Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING-NF-κB Signaling Pathway.

BACKGROUND & AIMS: Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that confers a broad range of functional effects in metabolic diseases. Lean nonalcoholic fatty liver disease (NAFLD) is characterized by a decrease in subcutaneous fat and ectopic fat deposition in the liver. SCAP may mediate the development of lean NAFLD, but the mechanism of action remains unclear. METHODS: C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAPΔMϕ) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING-NF-κB signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation. RESULTS: The data showed heterogeneity of lipid metabolic processes in liver and epididymal white adipose tissue due to inflammation mediated by macrophage infiltration. Meanwhile, we found that the macrophage SCAP was abnormally increased in the adipose and liver tissues of PD-fed mice. Intriguingly, the SCAPΔMϕ mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)-nuclear factor kappa B (NF-κB) pathway activation. In-depth molecular analysis revealed that SCAP specifically recruits the STING and tank-binding kinase 1 onto the Golgi to activate the NF-κB in macrophages, thereby promoting the release of inflammatory factors. This process ultimately led to an increased lipolysis in adipocytes and lipid uptake and synthesis in hepatocytes. CONCLUSIONS: Our findings suggest that SCAP acts as a novel regulator of the macrophage inflammatory response and the pathogenesis of lean NAFLD by activating the STING-NF-κB signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD.

Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted. METHODS: We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice. RESULTS: Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo. CONCLUSIONS: SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

SCAP knockout in SM22α-Cre mice induces defective angiogenesis in the placental labyrinth.

The placental labyrinth is important for the exchange of nutrients and gases between the mother and the embryo in mice. This interface contains cells of both trophoblast and allantoic mesodermal origin that together produce maternal blood sinuses and placental blood vessels. However, the molecular mechanisms that take place during process of placental labyrinth development, especially concerning fetal capillaries, are not well understood. SREBP cleavage-activating protein (SCAP), a membrane protein, is required for the synthesis of fatty acids and cholesterol. Recently, when we crossed the offspring of the cross between smooth muscle 22 alpha (SM22α)- Cre recombinase (Cre) mice and SCAPloxp/loxp mice to research the function of SCAP in vascular smooth muscle cells (VSMCs) during certain pathological processes, we found that there were no resultant SM22α-Cre-specific SCAP knockout (KO) pups (SM22α-Cre+SCAPflox/flox; hereafter referred to as SCAP KO). Through anatomic studies of these embryos and placentas, we found that SCAP KO resulted in defective placental vessels and abnormal fetal morphology. Further immunohistochemical and immunocytochemical analyses suggested that SCAP is knocked out in the pericytes of the placental labyrinth. Compared to wildtype mice, SCAP KO placentas had abnormal vasculature in the labyrinth and lower levels of angiogenesis. By using RNA-seq and western blotting, we found that the expression of some genes and proteins in SCAP KO placentas was changed, including those related to pericyte/endothelial interactions genes and angiogenesis. Our results suggest that the proper organizational structure of the placental labyrinth depends on SCAP expression in pericytes.

Short-term effects of specific humidity and temperature on COVID-19 morbidity in select US cities.

Little is known about the environmental conditions that drive the spatiotemporal patterns of SARS-CoV-2. Preliminary research suggests an association with meteorological parameters. However, the relationship with temperature and humidity is not yet apparent for COVID-19 cases in US cities first impacted. The objective of this study is to evaluate the association between COVID-19 cases and meteorological parameters in select US cities. A case-crossover design with a distributed lag nonlinear model was used to evaluate the contribution of ambient temperature and specific humidity on COVID-19 cases in select US cities. The case-crossover examines each COVID case as its own control at different time periods (before and after transmission occurred). We modeled the effect of temperature and humidity on COVID-19 transmission using a lag period of 7 days. A subset of 8 cities were evaluated for the relationship with meteorological parameters and 5 cities were evaluated in detail. Short-term exposure to humidity was positively associated with COVID-19 transmission in 4 cities. The associations were small with 3 out of 4 cities exhibiting higher COVID19 transmission with specific humidity that ranged from 6 to 9 g/kg. Our results suggest that weather should be considered in infectious disease modeling efforts. Future work is needed over a longer time period and across different locations to clearly establish the weather-COVID19 relationship.

Extraordinary catalysis induced by titanium foil cathode plasma for degradation of water pollutant.

The present paper reports a rapid and cost-effective bifunctional approach to the degradation of organic pollutants in the aqueous solution. This in situ hybrid induced photocatalytic method involves the advanced oxidation process, and photocatalytic process induced by ultraviolet radiated from the plasma discharge to improve the degradation efficiency. This powerful plasma allows the organic molecules to be cleaved either in the plasma zone or on the plasma/solution interface through hydrogen abstraction and electron transfer. Four parallel metal foil electrodes (i.e. Ta, Cu, Ti and Au coated Ti), used as cathodes in the two-electrode system, were evaluated in terms of their degradable performance to organic pollutants. It was found that the degradation rates are dependent on the electrical conduction of metal cathodes. During the discharge process, the Ti-based foil produces TiO2 particles, which then act as catalyst in the electrolyte and perform the photocatalytic process along with the plasma discharge process to degrade organic pollutants. It is of particular interest that gold nanoparticles, generated from Au coated Ti foil film during electrode discharging, are less than 5 nm in size and further enhance the TiO2 photocatalytic activity. In fact, this bifunctional plasma discharge process to the degradation of water pollutant provides an insight into more applications such as chemical conversion, water purification and dust pollution.

A method for screening climate change-sensitive infectious diseases.

Climate change is a significant and emerging threat to human health, especially where infectious diseases are involved. Because of the complex interactions between climate variables and infectious disease components (i.e., pathogen, host and transmission environment), systematically and quantitatively screening for infectious diseases that are sensitive to climate change is still a challenge. To address this challenge, we propose a new statistical indicator, Relative Sensitivity, to identify the difference between the sensitivity of the infectious disease to climate variables for two different climate statuses (i.e., historical climate and present climate) in non-exposure and exposure groups. The case study in Anhui Province, China has demonstrated the effectiveness of this Relative Sensitivity indicator. The application results indicate significant sensitivity of many epidemic infectious diseases to climate change in the form of changing climatic variables, such as temperature, precipitation and absolute humidity. As novel evidence, this research shows that absolute humidity has a critical influence on many observed infectious diseases in Anhui Province, including dysentery, hand, foot and mouth disease, hepatitis A, hemorrhagic fever, typhoid fever, malaria, meningitis, influenza and schistosomiasis. Moreover, some infectious diseases are more sensitive to climate change in rural areas than in urban areas. This insight provides guidance for future health inputs that consider spatial variability in response to climate change.

Identification of climate factors related to human infection with avian influenza A H7N9 and H5N1 viruses in China.

Human influenza infections display a strongly seasonal pattern. However, whether H7N9 and H5N1 infections correlate with climate factors has not been examined. Here, we analyzed 350 cases of H7N9 infection and 47 cases of H5N1 infection. The spatial characteristics of these cases revealed that H5N1 infections mainly occurred in the South, Middle, and Northwest of China, while the occurrence of H7N9 was concentrated in coastal areas of East and South of China. Aside from spatial-temporal characteristics, the most adaptive meteorological conditions for the occurrence of human infections by these two viral subtypes were different. We found that H7N9 infections correlate with climate factors, especially temperature (TEM) and relative humidity (RHU), while H5N1 infections correlate with TEM and atmospheric pressure (PRS). Hence, we propose a risky window (TEM 4-14 °C and RHU 65-95%) for H7N9 infection and (TEM 2-22 °C and PRS 980-1025 kPa) for H5N1 infection. Our results represent the first step in determining the effects of climate factors on two different virus infections in China and provide warning guidelines for the future when provinces fall into the risky windows. These findings revealed integrated predictive meteorological factors rooted in statistic data that enable the establishment of preventive actions and precautionary measures against future outbreaks.

Earlier vegetation green-up has reduced spring dust storms.

The observed decline of spring dust storms in Northeast Asia since the 1950s has been attributed to surface wind stilling. However, spring vegetation growth could also restrain dust storms through accumulating aboveground biomass and increasing surface roughness. To investigate the impacts of vegetation spring growth on dust storms, we examine the relationships between recorded spring dust storm outbreaks and satellite-derived vegetation green-up date in Inner Mongolia, Northern China from 1982 to 2008. We find a significant dampening effect of advanced vegetation growth on spring dust storms (r = 0.49, p = 0.01), with a one-day earlier green-up date corresponding to a decrease in annual spring dust storm outbreaks by 3%. Moreover, the higher correlation (r = 0.55, p < 0.01) between green-up date and dust storm outbreak ratio (the ratio of dust storm outbreaks to times of strong wind events) indicates that such effect is independent of changes in surface wind. Spatially, a negative correlation is detected between areas with advanced green-up dates and regional annual spring dust storms (r = -0.49, p = 0.01). This new insight is valuable for understanding dust storms dynamics under the changing climate. Our findings suggest that dust storms in Inner Mongolia will be further mitigated by the projected earlier vegetation green-up in the warming world.