follow-up. These findings suggest that the association of BDNF Val66Met with PTSD is longitudinally different in Chinese Han adolescents after the 2008 Wenchuan earthquake. The Val allele may be associated with reduced PTSD severity in male adolescents in the later stage of PTSD rehabilitation during follow-up.

Elevated Levels of Triglyceride and Triglyceride-Rich Lipoprotein Triglyceride Induced by a High-Carbohydrate Diet Is Associated with Polymorphisms of APOA5-1131T>C and APOC3-482C>T in Chinese Healthy Young Adults

Background/Aims: Changes in lipid profiles have been shown to be associated with diet and apolipoprotein (APO) polymorphisms. Therefore, 2 polymorphisms, i.e. APOA5-1131T>C and APOC3-482C>T, and serum lipids were examined in a Chinese healthy young population with high-carbohydrate/low-fat (HC/LF) diet intervention. Methods: After a wash-out diet for 7 days, 56 young adults (22.89 ± 1.80 years) received the HC/LF diet for 6 days. Body mass index (BMI) and fasting serum lipid profiles at baseline, after the wash-out diet, and after the HC/LF diet were measured. Results: APOA5-1131C carriers had higher triglyceride (TG) and TG-rich lipoprotein TG (TRL-TG) levels at baseline and after the HC/LF diet, though this mainly corresponded to the female cohort. APOC3-482T carriers had higher TRL-TG levels following the wash-out and HC/LF diets, but these were not directly attributable to a single gender. Conclusions: Both polymorphisms may play an important role in the elevated TG and TRL-TG levels induced by the HC/LF diet, especially in females, thus indicating a potential dietary prevention of coronary heart disease in this Chinese cohort.

A longitudinal study of the association of adiponectin gene rs1501299 with depression in Chinese Han adolescents after Wenchuan earthquake

BACKGROUND Previous studies showed inconsistent results of the association between plasma adiponectin and depression. The aim of this study is to longitudinally investigate the association of adiponectin rs1501299 with depression in Chinese Han adolescents who experienced the 2008 Wenchuan earthquake. METHOD Variants of adiponectin rs1501299 were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Depressive symptoms were assessed by Beck Depression Inventory (BDI) among 746 high school students at 6, 12 and 18 months after the earthquake. RESULTS The female T allele carriers of adiponectin rs1501299 had lower prevalence of depression (p=0.008) and BDI scores (p=0.024) than the female GG homozygotes at 18 months, but not at 6 or 12 months after the earthquake, which were significantly reduced (p=0.022 for the prevalence and p<0.001 for the scores) in the female T allele carriers at 18 months after the earthquake when compared with those at 12 months. In addition, the major predictors of depression for the GG homozygotes were gender and age at 6, 12 and 18 months after earthquake. On the other hand, the major predictor for the T allele carriers was gender at 6, 12 and 18 months after earthquake. LIMITATIONS There were some limitations in the present study. First, adiponectin expressions including serum adiponectin and mRNA in adipose tissues were not measured. Second, the effect of body mass index was not evaluated. CONCLUSIONS The adiponectin T allele is associated with reduced prevalence of depression and lower BDI scores of female adolescents in the later stage of rehabilitation of depression.

Predictive factors of depression symptoms among adolescents in the 18-month follow-up after Wenchuan earthquake in China

Abstract Background: It is unclear about the change and risk factors of depression among adolescent survivors after earthquake. Aims: This study aimed to explore the change of depression, and identify the predictive factors of depression among adolescent survivors after the 2008 Wenchuan earthquake in China. Methods: The depression among high school students at 6, 12 and 18 months after the Wenchuan earthquake were investigated. The Beck Depression Inventory (BDI) was used in this study to assess the severity of depression. Results: Subjects included 548 student survivors in an affected high school. The rates of depression among the adolescent survivors at 6-, 12- and 18-month after the earthquake were 27.3%, 42.9% and 33.3%, respectively, for males, and 42.9%, 61.9% and 53.4%, respectively, for females. Depression symptoms, trauma-related self-injury, suicidal ideation and PTSD symptoms at the 6-month follow-up were significant predictive factors for depression at the 18-month time interval following the earthquake. Conclusions: This study highlights the need for considering disaster-related psychological sequela and risk factors of depression symptoms in the planning and implementation of mental health services. Long-term mental and psychological supports for victims of natural disasters are imperative.

Associations of Lipoprotein Lipase Gene rs326 with Changes of Lipid Profiles after a High-Carbohydrate and Low-Fat Diet in Healthy Chinese Han Youth

To investigate the effects of a high-carbohydrate and low-fat (HC/LF) diet on plasma lipids and apolipoproteins (Apos) of healthy Chinese Han youth with different genotypes of lipoprotein lipase gene (LPL) rs326, 56 subjects were given a washout diet of 30.1% fat and 54.1% carbohydrate for seven days, followed by the HC/LF diet of 13.8% fat and 70.1% carbohydrate for six days, with no total energy restriction. Plasma glucose, triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), Apo B-100 and Apo A-I were analyzed at baseline and before and after the HC/LF diet. The results show that, when compared with before the HC/LF diet, only the male G carriers experienced increased HDL-C (p = 0.008) and Apo A-I (p = 0.005) after the HC/LF diet. Decreased TC in both males and females and increased TG in females were found regardless of the genotype after the HC/LF diet. LDL-C decreased in all the subjects although the decrease was not significant in the female G carriers. These results demonstrate that the G allele of LPL rs326 associates with the elevated levels of HDL-C and Apo A-I after the HC/LF diet in males of the healthy Chinese Han Youth.

A high-carbohydrate diet enhances the adverse effect of the S2 allele of APOC3 SstI polymorphism on the TG/HDL-C ratio only in young Chinese females

Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 ± 1.80 years) were given a washout diet of 54% carbohydrate for 7 days, followed by a high-CHO diet of 70% carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 ± 1.00 vs 2.36 ± 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 ± 0.74 vs 2.09 ± 0.55, P = 0.000; female S2 carriers: 2.68 ± 0.36 vs 2.24 ± 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 ± 0.41 vs 2.09 ± 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 ± 0.71 vs 1.06 ± 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 ± 0.61 vs 1.01 ± 0.29, P = 0.005; female S2 carriers: 1.18 ± 0.33 vs 1.00 ± 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 ± 0.35 vs 1.04 ± 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 ± 0.46 vs 1.63 ± 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has favorable effects on the TC/HDL-C and LDL-C/HDL-C ratios regardless of gender and of genotype of the APOC3 SstI polymorphism. Somehow, it enhanced the adverse effect of the S2 allele on the TG/HDL-C ratio only in females.

High-Carbohydrate/Low-Fat Diet-Induced Gender-Specific Serum Lipid Profile Changes Are Associated with LEPR Polymorphisms in Chinese Youth.

Background/Aims: The study aimed to investigate the interactions of genetic variants in the leptin receptor (LEPR) gene with lipid profile changes following a high-carbohydrate/low-fat (HC/LF) diet in a Chinese Han population. Methods: Fifty-six healthy young subjects were given washout diets, followed by HC/LF diets consisting of 15% fat and 70% carbohydrate for 6 days. Serum lipid profiles and insulin levels before and after HC/LF diets were analyzed. Results: Statistically elevated high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apoA-I), and insulin levels were only observed in the GG genotype of LEPR Lys109Arg but not in the A carriers after HC/LF diet. When gender was taken into account, significantly increased HDL-C, apoA-I, and insulin levels were found in women with the GG genotype. Moreover, lower low-density lipoprotein cholesterol (LDL-C) and higher insulin levels were only observed in subjects with the GG genotype of LEPR Gln223Arg, while higher HDL-C and apoA-I were only found in the A allele carriers. Additionally, the lower LDL-C and body mass index (BMI), and higher HDL-C and insulin levels were only observed in subjects with the GG genotype of LEPR Lys656Asn. Conclusions:LEPR polymorphisms contribute to the heterogeneities in BMI, LDL-C, and HDL-C responsiveness that are induced by a HC/LF diet in healthy young Chinese adults.