We evaluated whether orally administered astaxanthin (AST) protects against oxidative damage in the ocular tissues of streptozotocin (STZ)-induced diabetic rats.
Fifty 6-week-old female Wistar rats ...were randomly assigned to receive an injection of STZ to induce diabetes (n = 40) or to remain uninduced (n = 10). The diabetic rats were randomly selected into four groups and they were separately administered normal saline, 0.6 mg/kg AST, 3 mg/kg AST, or 0.5 mg/kg lutein daily for eight weeks. Retinal functions of each group were evaluated by electroretinography. The expression of oxidative stress and inflammatory mediators in the ocular tissues was then assessed by immunohistochemistry, western blot analysis, ELISA, RT-PCR, and electrophoretic mobility shift assay (EMSA). Retinal functions were preserved by AST and lutein in different levels. Ocular tissues from AST- and lutein-treated rats had significantly reduced levels of oxidative stress mediators (8-hydroxy-2'-deoxyguanosine, nitrotyrosine, and acrolein) and inflammatory mediators (intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and fractalkine), increased levels of antioxidant enzymes (heme oxygenase-1 and peroxiredoxin), and reduced activity of the transcription factor nuclear factor-kappaB (NF-κB).
The xanthophyll carotenoids AST and lutein have neuroprotective effects and reduce ocular oxidative stress, and inflammation in the STZ diabetic rat model, which may be mediated by downregulation of NF-κB activity.
Background & Aims: This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus ...(HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. Methods: A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RRa ) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Results: Extreme obesity (body mass index ≥30 kg/m2 ) was independently associated with a 4-fold risk of HCC (RRa , 4.13; 95% CI, 1.38–12.4) among anti-HCV–seropositive subjects and a 2-fold risk (RRa , 2.36; 95% CI, 0.91–6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RRa , 1.36; 95% CI, 0.64–2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RRa , 3.52; 95% CI, 1.29–9.24) and lowest in HBV carriers (RRa , 2.27; 95% CI, 1.10–4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. Conclusions: The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC.
Background and purpose
The pathogenesis of diabetic gastroparesis due to visceral neuropathy involves multidimensional mechanisms with limited exploration of gastric mucosal innervation. This study ...aimed to examine quantitatively this topic and its relationship with gastroparesis symptoms and gastric emptying in diabetes.
Methods
We prospectively enrolled 22 patients with type 2 diabetes and gastroparesis symptoms and 25 age‐ and gender‐matched healthy controls for comparison. The assessments included: (i) neuropathology with quantification of gastric mucosal innervation density (MID) on endoscopic biopsy; (ii) clinical manifestations based on the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire; and (iii) functional tests of gastric emptying scintigraphy (GES).
Results
In patients with diabetes, stomach fullness, bloating and feeling excessively full after meals constituted the most common GCSI symptoms. Seven patients with diabetes (32%) had prolonged gastric emptying patterns. In diabetes, gastric MID was significantly lower in all the regions examined compared with the controls: antrum (294.8 ± 237.0 vs. 644.0 ± 222.0 mm/mm3; p < 0.001), body (292.2 ± 239.0 vs. 652.6 ± 260.9 mm/mm3; p < 0.001), and fundus (238.0 ± 109.1 vs. 657.2 ± 332.8 mm/mm3; p < 0.001). Gastric MID was negatively correlated with gastroparesis symptoms and total scores on the GCSI (p < 0.001). Furthermore, gastric MID in the fundus was negatively correlated with fasting glucose and glycated hemoglobin levels. Gastric emptying variables, including half emptying time and gastric retention, were prolonged in patients with diabetes, and gastric retention at 3 h was correlated with fasting glucose level.
Conclusion
In diabetes, gastric MID was reduced and GES parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology.
In patients with type 2 diabetes, gastric mucosal innervation was reduced and gastric emptying parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology.
Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high-fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and ...stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex-specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step-down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open-field and hot-plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired-pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long-term potentiation (LTP) and long-term depression (LTD)) were lower at the Schaffer collateral-CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex-specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.
Scope
miR‐29a expression patterns influence numerous physiological phenomena. Of note, upregulation of miR‐29a ameliorates high‐fat diet (HFD)‐induced liver dysfunctions in mice. However, the miR‐29a ...effect on gut microbiome composition and HFD‐induced gut microbiota changes during metabolic disturbances remains unclear. The study provides compelling evidence for the protective role of miR‐29a in gut barrier dysfunction and steatohepatitis.
Methods and results
miR‐29a overexpressed mice (miR‐29aTg) are bred to characterize intestinal, serum biochemical, and fecal microbiota profiling features compared to wild‐type mice (WT). Mice are fed an HFD for 8 months to induce steatohepatitis, and intestinal dysfunction is determined via histopathological analysis. miR‐29aTg has better lipid metabolism capability that decreases total cholesterol and triglyceride levels in serum than WT of the same age. The study further demonstrates that miR‐29aTg contributes to intestinal integrity by maintaining periodic acid Schiff positive cell numbers and diversity of fecal microorganisms. HFD‐induced bacterial community disturbance and steatohepatitis result in more severe WT than miR‐29aTg. Gut microorganism profiling reveals Lactobacillus, Ruminiclostridium_9, and Lachnoclostridium enrichment in miR‐29aTg and significantly decreases interleukin‐6 expression in the liver and intestinal tract.
Conclusion
This study provides new evidence that sheds light on the host genetic background of miR‐29a, which protects against steatohepatitis and other intestinal disorders.
HFD feeding resulted in steatohepatitis, leaky gut, and dysbiosis, with more severe damage in WT than in miR‐29aTg. miR‐29a demonstrated to act as a master regulator influencing numerous physiological phenomena. Notably, miR‐29a accessibility ameliorates HFD‐induced metabolic dysregulation and inflammation. This study provides new evidence to shed light on the miR‐29a link between metabolic homeostasis and advanced intestinal microbiota diversity.
Since bone and fat mass are derived from mesenchyme in early development, adipokines secreted by adipose tissue may have an effect on bone metabolism. The relationship between adiponectin and bone ...mineral density (BMD) has been inconsistent in previous reports, with results being dependent on age, gender, menopausal status and bone sites. We investigated the relationship between serum adiponectin levels and the BMD of proximal femur and vertebrae bones in a 96-week longitudinal study of post-menopausal women with repeated measures of both. Linear regression models were used to determine the relation between adiponectin and BMD at each time point cross-sectionally, and a generalized estimating equation (GEE) model was used to investigate the longitudinal trends. Among 431 subjects, 376 (87%) provided baseline adiponectin measurements and 373 provided more than two measurements for longitudinal analysis. The means of serum adiponectin and BMD decreased with time. In linear regression models, adiponectin at baseline, the 48th week and the 96th week appeared to be inversely associated with BMD of proximal femur bone, but not lumbar spine after adjusting for age and various confounders. However, they all turn insignificant with further adjustment of body mass index. The inverse association between adiponectin and BMD of proximal femur is substantiated by all generalized equation models. Before adding the BMI in the model, the increase of 1 mg/dL of adiponectin can accelerate the decrease of proximal femur BMD by 0.001 (SE = 0.0004, p = 0.008). With BMI in the model, the drop rate was 0.0008 (SE = 0.0004, p = 0.026) and remained similar with further adjustment of two bone turnover markers. In this longitudinal analysis with both adiponectin and BMD measured at three time points, we demonstrate that with the increase of adiponectin level, the decline of proximal femur BMD in postmenopausal women accelerated during a period of 96 weeks.
S14 has been identified as a potent stimulator of de novo hepatic lipogenesis (DNL) in rodents. However, it is unclear how S14 is regulated in humans with non-alcoholic fatty liver disease (NAFLD). ...The aim of this study was to investigate the relationship between serum S14 and liver steatosis in humans with NAFLD. A total of 614 participants were recruited from community. Liver steatosis were evaluated according to the Ultrasonographic Fatty Liver Indicator (US-FLI), which is a semi-quantitative liver ultrasound score. Anthropometric and biochemical indices were collected for further analysis. The risk of liver steatosis severity was estimated by a cumulative logistic regression model. NAFLD was found in 52.2% of the participants. The subjects with NAFLD showed higher levels of waist circumference, body mass index, insulin resistance, aspartate aminotransferase, dyslipidemia, visceral fat, serum S14 and risk of metabolic syndrome (MetS) than those of controls. Compared with the first tertile of serum S14, the odds ratios for the risk of more severe liver steatosis were 1.22 (95% confidence interval CI: 0.78-1.92) for those of the second tertile and 2.08 (95% CI: 1.28-3.39) for the third tertile (P for trend < 0.05) after adjusting for confounding factors. Higher serum S14 level was not only found in NAFLD subjects but also was positively correlated with the severity of liver steatosis. S14 may play an important role in the mechanism of DNL for NAFLD in humans.
Background/Aims
Chronic hepatitis B virus (HBV) infection still poses a major threat to global health. Oligoadenylate synthetase–ribonuclease L (RNase L) antiviral pathway is one of ...interferon‐induced antiviral effectors. The relationship between RNase L and HBV has never been investigated and we aim to examine the serum RNase L levels in patients with different stages of chronic HBV infection.
Methods
The patients were enrolled from 1985 to 2000, who had been HBsAg positive for longer than 6 months, at the National Taiwan University Hospital. In total, 426 patients with chronic HBV infection were included in this study, including 135 inactive carriers, 148 cirrhosis, and 143 hepatocellular carcinoma (HCC) cases.
Results
The RNase L levels increase as the disease severity increases. Higher RNase L levels were associated with higher HBV viral load, and the HBV‐RNase L relationship was replaced by the disease severity status when adding disease status into the model. Compared with inactive carriers, the risk of liver cirrhosis was 60‐fold (odds ratio = 60.8, 95% confidence interval = 3.49–1061) with the highest quintile of RNase L levels, after the adjustment of HBV DNA. The dose–response trend was statistically significant with quintiles and one increment of RNase L level in relation to liver cirrhosis. Similar results were found when HCC was compared with inactive carriers, while there was no association when compared between liver cirrhosis and HCC.
Conclusions
A positive relationship between serum RNase L and HBV viral titers or advanced disease status is uncovered in this study. Further investigation in this area may provide more details of an innate immune response for HBV and opportunity for novel therapeutic strategy.
SARS-CoV-2 began spreading in December 2019 and has since become a pandemic that has impacted many aspects of human society. Several issues concerning the origin, time of introduction to humans, ...evolutionary patterns, and underlying force driving the SARS-CoV-2 outbreak remain unclear.
Genetic variation in 137 SARS-CoV-2 genomes and related coronaviruses as of 2/23/2020 was analyzed.
After correcting for mutational bias, the excess of low frequency mutations on both synonymous and nonsynonymous sites was revealed which is consistent with the recent outbreak of the virus. In contrast to adaptive evolution previously reported for SARS-CoV during its brief epidemic in 2003, our analysis of SARS-CoV-2 genomes shows signs of relaxation. The sequence similarity in the spike receptor binding domain between SARS-CoV-2 and a sequence from pangolin is probably due to an ancient intergenomic introgression that occurred approximately 40 years ago. The current outbreak of SARS-CoV-2 was estimated to have originated on 12/11/2019 (95% HPD 11/13/2019-12/23/2019). The effective population size of the virus showed an approximately 20-fold increase from the onset of the outbreak to the lockdown of Wuhan (1/23/2020) and ceased to increase afterwards, demonstrating the effectiveness of social distancing in preventing its spread. Two mutations, 84S in orf8 protein and 251 V in orf3 protein, occurred coincidentally with human intervention. The former first appeared on 1/5/2020 and plateaued around 1/23/2020. The latter rapidly increased in frequency after 1/23/2020. Thus, the roles of these mutations on infectivity need to be elucidated. Genetic diversity of SARS-CoV-2 collected from China is two times higher than those derived from the rest of the world. A network analysis found that haplotypes collected from Wuhan were interior and had more mutational connections, both of which are consistent with the observation that the SARS-CoV-2 outbreak originated in China.
SARS-CoV-2 might have cryptically circulated within humans for years before being discovered. Data from the early outbreak and hospital archives are needed to trace its evolutionary path and determine the critical steps required for effective spreading.
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