Targeting STING: From antiviral immunity to treat osteoporosis.

The cGAS-STING signaling pathway can trigger innate immune responses by detecting dsDNA from outside or within the host. In addition, the cGAS-STING signaling pathway has emerged as a critical mediator of the inflammatory response and a new target for inflammatory diseases. STING activation leads to dimerization and translocation to the endoplasmic reticulum Golgi intermediate compartment or Golgi apparatus catalyzed by TBK1, triggers the production of IRF3 and NF-κB and translocates to the nucleus to induce a subsequent interferon response and pro-inflammatory factor production. Osteoporosis is a degenerative bone metabolic disease accompanied by chronic sterile inflammation. Activating the STING/IFN-ß signaling pathway can reduce bone resorption by inhibiting osteoclast differentiation. Conversely, activation of STING/NF-κB leads to the formation of osteoporosis by increasing bone resorption and decreasing bone formation. In addition, activation of STING inhibits the generation of type H vessels with the capacity to osteogenesis, thereby inhibiting bone formation. Here, we outline the mechanism of action of STING and its downstream in osteoporosis and discuss the role of targeting STING in the treatment of osteoporosis, thus providing new ideas for the treatment of osteoporosis.

The roles of IGF2 and DNMT methylation and elongase6 related fatty acids in metabolic syndrome.

Background: The prevalence of metabolic syndrome (MetS) has increased along with rapid socio-economic development in China in recent decades, aggravating the burden of the health care system. Both plasma levels of fatty acids (FAs) and aberrant DNA methylation profiles are associated with MetS risk. However, studies exploring the role of DNA methylation and FAs simultaneously in MetS etiology are sparse. Objective: We aimed to explore the association between the gene methylation levels of insulin-like growth factor II (IGF2), H19, DNA methyltransferases 1 (DNMT1), DNA methyltransferases 3a (DNMT3a), and DNA methyltransferases 3b (DNMT3b) and MetS risk, and the etiological role of elongation of very-long-chain fatty acid elongase 6 (ELOVL6) related fatty acids. Method: Plasma levels of FAs were measured using a Gas Chromatography-Flame Ionization Detector (GC-FID) after organic extraction, and gene methylation was quantified using a real-time Quantitative Polymerase Chain Reaction (Q-PCR) detecting system after bisulfite treatment. The C18/C16 ratio was used as the indicator of ELOVL6 activity. Odds Ratio (OR) and 95% Confidence Interval (CI) were estimated with logistic regression. Results: Methylation levels in IGF2 and DNMT3a were not significantly associated with MetS risk. However, when stratified by C18/C16 ratio (high vs. low), positive associations were observed between the risk of MetS and methylation levels (>median) of IGF2a3 (OR = 3.1, 95% CI = 1.3-7.5) and DNMT3a (OR = 2.5, 95% CI = 1.1-5.8) genes, in individuals with lower C18/C16 ratios, while no significant associations were observed in subjects with high C18/C16 ratios. Conclusion: Methylation levels in IGF2 and DNMT3a genes may affect the risk of MetS in an ELOVL6 activity-dependent way among Chinese adults. Further studies in other populations are needed to validate this finding.

Alterations of Lipidomes in Rat Photoreceptor Degeneration Induced by N-Methyl-N-nitrosourea.

To investigate alterations of lipidomes in the progress of photoreceptor degeneration induced by N-methyl-N-nitrosourea (MNU) in a rat model, retinal lipid molecular species in adult Sprague-Dawley (SD) rats at 1, 3, and 7 days after MNU administration and age-matched controls were analyzed by the shotgun lipidomics technology. Moreover, total fatty acid levels in retinal, liver, and plasma samples of different groups were determined with gas chromatography. Generally, at day 1, the levels of ethanolamine plasmalogen species in retinas were markedly elevated after treatment with MNU, while the contents of other phospholipids and sphingolipids in the retina were not significantly changed than those of the control group. The compositions of almost all of unsaturated fatty acids in the retina increased significantly at day 1 after MNU administration. At day 7, the MNU treatment group has significant increases in lipid species in the retina. However, the majority of lipids containing docosahexaenoic acid (DHA, 22:6n-3) and docosapentaenoic acid (22:5n-6) declined, especially di-DHA phospholipids were dramatically reduced in the retina. In contrast, similar alterations did not occur in plasma or the liver after MNU treatment. These results suggested that at the early stage of photoreceptor degeneration, lipidome remodeling in the retina might involve protection of photoreceptor from apoptosis and continue their transduction of light. However, at the late stage of photoreceptor apoptosis, increases in comprehensive lipid species occurred, likely due to the myelination of the retina. Finally, the deficiency of DHA in photoreceptor degeneration could exacerbate the influence of myelination on retinal function. We further investigated the effects of unsaturated fatty acids on neuronal apoptosis. The preliminary experiments confirmed our observation from lipidomics analysis that unsaturated fatty acids can protect neurons from apoptosis. Collectively, our study suggests that increased levels of DHA should be protective from photoreceptor degeneration.

Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection.

Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.

Associations of plasma very-long-chain SFA and the metabolic syndrome in adults.

Plasma levels of very-long-chain SFA (VLCSFA) are associated with the metabolic syndrome (MetS). However, the associations may vary by different biological activities of individual VLCSFA or population characteristics. We aimed to examine the associations of VLCSFA and MetS risk in Chinese adults. Totally, 2008 Chinese population aged 35-59 years were recruited and followed up from 2010 to 2012. Baseline MetS status and plasma fatty acids data were available for 1729 individuals without serious diseases. Among 899 initially metabolically healthy individuals, we identified 212 incident MetS during the follow-up. Logistic regression analysis was used to estimate OR and 95 % CI. Cross-sectionally, each VLCSFA was inversely associated with MetS risk; comparing with the lowest quartile, the multivariate-adjusted OR for the highest quartile were 0·18 (95 % CI 0·13, 0·25) for C20 : 0, 0·26 (95 % CI 0·18, 0·35) for C22 : 0, 0·19 (95 % CI 0·13, 0·26) for C24 : 0 and 0·16 (0·11, 0·22) for total VLCSFA (all P for trend<0·001). The associations remained significant after further adjusting for C16 : 0, C18 : 0, C18 : 3n-3, C22 : 6n-3, n-6 PUFA and MUFA, respectively. Based on follow-up data, C20 : 0 or C22 : 0 was also inversely associated with incident MetS risk. Among the five individual MetS components, higher levels of VLCSFA were most strongly inversely associated with elevated TAG (≥1·7 mmol/l). Plasma levels of VLCSFA were significantly and inversely associated with MetS risk and individual MetS components, especially TAG. Further studies are warranted to confirm the findings and explore underlying mechanisms.

Discovering a critical transition state from nonalcoholic hepatosteatosis to nonalcoholic steatohepatitis by lipidomics and dynamical network biomarkers.

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for type 2 diabetes and metabolic syndrome. However, accurately differentiating nonalcoholic steatohepatitis (NASH) from hepatosteatosis remains a clinical challenge. We identified a critical transition stage (termed pre-NASH) during the progression from hepatosteatosis to NASH in a mouse model of high fat-induced NAFLD, using lipidomics and a mathematical model termed dynamic network biomarkers (DNB). Different from the conventional biomarker approach based on the abundance of molecular expressions, the DNB model exploits collective fluctuations and correlations of different metabolites at a network level. We found that the correlations between the blood and liver lipid species drastically decreased after the transition from steatosis to NASH, which may account for the current difficulty in differentiating NASH from steatosis based on blood lipids. Furthermore, most DNB members in the blood circulation, especially for triacylglycerol (TAG), are also identified in the liver during the disease progression, suggesting a potential clinical application of DNB to diagnose NASH based on blood lipids. We further identified metabolic pathways responsible for this transition. Our study suggests that the transition from steatosis to NASH is not smooth and the existence of pre-NASH may be partially responsible for the current clinical limitations to diagnose NASH. If validated in humans, our study will open a new avenue to reliably diagnose pre-NASH and achieve early intervention of NAFLD.

Behavioral Risk Profile of Men Who Have Sex with Men in Beijing, China: Results from a Cross-sectional Survey with Randomized Response Techniques.

BACKGROUND: Human immunodeficiency virus (HIV) is spreading rapidly among men who have sex with men (MSM) in China. Anonymous questionnaires or direct interviews have been frequently used to study their behavior. The aim of the study was to describe the behavioral risk profile of the MSM in Beijing using the randomized response techniques (RRTs). METHODS: A cross-sectional survey of sexual behavior among a sample of MSM was conducted in two HIV counseling and testing clinics in Beijing. The survey was carried out with an anonymous questionnaire containing sensitive questions on sexual behavior. To obtain the honest responses to the sensitive questions, three distinctive RRTs were used in the questionnaire: (1) Additive randomized response model for quantitative questions, (2) randomized response model for multiple choice questions, and (3) Simmons randomized response model for binomial questions. Formulae for the point estimate, variance, and confidence interval (CI) were provided for each specific model. RESULTS: Using RRTs in a sample of 659 participants, the mean age at first homosexual encounter was estimated to be 21.7 years (95% CI: 21.2-22.2), and each had sex with about three (2.9, 95% CI: 2.4-3.4) male partners on average in the past month. The estimated rate for consistent condom use was 56.4% (95% CI: 50.1-62.8%). In addition, condom was estimated to be used among 80.0% (95% CI: 74.1-85.9%) of the population during last anal sex with a male partner. CONCLUSIONS: Our study employed RRTs in a survey containing questions on sexual behavior among MSM, and the results showed that RRT might be a useful tool to obtain truthful feedback on sensitive information such as sexual behavior from the respondents, especially in traditional Chinese cultural settings.

Incidence of Co-Infections of HIV, Herpes Simplex Virus Type 2 and Syphilis in a Large Cohort of Men Who Have Sex with Men in Beijing, China.

BACKGROUND: The HIV-epidemic among MSM in China has worsened. In this key population, prevalence of HSV-2 and syphilis infection and co-infection with HIV is high. METHODS: A longitudinal study was conducted (n = 962) in Beijing, China, with three overlapping cohorts (n = 857, 757 and 760) consisting of MSM that were free from pairs of infections of concern (i.e. HIV-HSV-2, HIV-syphilis, HSV-2-syphilis) at baseline to estimate incidence of HIV, HSV-2, syphilis, and those of co-infection. RESULTS: The incidence of HIV, HSV-2 and syphilis in the overall cohort was 3.90 (95% CI = 2.37, 5.43), 7.87 (95% CI = 5.74, 10.00) and 6.06 (95% CI = 4.18, 7.94) cases per 100 person-years (PYs), respectively. The incidence of HIV-HSV-2, HIV-Syphilis and HSV-2-Syphilis co-infections was 0.30 (95% CI = 0.29, 0.88), 1.02 (95% CI = 0.13, 2.17) and 1.41 (95% CI: 0.04, 2.78) cases per 100 PYs, respectively, in the three sub-cohorts constructed for this study. CONCLUSIONS: The incidence of HIV, HSV-2 and syphilis was very high and those of their co-infections were relatively high. Such co-infections have negative impacts on the HIV/STI epidemics. Prevention practices need to take such co-infections into account.

Prevalence of HIV and syphilis infection among men who have sex with men in China: a meta-analysis.

OBJECTIVES: To figure out the most current prevalence of HIV and syphilis in MSM in China. METHODS: A meta-analysis was conducted on the studies searched through PubMed, CNKI, and Wanfang published between 1 January 2009 and 11 April 2013. RESULTS: Eighty-four eligible studies, either in Chinese or in English, were included in this review. The pooled prevalence of HIV and syphilis infection in MSM in China was 6.5% and 11.2%, respectively. The subgroup analyses indicated that the prevalence of HIV infection was higher in the economically less developed cities than that in the developed cities (7.5% versus 6.1%, P<0.05). In contrast, the prevalence of syphilis infection was lower in less developed cities than in developed cities (8.6% versus 15.1%). Studies with a sample size smaller than 500 had a lower prevalence of HIV and syphilis infection than those with a sample size greater than 500 (5.9% versus 7.2% for HIV; 11.0% versus 11.5% for syphilis, respectively). CONCLUSIONS: HIV and syphilis infection are prevalent in MSM in China. The different prevalence of HIV and syphilis infection between developing and developed cities underscores the need to target prevention strategies based on economic conditions.

Alterations in mouse brain lipidome after disruption of CST gene: a lipidomics study.

To investigate the effects of a critical enzyme, cerebroside sulfotransferase (CST), involving sulfatide biosynthesis on lipid (particularly sphingolipid) homeostasis, herein, we determined the lipidomes of brain cortex and spinal cord from CST null and heterozygous (CST(-/-) and CST(+/-), respectively) mice in comparison to their wild-type littermates by multi-dimensional mass spectrometry-based shotgun lipidomics. As anticipated, we demonstrated the absence of sulfatide in the tissues from CST(-/-) mice and found that significant reduction of sulfatide mass levels was also present, but in an age-dependent manner, in CST(+/-) mice. Unexpectedly, we revealed that the profiles of sulfatide species in CST(+/-) mice were significantly different from that of littermate controls with an increase in the composition of species containing saturated and hydroxylated fatty acyl chains. Contrary to the changes of sulfatide levels, shotgun lipidomics analysis did not detect significant changes of the mass levels of other lipid classes examined. Taken together, shotgun lipidomics analysis demonstrated anticipated sulfatide mass deficiency in CST defect mouse brain and revealed novel brain lipidome homeostasis in these mice. These results might provide new insights into the role of CST in myelin function.

Role of mitochondria in programmed cell death mediated by arachidonic acid-derived eicosanoids.

Arachidonic acid-derived eicosanoids from cyclooxygenases, lipoxygenases, and cytochrome P450 are important lipid mediators involved in numerous homeostatic and pathophysiological processes. Most eicosanoids act primarily on their respective cell surface G-protein coupled receptors to elicit downstream signaling in an autocrine and paracrine fashion. Emerging evidence indicates that these hormones are also critical in apoptosis in a cell/tissue specific manner. In this review, we summarize the formation of eicosanoids and their roles as mediators in apoptosis, specifically on the roles of mitochondria in mediating these events and the signaling pathways involved. The biological relevance of eicosanoid-mediated apoptosis is also discussed.

Erythrocyte n-3 fatty acids and metabolic syndrome in middle-aged and older Chinese.

CONTEXT: Few studies examined associations of circulating n-3 fatty acid levels with metabolic syndrome (MetS) among Chinese populations who have low consumption of these fatty acids and high risk of developing MetS. OBJECTIVE: The objective of the study was to determine associations between erythrocyte n-3 fatty acids and MetS as well as its components among middle-aged and older Chinese men and women. DESIGN AND PARTICIPANTS: Erythrocyte levels of docosahexaenoic acid (DHA), docosapentaenoic acid, eicosapentaenoic acid, and α-linolenic acid (ALA) were measured by gas chromatography among 2754 participants aged 50-70 yr living in Beijing and Shanghai. MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. RESULTS: After multivariable adjustment, higher levels of DHA, but neither eicosapentaenoic acid nor docosapentaenoic acid, were associated with lower odds of MetS as well as elevated blood pressure and triglycerides. Comparing extreme quartiles of DHA, odds ratios (95% confidence interval) were 0.75 (0.55, 1.01; P for trend = 0.04) for MetS; 0.70 (0.53, 0.92; P for trend = 0.01) for elevated blood pressure; and 0.64 (0.48, 0.87; P for trend = 0.005) for elevated triglycerides. In contrast, ALA concentrations were positively associated with MetS odds (odds ratio 4.06; 95% confidence interval 2.85, 5.80; P for trend <0.001). CONCLUSIONS: Higher concentrations of erythrocyte DHA were associated with lower odds of MetS, whereas higher concentrations of ALA were associated with increased odds among middle-aged and older Chinese. These findings warrant replication in other populations.

Lifestyle counseling and supplementation with flaxseed or walnuts influence the management of metabolic syndrome.

A healthy lifestyle may ameliorate metabolic syndrome (MetS); however, it remains unclear if incorporating nuts or seeds into lifestyle counseling (LC) has additional benefit. A 3-arm, randomized, controlled trial was conducted among 283 participants screened for MetS using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. Participants were assigned to a LC on the AHA guidelines, LC + flaxseed (30 g/d) (LCF), or LC + walnuts (30 g/d) (LCW) group. After the 12-wk intervention, the prevalence of MetS decreased significantly in all groups: -16.9% (LC), -20.2% (LCF), and -16.0% (LCW). The reversion rate of MetS, i.e. those no longer meeting the MetS criteria at 12 wk, was not significantly different among groups (LC group, 21.1%; LCF group, 26.6%; and LCW group, 25.5%). However, the reversion rate of central obesity was higher in the LCF (19.2%; P = 0.008) and LCW (16.0%; P = 0.04) groups than in the LC group (6.3%). Most of the metabolic variables (weight, waist circumference, serum glucose, total cholesterol, LDL cholesterol, apolipoprotein (Apo) B, ApoE, and blood pressure) were significantly reduced from baseline in all 3 groups. However, the severity of MetS, presented as the mean count of MetS components, was significantly reduced in the LCW group compared with the LC group among participants with confirmed MetS at baseline (P = 0.045). Our results suggest that a low-intensity lifestyle education program is effective in MetS management. Flaxseed and walnut supplementation may ameliorate central obesity. Further studies with larger sample sizes and of longer duration are needed to examine the role of these foods in the prevention and management of MetS.

Deficiency in hepatic ATP-citrate lyase affects VLDL-triglyceride mobilization and liver fatty acid composition in mice.

ATP-citrate lyase (ACL) is a key lipogenic enzyme that converts citrate in the cytoplasm to acetyl-CoA, the initial precursor that yields malonyl-CoA for fatty acid biosynthesis. As cytosolic citrate is derived from the tricarboxylic acid cycle in the mitochondrion, ACL catalyzes a critical reaction linking cellular glucose catabolism and lipid synthesis. To investigate the metabolic action of ACL in lipid homeostasis, we specifically knocked down hepatic ACL expression by adenovirus-mediated RNA interference in mice maintained on a low-fat or high-fat diet. Hepatic ACL abrogation markedly reduced the liver abundance of both acetyl-CoA and malonyl-CoA regardless of dietary fat intake, which was paralleled with decreases in circulating levels of triglycerides and free fatty acids. Moreover, hepatic ACL knockdown resulted in diet-dependent changes in the expression of other lipogenic enzymes, accompanied by altered fatty acid compositions in the liver. Interestingly, ACL deficiency led to reduced serum VLDL-triglyceride levels but increased hepatic triglyceride content, resulting at least partially from decreased hepatic secretion of VLDL-containing apolipoprotein B-48. Together, these results demonstrate that hepatic ACL suppression exerts profound effects on triglyceride mobilization as well as fatty acid compositions in the liver, suggesting an important role for ACL in lipid metabolism.

Apolipoprotein E mediates sulfatide depletion in animal models of Alzheimer's disease.

Herein, we tested a recently proposed working model of apolipoprotein E (apoE)-mediated sulfatide metabolism/trafficking/homeostasis with two well-characterized amyloid precursor protein (APP) transgenic (Tg) animal models of Alzheimer's disease (AD) (i.e., APP(V717F) and APPsw) on a wild-type murine apoE background or after being bred onto an Apoe(-/-) background. As anticipated, lipidomics analysis demonstrated that the sulfatide levels in brain tissues were reduced beginning at approximately 6 months of age in APP(V717F) Tg, Apoe(+/+) mice and at 9 months of age in APPsw Tg, Apoe(+/+) mice relative to their respective non-APP Tg littermates. This reduction increased in both APP Tg mice as they aged. In contrast, sulfatide depletion did not occur in APP Tg, Apoe(-/-) animals relative to the Apoe(-/-) littermates. The lack of sulfatide depletion in APP Tg, Apoe(-/-) mice strongly supports the role of apoE in the deficient sulfatide content in APP Tg, Apoe(+/+) mice. Collectively, through different animal models of AD, this study provides evidence for an identified biochemical mechanism that may be responsible for the sulfatide depletion at the earliest stages of AD.

The influence of maternal early to mid-gestation nutrient restriction on long chain polyunsaturated fatty acids in fetal sheep.

The early to mid-gestational period (days 28-78) in sheep is the period of most rapid placental development. Maternal nutrient restriction (MNR) in this phase has negative consequences on fetal growth and development, predisposing the fetus to disease in adult life. The influence of MNR on fetal tissue fatty acids has not been reported. Ewes were fed to 50% (MNR) or 100% (control fed) of total digestible nutrients from days 28 to 78 of gestation. At 78 days, fetuses were sacrificed and the fatty acids in fetal liver, lung and muscle as well as maternal and fetal plasma were analyzed. Most fatty acids were not influenced by MNR. The n-3 long chain PUFA eicosapentaenoic acid (20:5n-3, EPA) concentration (microg/mg) was low and more than doubled in the MNR sheep. Similarly, docosapentaenoic acid (22:5n-3, DPA) increased by 60, 19, and 38% in liver, lung, and muscle, respectively. Neither docosahexaenoic acid (22:6n-3, DHA) nor any of n-6 PUFA changed. Arachidonic acid (20:4n-6; ARA) increased in MNR maternal plasma as a percent of total fatty acids only, while in MNR fetal plasma only EPA increased. These results provide the first indication that MNR in early to mid-gestation influences the profiles of LCPUFA in fetal tissues, and suggest that metabolic processes involving LCPUFA should be considered in evaluations of the impact of maternal nutriture on perinatal health.

Expression profiles of adiponectin receptors in mouse embryos.

Adiponectin is a protein secreted from adipocytes and it plays an important endocrine role in glucose and lipid homeostasis. A reverse correlation between plasma adiponectin concentrations and insulin resistance has been established in both animals and humans. Adiponectin exerts its function by interacting with membrane receptors, including AdipoR1 and AdipoR2. We investigated the expression pattern of these two adiponectin receptors in mouse embryos. At stages E12.5 and E15.5, both AdipoR1 and AdipoR2 are highly expressed in the nervous system including the trigeminal ganglion, glossopharyngeal ganglion and dorsal root ganglia. AdipoR1 is highly expressed in many tissues derived from primitive gut, including the lung, liver, pancreas and small intestines. Generally, the expression level of AdipoR2 is weaker and more restricted than AdipoR1 in most of the tissues. In addition, AdipoR1 expression can be found in heart, vertebrate, developing bones and cartilage, and many other tissues. This study reveals that AdipoR1 and AdipoR2 have differential but overlapping expression profiles during mouse development.

Expression pattern of TG-interacting factor 2 during mouse development.

TGIF2 is a close homologue of TGIF that functions as a transcriptional corepressor by interaction with transforming growth factor-beta (TGF-beta)-activated Smads. Mutations of TGIF have been found in holoprosencephaly, a genetic disease affecting forebrain and craniofacial developmental. Here we analyzed the expression pattern of TGIF2 during mouse embryogenesis. Expression of TGIF2 transcripts was detected at high level at E12.5 and E15.5 in the nervous system including neopallial cortex, mesencephalon, metencephalon, medulla oblongata, spinal cord, trigeminal ganglion, vestibulocochlear ganglion and dorsal root ganglion. In addition, TGIF2 transcripts could be detected in other tissues including heart, lung, liver, pancreas, kidney, small intestine and nasal cavity. These data indicated that TGIF2 has a wide but well controlled expression pattern during mouse development.