Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1-/- cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.
Depression and obesity are prevalent disorders with significant public health implications. In this study, we used a high-fat diet (HFD)-induced obese mouse model to investigate the mechanism underlying HFD-induced depression-like behaviors. HFD-induced obese mice exhibited depression-like behaviors and a reduction in hippocampus volume, which were reversed by treatment with an indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post-1-MT treatment, suggesting that other mechanisms may be involved in the anti-depressive effect of 1-MT. We further conducted RNA sequencing analysis to clarify the potential underlying mechanism of the anti-depressive effect of 1-MT in HFD-induced depressive mice and found a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depressive mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and upregulation of PNNs, affecting synaptic transmission in PV-positive neurons and leading to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. The 1-MT effectively reversed these changes, highlighting a PNN-related mechanism by which 1-MT exerts its anti-depressive effect.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive medications managing osteoporosis, such as bisphosphonates (BPs). To date, there is very limited evidence from prospective, controlled studies to support or refute the controversial prevention regimen that if a discontinuation of BPs before dentoalveolar surgery, so called "drug holiday", is effective in reducing the risk of MRONJ development in patients with osteoporosis. We proposed an experimental animal study, aiming to investigate the prevention of MRONJ following tooth extractions in osteoporotic condition, with the implementation of a BP drug holiday.Twenty rats were subjected to bilateral ovariectomy. After establishing the osteoporotic condition, all rats were exposed to weekly injections of zoledronate acid (ZA) for 8 weeks. After ZA treatment, 10 rats were subjected to dental extraction and defined as control group, and the rest 10 rats assigned to the DH group had a drug holiday of 8 weeks prior to dental extraction. Eight weeks after the dentoalveolar surgery, bone turnover biomarker in serum, occurrence of MRONJ-like lesion and histomorphometric assessment of osteonecrosis in mandible, and bone microarchitecture indices in femur, were examined.Eight weeks after dental extraction, the DH group showed a recovered osteoclastic activity, indicated by significantly increased number of osteoclasts in the mandibles and serum level of C-terminal telopeptides of type I collagen, as compared to the control group. No significant differences were observed in the gross-view and histological occurrences of MRONJ-like lesions between the two groups.There was no significant difference in bone microarchitecture in the femur between the control and DH groups before ZA therapy and 8 weeks after dental extraction.Our data provided the first experimental evidence in the osteoporotic animal model that the implementation of a BP holiday in prior to dental extractions could partially recover osteoclastic activity, but could not alleviate the development of MRONJ-like lesion or exacerbate the osteoporotic condition in the femur. Longer-term drug holiday, or combination of drug holiday and other prophylaxes to prevent MRONJ in patients with osteoporosis could be worth exploring in future studies, to pave the way for clinical managements.This in vivo prospective study reported that a recovery of osteoclastic activity by a BP drug holiday for 8 weeks in osteoporosis rats did not alleviate the development of MRONJ-like lesion followed by dental extractions. It contributes to the understanding of regimens to prevent MRONJ.
Cordyceps cicadae is an entomogenous fungus, which is used as both medicine and food due to the presence of rich bioactive substances. Currently, most studies focus on the pharmacological effects of the bioactive components of C. cicadae, but the research on their processing is still in its infancy. In this study, polysaccharides were extracted from insect-cultivated C. cicadae (tussah pupae C. cicadae and domestic silkworm pupae C. cicadae) and wild C. cicadae. The functional properties of C. cicadae polysaccharides were evaluated. At the same time, the in vitro antioxidant activity of the insect-cultivated C. cicadae was determined and compared with the wild C. cicadae. The results showed that the cultivated C. cicadae polysaccharides and the wild one had similar structures, and both had appreciable water solubility, oilholding capacity, thermal stability, and emulsifying property compared to foaming property and foaming stability. Further, the C. cicadae polysaccharides cultured on silkworm pupae and tussah pupae showed comparable antioxidant and reducing power to the wild C. cicadae. Our data indicates that the C. cicadae polysaccharides have the potential as a food additive, among which the domestic silkworm pupae C. cicadae showed the best outcome, and the C. cicadae polysaccharides cultured by bionic method have the same antioxidant activity as the wild one.
Total 732 subjects aged 30-60 years undergoing health check-up at Beijing Hospital Medical Examination Center in 2009, who had no history of non-alcoholic fatty liver disease (NAFLD) were recruited in the study.According to the quartile of hemoglobin (HGB) level, the subjects were divided into 4 groups: Q1: HGB≤131 g/L (n=192), Q2: HGB>131 g/L and ≤140 g/L (n=178), Q3: HGB>140 g/L and ≤152 g/L (n=184), Q4: HGB>152 g/L (n=178). All participants were followed up for 4 years, the prevalence rates of NAFLD in groups Q1, Q2, Q3 and Q4 were 8.3% (16/192), 17.4% (31/178), 23.4% (43/184) and 25.3% (45/178), respectively (P<0.05). Logistic regression showed that the rates of NAFLD in groups Q2, Q3 and Q4 were 2.32 (1.22-4.41), 3.36 (1.81-6.21) and 3.72(2.02-6.87) times higher as group Q1(P<0.05). Multiple logistic regression analysis showed that the hemoglobin level, TG and BMI were the independent risk factors of NAFLD.
Key words:
Fatty liver; Hemoglobins; Cohort studies
Objective
To evaluate the vascular endothelial function and explore the related influencing factors in patients with abnormal glucose metabolism by use of ultrasound technology.
Methods
A total of 109 participants selected from endocrinology outpatients of Beijing Hospital from October 2011 to June 2013 were enrolled in this study. Oral glucose tolerance test(OGTT) was carried out, including fasting plasma glucose(FPG) and postprandial glucose(PPG), fasting and 2 hours after glucose load testing insulin, C-peptide, glycated hemoglobin A1c(HbA1c), glycated albumin(GA), lipids, liver and kidney function, blood uric acid,flow-mediated endothelium-dependent vasodilation (FMEDD), serum nitric oxide (NO), endothelin-1(ET-1), serum malondialdehyde(MDA) and superoxide dismutase(SOD).With the receiver operating characteristic (ROC)curve, the best critical points of fasting and glucose loading vascular endothelial function were obtained.
Results
(1)The critical points of FMEDD in the state of abnormal glucose metabolism: fasting FMEDD was 13.37%, Youden index was 0.467, and the area under the curve was 0.786 (95%CI:0.697-0.876); FMEDD of OGTT 2 h was 10.67%,Youden index was 0.458, and the area under the curve was 0.774(95%CI:0.687- 0.861). (2)Body mass index(BMI), FPG, HbA1c, GA, triglyceride (TG), MDA in the patients withabnormal fasting FMEDD were significantly higher than those in the normalgroup(t=- 3.013,- 4.567,- 3.487,- 4.611,- 2.309,- 2.909, all P<0.05); and the homeostasis model assessment-β(HOMA-β), NO, SOD were significantly lower than those in the normal group(t=2.765,2.472, 5.937, all P<0.05). PPG, HbA1c, GA in the patients with abnormal FMEDD after glucose load were significantly higher than those in the normal group(t=-4.907,-4.236,-3.896, all P<0.05); and the HOMA-β, NO, SOD were all significantly lower than those in the normal group(t=2.704,4.675,4.633, all P<0.05).(3) FPG,HbA1c,GA were negatively correlated with fasting FMEDD(r=- 0.460,- 0.390,- 0.391, all P<0.05), whereas fasting NO, SOD, HOMA - β were positively correlated with fasting FMEDD(r=0.301,0.321, 0.310, all P<0.05). PPG, HbA1c, GA were negatively correlated with FMEDD after glucose load (r=- 0.460,- 0.450,- 0.389, all P<0.05), whereas NO, SOD, HOMA- β were positively correlated with FMEDD after glucose load(r=0.196,0.360,0.257, all P<0.05).
Conclusions
Blood sugar levels, islet β-cell function index, vasodilators, and the indicators of antioxidative stress can affect vascular endothelial functions in different state of glucose metabolism.
Key words:
Glucose metabolism disorders; Vascular endothelial function; Oxidative stress
Flaviviruses have evolved complex mechanisms to evade the mammalian host immune systems including the RIG-I (retinoic acid-inducible gene I) like receptor (RLR) signaling. Zika virus (ZIKV) is a re-emerging flavivirus that is associated with severe neonatal microcephaly and adult Guillain-Barre syndrome. However, the molecular mechanisms underlying ZIKV pathogenesis remain poorly defined. Here we report that ZIKV non-structural protein 4A (NS4A) impairs the RLR-mitochondrial antiviral-signaling protein (MAVS) interaction and subsequent induction of antiviral immune responses. In human trophoblasts, both RIG-I and melanoma differentiation-associated protein 5 (MDA5) contribute to type I interferon (IFN) induction and control ZIKV replication. Type I IFN induction by ZIKV is almost completely abolished in MAVS-/- cells. NS4A represses RLR-, but not Toll-like receptor-mediated immune responses. NS4A specifically binds the N-terminal caspase activation and recruitment domain (CARD) of MAVS and thus blocks its accessibility by RLRs. Our study provides in-depth understanding of the molecular mechanisms of immune evasion by ZIKV and its pathogenesis.
Abstract Background With the development of big health and big data, cohort research has become a medical research hotspot. As an important repository of human genetic resources, biobanks must adapt to the requirements of large-scale and efficient operation. Thus, biobanks urgently need to design and build a legal, convenient, and efficient information management system. Methods This study applies the concept of “quality by design” to build a comprehensive biobank information management system based on the analysis of user requirements, legal and regulatory risks, and industry-standard requirements. The system integrates the management of scientific research projects, biological specimens, clinical information, quality control, and multi-dimensional information query and development. After 10 months of its operation, the comprehensive management system was evaluated through statistical analysis of the efficiency of the construction of the pregnancy–birth cohort and the quality of genetic resources. Results Since the system’s launch, the statistics on cohort construction efficiency show that the enrollment rate of eligible pregnant women has increased, and the rate of missing volunteers has dropped. The time needed to establish a 1000-person cohort (with complete biological samples and clinical information in early, middle, and late pregnancy) was reduced, and the effective tracking rate of the samples was 77.42%. The error rate of the deep cryogenic refrigerator decreased, with a clinical information integrity rate of 96.47%. Conclusions The comprehensive biobank information management system constructed with the “quality by design” concept is well suited to meet the requirements of medical research. This study provides a solution for designing a comprehensive information system for medical institutions’ biobanks.
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