Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

[Epidemiological characteristics of cardio-metabolic risk factors in women aged 15-49 years in 4 provinces of China in 2018].

OBJECTIVE: To analyze the prevalence of cardio-metabolic(CM) risk in women aged 15-49 years in 4 provinces of China and the influence of socioeconomic factors on them. METHODS: A total of 2851 women aged 15-49 years from Community-based Cohort Study on Nervous System Disease in 2018 were selected. Obesity, central obesity, elevated triglyceride(TG), elevated total cholesterol(TC), decreased high-density lipoprotein cholesterol(HDL-C), elevated low-density lipoprotein cholesterol(LDL-C), elevated blood pressure, elevated blood glucose and risk factor aggregation were analyzed. χ~2 test was used for univariate analysis, multinomial Logit model was used to evaluate the relationship between socioeconomic factors and CM risk factors, and Cochran-Armitage trend test was used for trend analysis. RESULTS: The detection rate of CM risk factors in this study from high to low were central obesity(26.76%), overweight(22.41%), pre central obesity(17.47%), decreased HDL-C(15.36%), elevated TG(11.78%), borderline elevated TC(11.40%), borderline elevated TG(11.12%), elevated blood pressure(9.71%) and hypertension(9.12%). The prevalence rates of CM risk factors were different among different age groups, income groups and education levels(P<0.05). In addition to decreased HDL-C, the prevalence of other metabolic risk factors increased with age(P_(trend)<0.05). With the improvement of educational level, the prevalence rates of overweight, obesity, central obesity, central obesity, elevated TG, decreased HDL-C, elevated blood pressure, hypertension, elevated blood pressure and diabetes showed a downward trend(P_(trend)<0.05). Multinomial Logit model showed that the rick of metabolic risk factors in the age group of 40 to 49 years old was higher than that in the younger age group aged 15-29 years, and was more significant in hypertension, elevated blood pressure and elevated blood glucose, which were 8.51 times(95% CI 5.45-13.27), 3.14 times(95%CI 2.20-4.48)and 2.66(95% CI 1.52-4.66)times of the younger age group, respectively. Women with high-income level have a higher risk of borderline elevated TC, elevated TC and borderline elevated LDL-C(OR=1.85, 95% CI 1.44-2.38;OR=2.01, 95% CI 1.25-3.22;OR=2.16, 95% CI 1.61-2.90), but the lower risk of overweight and elevated blood pressure(OR=0.79, 95% CI 0.64-0.98;OR=0.69, 95% CI 0.50-0.94). The risk of obesity, hypertension and diabetes of people with college degree or above was about 50% lower than those with junior high school education or below(OR=0.52, 95% CI 0.35-0.78;OR=0.43, 95% CI 0.27-0.67; OR=0.52, 95% CI 0.28-0.96). CONCLUSION: Central obesity, overweight, pre central obesity and HDL-C decrease were prominent CM risk factors in women aged 15-49 years in four provinces of China in 2018. The detection rate of CM risk factors is higher in women of high age group or low education level.

[Analysis of food carbon footprint and its socio-demographic disparities in China in 2018].

OBJECTIVE: To analyze food carbon footprint and its socio-demographic disparities among adults in China. METHODS: A total of 12 777 adults aged 18 years and above from the China Health and Nutrition Survey in 2018 who have completed dietary and socio-demographic data were analyzed. The information of food intake were collected by 24 h recalls combined with the weighing of household seasonings. Food consumption was converted into energy intake by the China Food Composition Table. Carbon footprint of 26 food groups were calculated by the food carbon footprint database based on life-cycle assessment(LCA), multinomial logit model was used to analyze the association of socio-demographic factors and food carbon footprint. RESULTS: Average food carbon footprint were decreased with increasing age while increased with increasing income and education levels, and was higher among male than that among female, was higher among urban residents than that among rural residents, was higher in the south than that in the north. Multinomial logit analysis showed that compared with people aged 18-44, the likelihood of occurring high carbon footprint in 60y and above group were 29%(OR=0.71, 95%CI 0.61-0.83) lower than that occurring low carbon footprint. Women were 11%(OR=0.89, 95%CI 0.81-0.99) and 25%(OR=0.75, 95%CI 0.67-0.84) less likely to appear medium and high carbon footprint than low carbon footprint, compared with their male counterparts. In comparison to people living in cities, rural dwellers were 24%(OR=0.76, 95%CI 0.69-0.85) and 38%(OR=0.62, 95%CI 0.55-0.70) less likely to appear medium and high carbon footprint than low carbon footprint. People in the south were 3.89 times(95%CI 3.52-4.30) and 11.35 times(95%CI 10.01-12.88) more likely to occur medium and high carbon footprint than low carbon footprint, compared with people in the north. Participants were more likely to occur medium carbon footprint and high carbon footprint with the increasing income level(OR>1), and were more likely to occur high carbon footprint with the increasing education level(OR>1). CONCLUSION: The food carbon footprint of adults in China in 2018 show different socio-demographic disparities, gender, income and education level are significant factors.

Avatrombopag for the salvage treatment of platelet transfusion refractoriness.

Background: Platelet transfusion refractoriness (PTR) is a life-threatening and intractable condition in hematological patients. Thrombopoietin receptor agonists such as avatrombopag promote platelet production and modulate immune intolerance. However, its application in PTR has not been extensively studied. Objectives: We aimed to compare the platelet response (PR) as well as bleeding events and mortality rate between the best available therapies (BATs) and avatrombopag (Ava) treatments in refractory PTR patients. Design: A total of 71 refractory PTR patients were enrolled at Nanfang Hospital. Intravenous immunoglobulin, steroids, and human leucocyte antigen-matched platelet transfusions were administered to 30 patients in the BATs group. The Ava group included 41 patients. Methods: Data of refractory PTR patients were retrospectively collected. The primary endpoint was PR (defined as an increase of platelet count to ⩾50 × 109/L without platelet transfusion support for 7 consecutive days). Secondary endpoints included platelet-transfusion independence rate, cumulative platelet transfusion units, World Health Organization bleeding grades, adverse events, overall survival (OS), and bleeding event-free survival (EFS). Results: There were 75.6% and 13.3% refractory PTR patients who reached PR within 3 months in Ava and BATs groups. The median platelet counts were significantly higher in Ava group from day 7. Platelet-transfusion independence rate in Ava was higher than BATs group. The median cumulative platelet transfusion unit in Ava was lower than that of BATs group. The OS and bleeding events-free EFS rate of Ava group improved within 3 months as compared to BATs group. Cox proportional hazards regression analysis revealed that Ava therapy was a protective factor for the OS and EFS. No primary disease progression or termination of avatrombopag was observed due to intolerability. Conclusion: Our study suggests that avatrombopag is an effective and safe treatment option for refractory PTR patients.

Avatrombopag in platelet transfusion refractoriness PTR is a challenging clinical issue in patients with hematologic disorders which increases early death and hospitalization costs. Thrombopoietin receptor agonists have shown inspiring effects in treating thrombocytopenia. However, there are few studies focused on the application of these drugs in PTR patients. In this study, we investigated 71 patients with PTR in which 30 patients received the best available therapies, while 41 patients received avatrombopag treatment. We found that avatrombopag increases platelet response rate, reduces platelet transfusions dependence and occurrence of severe bleeding events, as well as improves overall survival rate and event free survival in PTR patients. Avatrombopag also exhibited good tolerance and safety. We reported for the first time that avatrombopag was an effective and safe treatment in PTR, which may also help to expand the clinical application of TPO-RAs.

A strategy to reduce the byproduct glucose by simultaneously producing levan and single cell oil using an engineered Yarrowia lipolytica strain displaying levansucrase on the surface.

Currently, levan is attracting attention due to its promising applications in the food and biomedical fields. Levansucrase synthesizes levan by polymerizing the fructosyl unit in sucrose. However, a large amount of the byproduct glucose is produced during this process. In this paper, an engineered oleaginous yeast (Yarrowia lipolytica) strain was constructed using a surface display plasmid containing the LevS gene of Gluconobacter sp. MP2116. The levansucrase activity of the engineered yeast strain reached 327.8 U/g of cell dry weight. The maximal levan concentration (58.9 g/l) was achieved within 156 h in the 5-liter fermentation. Over 81.2 % of the sucrose was enzymolyzed by the levansucrase, and the byproduct glucose was converted to 21.8 g/l biomass with an intracellular oil content of 25.5 % (w/w). The obtained oil was comprised of 91.3 % long-chain fatty acids (C16-C18). This study provides new insight for levan production and comprehensive utilization of the byproduct in levan biosynthesis.