The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway

Aspartame (ASP) as an important sugar substitute is widely used in pharmaceutical and food processing. Here, we compared the effects of ASP and sucrose on mice pancreatic islet cells in vivo and observed that ASP with the condition of high concentration and long-term exposure (HASP) could cause insulin secretion (500 mg/kg for 1 month). Next, we conducted iTRAQ mass spectrometry to profile the global phosphoproteome and found that phosphorylation of zipper-interacting protein kinase (ZIPK) in murine pancreatic islet tissues were induced at Thr197, Thr242, Thr282, and Ser328 by high-sucrose (HS) treatment, but only induced at Thr197 and Ser328 by HASP treatment. Simultaneously, phosphorylation of STAT3 could be induced at Tyr705 and Ser727 by HS but not by HASP. Furthermore, presence of activated STAT3 accompanied with autophagy was observed in HS treatment. In turn, the inactivation of STAT3 as well as enhanced expression of caspase 3 was observed in HASP treatment. We generated Thr242APro and Thr282Pro on ZIPK using CRISPR-Cas9 in β-TC3 cells and found the weakened interaction with STAT3 as well as the reduced phosphorylation of STAT3 even under HS stimulation. Finally, we observed that ankyrin repeat domain containing 11 (ANKRD11) could interact with ZIPK and play an inhibitory role in the phosphorylation of Thr242APro and Thr282Pro of ZIPK. However, HASP can induce the retention of ANKRD11 in the cytoplasm by phenylpyruvic acid (the metabolite of ASP). Taken together, this study determined that ASP with high concentration and long-term exposure could lead to caspase-dependent apoptosis of pancreatic islet cells through ANKRD11/ZIPK/STAT3 inhibition. Our results give evidence of adverse effects of aspartame on islet cells in some extreme conditions, which might help people to reconsider the biosafety of non-nutritive sweeteners. (AU)

The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway

Aspartame (ASP) as an important sugar substitute is widely used in pharmaceutical and food processing. Here, we compared the effects of ASP and sucrose on mice pancreatic islet cells in vivo and observed that ASP with the condition of high concentration and long-term exposure (HASP) could cause insulin secretion (500 mg/kg for 1 month). Next, we conducted iTRAQ mass spectrometry to profile the global phosphoproteome and found that phosphorylation of zipper-interacting protein kinase (ZIPK) in murine pancreatic islet tissues were induced at Thr197, Thr242, Thr282, and Ser328 by high-sucrose (HS) treatment, but only induced at Thr197 and Ser328 by HASP treatment. Simultaneously, phosphorylation of STAT3 could be induced at Tyr705 and Ser727 by HS but not by HASP. Furthermore, presence of activated STAT3 accompanied with autophagy was observed in HS treatment. In turn, the inactivation of STAT3 as well as enhanced expression of caspase 3 was observed in HASP treatment. We generated Thr242APro and Thr282Pro on ZIPK using CRISPR-Cas9 in β-TC3 cells and found the weakened interaction with STAT3 as well as the reduced phosphorylation of STAT3 even under HS stimulation. Finally, we observed that ankyrin repeat domain containing 11 (ANKRD11) could interact with ZIPK and play an inhibitory role in the phosphorylation of Thr242APro and Thr282Pro of ZIPK. However, HASP can induce the retention of ANKRD11 in the cytoplasm by phenylpyruvic acid (the metabolite of ASP). Taken together, this study determined that ASP with high concentration and long-term exposure could lead to caspase-dependent apoptosis of pancreatic islet cells through ANKRD11/ZIPK/STAT3 inhibition. Our results give evidence of adverse effects of aspartame on islet cells in some extreme conditions, which might help people to reconsider the biosafety of non-nutritive sweeteners. (AU)

The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway.

Aspartame (ASP) as an important sugar substitute is widely used in pharmaceutical and food processing. Here, we compared the effects of ASP and sucrose on mice pancreatic islet cells in vivo and observed that ASP with the condition of high concentration and long-term exposure (HASP) could cause insulin secretion (500 mg/kg for 1 month). Next, we conducted iTRAQ mass spectrometry to profile the global phosphoproteome and found that phosphorylation of zipper-interacting protein kinase (ZIPK) in murine pancreatic islet tissues were induced at Thr197, Thr242, Thr282, and Ser328 by high-sucrose (HS) treatment, but only induced at Thr197 and Ser328 by HASP treatment. Simultaneously, phosphorylation of STAT3 could be induced at Tyr705 and Ser727 by HS but not by HASP. Furthermore, presence of activated STAT3 accompanied with autophagy was observed in HS treatment. In turn, the inactivation of STAT3 as well as enhanced expression of caspase 3 was observed in HASP treatment. We generated Thr242APro and Thr282Pro on ZIPK using CRISPR-Cas9 in ß-TC3 cells and found the weakened interaction with STAT3 as well as the reduced phosphorylation of STAT3 even under HS stimulation. Finally, we observed that ankyrin repeat domain containing 11 (ANKRD11) could interact with ZIPK and play an inhibitory role in the phosphorylation of Thr242APro and Thr282Pro of ZIPK. However, HASP can induce the retention of ANKRD11 in the cytoplasm by phenylpyruvic acid (the metabolite of ASP). Taken together, this study determined that ASP with high concentration and long-term exposure could lead to caspase-dependent apoptosis of pancreatic islet cells through ANKRD11/ZIPK/STAT3 inhibition. Our results give evidence of adverse effects of aspartame on islet cells in some extreme conditions, which might help people to reconsider the biosafety of non-nutritive sweeteners.

The Global Burden of Diseases attributed to high low-density lipoprotein cholesterol from 1990 to 2019.

Background: To demonstrate the real-word situation of burdens that are attributed to the risk factor of high low-density lipoprotein cholesterol (LDL-C) at the global, regional, national levels, among different age groups and between genders. Methods: We analyzed data from the Global Burden of Disease study 2019 related to global deaths, disability-adjusted life years (DALYs), summary exposure value (SEV), average annual percentage change (AAPC), and observed to expected ratios (O/E ratios) attributable to high LDL-C from 1990 to 2019. Results: Globally, in 2019, the total numbers of deaths and DALYs attributed to high LDL cholesterol were 1.47 and 1.41 times higher than that in 1990. The age-standardized deaths and DALYs rate was 1.45 and 1.70 times in males compared to females, while the age-standardized SEVs rate was 1.10 times in females compared to males. The deaths, DALYs, and SEV rates increased with age. In 2019, the highest age-standardized rates of both deaths and DALYs occurred in Eastern Europe while the lowest occurred in high-income Asia Pacific. High-income North America experienced a dramatic reduction of risk related to high LDL-C. Correlation analysis identified that the age-standardized SEV rate was positively correlated with Socio-demographic Index (SDI; r = 0.7753, P < 0.001). The average annual percentage change (AAPC) of age-standardized SEV rate decreased in the high SDI and high-middle SDI regions but increased in the middle SDI, low-middle SDI, and low SDI regions. High LDL-C mainly contributed to ischemic heart diseases. Conclusion: High LDL-C contributed considerably to health burden worldwide. Males suffered worse health outcomes attributed to high LDL-C when compared to females. The burden attributed to high LDL-C increased with age. Lower SDI regions and countries experienced more health problem challenges attributed to high LDL-C as the result of social development and this should be reflected in policymaking.

Effects of low-carbohydrate vs low-fat diets on weight loss and metabolic risk factors in obese/overweight individuals with impaired glucose regulation: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effects of low-carbohydrate diet (LCD) versus low-fat diet (LFD) on weight loss, glycemic control and metabolic risk factors in individuals with impaired glucose regulation (IGR) after 10-week intervention. METHODS AND STUDY DESIGN: In this 10-week randomized controlled trial, 90 obese/overweight adults with IGR were randomly assigned to consume either low-carbohydrate diet (20%-25% energy from carbohydrates, 30%-45% energy from fat, 40%-45% en-ergy from protein), or low-fat diet (40%-55% energy from carbohydrates, 20%-30% energy from fat, 20%-30% energy from protein), or heath education (HE) group. The anthropometry and body composition were collected at baseline, week 4, week 8 and week 10. The glycemia and metabolic indicators were assessed at baseline and week 10. RESULTS: A total of 69 participants (mean±SE age: 39.2±1.0 years, 72.5% women) completed the intervention and were included in the final analysis. At week 10, all three groups presented similar mean reduction in weight (LCD: 5.80±0.6 kg; LFD: 6.36±0.57 kg; HE: 4.49±0.98 kg), and fasting blood glucose (LCD: 0.73±0.13 mmol/L; LFD: 0.84±0.17 mmol/L; HE: 0.58±0.14 mmol/L). Additionally, there were no differences in the improvements of TG and liver function markers between diets, the low-fat diet exhibited more favorable effects on TC level. CONCLUSIONS: Both diets achieved similar weight loss, fasting glucose, and insulin reduction in short-term, suggesting each diet pattern could be an effective strategy for the prediabetes management.

Efficacy of the ketogenic diet in Chinese adults versus children with drug-resistant epilepsy: A pilot study.

OBJECTIVE: We compared the efficacy and safety of ketogenic diet (KD) therapy as a treatment for Chinese adults versus children with drug-resistant epilepsy. METHODS: The classic KD was initiated in 19 adults and 29 children with drug-resistant epilepsy. The KD ratio and the dosage of antiseizure medication (ASM) were delicately modulated by the ketogenic team. RESULTS: At 12 months after diet initiation, 11 adults (8 on a KD ratio of 3:1 and 3 on a ratio of 2:1) and 20 children (9 on a ketogenic diet ratio of 3:1 and 11 on a ratio of 2:1) remained on the diet. The retention rate for adult KD therapy recipients was 79.0% at 6 months and 57.9% at 12 months after diet initiation, which was not significantly different from the retention rate for children (82.8% at 6 months and 68.9% at 12 months; P > 0.05). The efficacy rate of KD therapy (seizure freedom or ≥50% reduction in seizure frequency) did not significantly differ between adults (63.2%) and children (75.8%, P = 0.517). Alleviation of seizure severity was observed in 68.4% of adults and 63.6% of children who were not seizure free on KD therapy. Antiseizure medication was reduced in 34 out of all 48 individuals at the final follow-up. CONCLUSION: Our study demonstrated that KD therapy is a safe and effective treatment for Chinese adults as well as children with drug-resistant epilepsy.

Research progress on low carbohydrate diet in the control of overweight and obesity / 预防医学

@#Overweight and obesity are main risk factors for chronic metabolic diseases, and are strongly associated with the increased risk of premature death. Low carbohydrate diet (LCD) has been proven to effectively control body weight and fat mass in overweight and obese patients by short-term (≤6 months) dietary intervention studies. The mechanisms include regulation of energy metabolism, anti-inflammatory, antioxidant, alteration in expression of lipid metabolic-related genes and modulation of intestinal flora. However, the conclusions are inconsistent on whether LCD can cause durable weight loss and reduce the risk of overweight and obesity. This review summarizes the current research progress on the mechanisms, epidemiological studies, intervention studies and potential risks of LCD in controlling overweight and obesity, providing a reference for the future research and clinical application.

Dry eye and sleep quality: a large community-based study in Hangzhou.

STUDY OBJECTIVES: To investigate the relationship between dry eye and sleep quality in a large community-based Chinese population. METHODS: A total of 3,070 participants aged 18-80 were recruited from a community-based study in Hangzhou, China during 2016-2017. Sleep quality was evaluated using the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), and dry eye was evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Multivariable linear regression and logistic regression models were used to investigate the associations, adjusting for age, smoking, drinking, season, and other potential confounders. RESULTS: Overall, CPSQI score and sleep dysfunction were significantly associated with mild, moderate, and severe dry eye (ORs for CPSQI score: 1.07, 1.13, 1.14, all p < 0.001; for sleep dysfunction: 1.31, 1.73, 1.66, all p < 0.05). Furthermore, worse OSDI score was presented in participants with worse CPSQI score or sleep dysfunction (CPSQI score > 7) (ß: 0.13, 0.54; all p < 0.001). In addition, six of the seven components of CPSQI showed significant associations with dry eye (all p < 0.001), except for the component of sleep medication use. Moreover, we observed significant associations of dry eye in all three subscales of OSDI with CPSQI score and sleep dysfunction. CONCLUSION: Our large, community-based study showed a strong association between poor sleep quality and an increased severity of dry eye, suggesting that preventing either one of the discomforts might alleviate the other.

Associations of nicotine dependence and fat distribution in Chinese male adults: a cross-sectional study in Lanxi, China.

INTRODUCTION: Previous studies have showed association between smoking and central fat distribution. However, the impact of smoking on whole body fat distribution, particularly peripheral fat distribution remains unclear. METHODS: Nicotine dependence was assessed in a total of 1264 male adults aged 18-80 years using the Fagerström Test for Nicotine Dependence (FTND). Smoking status was categorised as non-smokers, former and current smokers with very low, low/moderate, or high FTND scores. Body fat distribution was determined using the dual energy X-ray absorptiometry and anthropometric measurements. Multivariable linear regression models were applied to examine the adjusted associations between body fat distribution and smoking in all participants, and its association with FTND scores in the current smokers. RESULTS: Greater waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), trunk fat percentage (%TF), android fat percentage (%AF) and android-to-gynoid fat mass ratio (AOI); but lower legs fat percentage (%LegF), limb fat percentage (%LimbF) and gynoid fat percentage (%GF) were found in current smokers with high FTND scores compared with non-smokers. In current smokers aged 60 years or older, FTND scores had positive associations with WC, WHR, WHtR, %TF, %AF and AOI, and negative associations with %LegF, %LimbF and %GF. CONCLUSIONS: Nicotine dependence was positively associated with central fat distribution and negatively associated with peripheral fat distribution in Chinese male adults, particularly in those older or heavy smokers, and these associations were independent from body mass index, which might be due to long exposure to smoking.

A Single Nucleotide Polymorphism in the FADS1 Gene is Associated with Plasma Fatty Acid and Lipid Profiles and Might Explain Gender Difference in Body Fat Distribution.

BACKGROUND: Genotyping of the rs174547 polymorphism in the fatty acid desaturase 1 gene (FADS1) shows that it is associated with the FA composition of plasma phospholipids and lipid metabolic indices among several ethnic groups. However, this association requires further confirmation in the Chinese population, and little is known about the effect of polymorphisms in fatty acid-related genes on body fat distribution. METHODS: Anthropometric measurements of 951 Chinese adults aged 18-79 were obtained and body fat distribution was estimated using dual-energy X-ray absorptiometry. The FA composition of plasma phospholipids was measured by gas chromatography. Multiple linear regression assessed whether the rs174547 genotype was associated with FA composition, body fat distribution, and metabolic traits in additive, dominant, and recessive models. RESULTS: The rs174547 C minor allele was associated with a higher proportion of linoleic acid, lower arachidonic acid and docosahexaenoic acid, as well as lower delta-6-desaturase and delta-5-desaturase activity. Female C allele carriers had lower android fat percentages and lower levels of low-density lipoprotein-cholesterol, while male C allele carriers had lower gynoid fat percentages and higher triglyceride after adjusting for age, income, BMI, behavioral risk factors, and regional fat percentages. CONCLUSION: An association of FADS1 rs174547 with the FA composition of plasma phospholipids was identified among this Chinese adult population. The association with body fat distribution and lipid metabolic indices differed between men and women, which might explain sexual differences in body fat distribution and lipid metabolism.

[Study of autofluorescence spectrum of dilute gastric juice in the diagnosis of gastric carcinoma].

OBJECTIVE: To investigate the value of the autofluorescence spectrum of dilute gastric juice in the diagnosis of gastric carcinoma. METHODS: The autofluorescence spectrum of dilute gastric juice was scanned with RF-5000 spectrophotofluorometer when the excitation wavelength was set to 288 nm and the emission wavelength ranged from 300 nm to 800 nm. RESULTS: We enrolled 251 patients with different gastric diseases including 40 cases with gastric carcinoma in our study. There were three characteristic peaks in the autofluorescence spectrum of gastric juice, which appeared in the spectra of both dilute and indilute specimens, but relative fluorescence intensity index (FI) of the peaks changed with concentration. The spectra of dilute gastric juice (1:20) of both benign and malignant gastric diseases had those three peaks. However, the fluorescence intensity index of the first peak (P1FI) at 320-360 nm of patients with gastric carcinoma was higher than that of patients with benign gastric diseases. The diagnosis model for gastric carcinoma was made by CART V2.0 software. The diagnosis standard for gastric carcinoma was P1FI > 38.995. The model's sensitivity and specificity of prior probability were 85.0% and 91.9% respectively. The sensitivity and specificity of posterior probability were 82.5% and 91.9% respectively. When the diagnosis standard was set to P1FI > 24.34, the sensitivity and specificity were 95.0% and 75.8%, respectively. CONCLUSION: The autofluorescence spectrum of dilute gastric juice may become an effective means in the diagnosis and screening of gastric carcinoma.

[Changes of gastric mucosa histopathology after Helicobacter pylori eradication].

OBJECTIVE: To investigate the relationship between Helicobacter pylori (Hp) infection and gastric cancer through the changes of gastric mucosa histopathology within 5 years after Hp eradication in Hp-positive subjects in the high incidence region of gastric cancer. METHODS: One thousand and six adults were selected from general population in Yantai, Shandong Province, the high incidence region of gastric cancer. Gastroscopy and CLO test were performed in all subjects. Biopsy samples from the gastric antrum and body were obtained for histology and assessment of Hp infection. All the Hp-positive subjects were then randomly divided into two groups: treatment group receiving OAC triple therapy and placebo as controls. These subjects were endoscopically followed up in the second and fifth year. In this article, we compared the endoscopic appearance and histology of the biopsy specimens from the same site obtained at the first and final visit. Statistical analysis was done by chi(2) test. RESULTS: All the 552 Hp-positive subjects were randomly divided into treatment group or control group, 276 in each. During the five-year follow-up, the number of patients who continued to be negative or positive for Hp was 161 and 198, respectively. Statistical analysis revealed that: (1) At the initial visit, there were no significant differences in the severity and activity of inflammation between the biopsy specimens from the antrum (P = 0.105) and body (P = 0.084) in both groups. But the proportion of atrophy and intestinal metaplasia in the antrum was much higher than that in the body (P = 0.000). (2) The severity and activity of inflammation in both the antrum and body were markedly reduced after Hp eradication (P = 0.000). (3) Within the five years after Hp eradication, intestinal metaplasia in the antrum regressed or had no progression, while the proportion of intestinal metaplasia in the Hp-positive group increased significantly (P = 0.032). (4) After Hp eradication, the atrophy in both the antrum and body had no significant regression. P value was 0.223 and 0.402, respectively. CONCLUSIONS: Hp eradication results in remarkable reduction in the severity and activity of chronic gastritis, marked resolution of intestinal metaplasia in the antrum. On the other hand, continued Hp infection leads to progressive aggrevation of atrophy and intestinal metaplasia.

[The value of autofluorescence spectrum analysis of gastric juice in diagnosing gastric carcinoma: a preliminary result].

OBJECTIVE: To reveal the difference of autofluorescence spectrums of gastric juice derived from malignancy and benignancy for screening and diagnosis of gastric carcinoma. METHOD: Gastric juice from 202 patients with different gastric diseases were collected, then detected their autofluorescence spectrums (the excitation wavelength is 288 nm, whereas the range of emission wavelength is 300 - 800 nm) after diluted by 1:10. The diagnostic model for gastric cancer was made by Classification and Regression Trees V2.0 software. RESULTS: There were three peaks (the emission wavelength were 320 - 360 nm, 576 nm and 670 - 690 nm respectively) in the autofluorescence spectrums of all patients, though the intensity of the first peak (with the emission wavelength of 320 - 360 nm) were enhanced distinctively in malignance than those in benignancy. The diagnostic model's sensitivity and specificity of prior probability were 91.4% and 83.2% respectively, whereas the sensitivity and specificity of posterior probability were 85.7% and 82.6%. CONCLUSION: Detection of autofluorescence spectrum of gastric juice has great prospect in the diagnosis and screening gastric carcinoma.

A five-year follow-up study on the pathological changes of gastric mucosa after H. pylori eradication.

OBJECTIVES: To investigate the relationship between H. pylori infection, gastric cancer and other gastric diseases through the changes in gastric mucosa and the status of different gastric diseases within 5 years after H. pylori eradication in H. pylori-positive subjects in a high incidence region of gastric cancer. METHODS: One thousand and six adults were selected from the general population in Yantai, Shandong province, a high incidence region for gastric cancer in China. Gastroscopy and Campylobacter-like organism (CLO) testing were performed on all subjects. Biopsy samples from the gastric antrum and body were obtained for histology and assessment of H. pylori infection. All H. pylori-positive subjects were then randomly divided into two groups: treatment group receiving Omeprazole Amoxicillin Clarythromycin (OAC) triple therapy and placebo as controls. These subjects were endoscopically followed up in the second and fifth year. We compared the endoscopic appearance and histology of the biopsy specimens from the same site obtained at the first and last visits. RESULTS: All 552 H. pylori-positive subjects were randomly and evenly divided into treatment group or control group. During the five-year follow-up, the numbers of patients who continued to be negative or positive for H. pylori were 161 and 198, respectively. Statistical analysis revealed that: (1) At the initial visit, there were no significant differences in the severity and activity of inflammation, atrophy and intestinal metaplasia between the biopsy specimens from the antrum and body respectively in both groups. (2) The severity and activity of inflammation in both the antrum and body were markedly reduced after H. pylori eradication (P = 0.000). (3) Within five years after H. pylori eradication, intestinal metaplasia in the antrum either regressed or had no progression, while the proportion of intestinal metaplasia in the H. pylori-positive group increased significantly (P = 0.032). (4) After H. pylori eradication, the atrophy in both the antrum and body had no significant regression. The P value was 0.223 and 0.402, respectively. CONCLUSIONS: H. pylori eradication results in remarkable reduction in the severity and activity of chronic gastritis, marked resolution of intestinal metaplasia in the antrum. On the other hand, continuous H. pylori infection leads to progressive aggravation of atrophy and intestinal metaplasia.