Acute exposure to gold nanoparticles aggravates lipopolysaccharide-induced liver injury by amplifying apoptosis via ROS-mediated macrophage-hepatocyte crosstalk.

BACKGROUND: Gold nanoparticles (AuNPs) are increasingly utilized in industrial and biomedical fields, thereby demanding a more comprehensive knowledge about their safety. Current toxicological studies mainly focus on the unfavorable biological impact governed by the physicochemical properties of AuNPs, yet the consequences of their interplay with other bioactive compounds in biological systems are poorly understood. RESULTS: In this study, AuNPs with a size of 10 nm, the most favorable size for interaction with host cells, were given alone or in combination with bacterial lipopolysaccharide (LPS) in mice or cultured hepatic cells. The results demonstrated that co exposure to AuNPs and LPS exacerbated fatal acute liver injury (ALI) in mice, although AuNPs are apparently non-toxic when administered alone. AuNPs do not enhance systemic or hepatic inflammation but synergize with LPS to upregulate hepatic apoptosis by augmenting macrophage-hepatocyte crosstalk. Mechanistically, AuNPs and LPS coordinate to upregulate NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation and activate the intrinsic apoptotic pathway in hepatic macrophages. Extracellular ROS generation from macrophages is then augmented, thereby inducing calcium-dependent ROS generation and promoting apoptosis in hepatocytes. Furthermore, AuNPs and LPS upregulate scavenger receptor A expression in macrophages and thus increase AuNP uptake to mediate further apoptosis induction. CONCLUSIONS: This study reveals a profound impact of AuNPs in aggravating the hepatotoxic effect of LPS by amplifying ROS-dependent crosstalk in hepatic macrophages and hepatocytes.

Diphenyleneiodonium enhances P2X7 dependent non-opsonized phagocytosis and suppresses inflammasome activation via blocking CX43-mediated ATP leakage.

The beneficial effects of antioxidants against oxidative stress have been well described. However, the pharmacological impacts of antioxidants other than inhibiting the production of reactive oxygen species (ROS) remain less understood. This study demonstrated that diphenyleneiodonium (DPI), a canonical NADPH oxidase 2 (NOX2) inhibitor, effectively promoted non-opsonized bacterial phagocytosis. Indeed, DPI abrogated the elevation in the extracellular ATP level of Escherichia coli (E. coli) -infected murine peritoneal macrophages, thereby restoring the association of the purinergic receptor P2X7 with non-muscle myosin heavy chain 9 (MYH9) to upregulate the P2X7 -dependent phagocytosis of E. coli. DPI also suppressed inflammasome activation and reduced necroptosis in E. coli-infected macrophages by decreasing extracellular ATP levels. Mechanistically, DPI upregulated p38 MAPK phosphorylation to suppress the expression and activity of the hemichannel protein connexin 43 (CX43), leading to the inhibition of CX43-mediated ATP efflux in E. coli-infected macrophages. In a murine E. coli infection model, DPI effectively reduced ATP release, decreased bacterial load and inhibited inflammasome activation, thereby improving survival and ameliorating organ injuries in model mice. In summary, our study demonstrates a previously unknown function of DPI in conferring protection against bacterial infection and suggests a putative antimicrobial strategy of modulating CX43 -dependent ATP leakage.

The screening of albumin as a key serum component in preventing release of neutrophil extracellular traps by selectively inhibiting mitochondrial ROS generation.

Neutrophil extracellular traps (NETs) are extracellular DNA webs released from neutrophils to mediate the host antimicrobial defense. As NETs could also induce thrombosis and cause organ injury, their release should be strictly controlled; however, the intrinsic mechanisms that prevent unfavorable NETs are not well understood. Herein, an accidental finding of NET release from human peripheral neutrophils was first described in a serum-free culture, which was later determined to be a conserved NET prevention effect of serum. In contrast to canonical NETs induced by phorbol-12-myristate-13-acetate (PMA), NET formation by serum-free culture was rapid and without prevalent NETosis. Next, albumin was screened out as a key serum component that mediated the suppression of NETs. Moreover, NETs induced upon serum or albumin deficiency were independent of the canonical pathway that involves NADPH oxidase 2 (NOX2) activation and cytosol reactive oxygen species (ROS) production. Instead, the generation of mitochondrial ROS (mtROS) was upregulated to promote NET release. Albumin exhibited mtROS scavenging activity and thus inhibited NETs. Serum-free culture also induced the release of NET-bound oxidized mtDNA, which stimulated interferon-ß (IFN-ß) production. Overall, our research provides new evidence that characterizes the NET production in serum-free culture and determines the mechanisms by which serum albumin inhibits NETs.

Gold nanoparticles synergize with bacterial lipopolysaccharide to enhance class A scavenger receptor dependent particle uptake in neutrophils and augment neutrophil extracellular traps formation.

Gold nanoparticles (AuNPs) are extensively utilized in biomedical fields. However, their potential interaction with host cells has not been comprehensively elucidated. In this study, we demonstrated a size-dependent effect of AuNPs to synergize with bacterial lipopolysaccharide (LPS) in promoting neutrophil extracellular traps (NETs) release in human peripheral neutrophils. Mechanistically, LPS was more efficient to contact with 10 nm AuNPs and promote their uptake in neutrophils compared to 40 and 100 nm AuNPs, leading to a synergistic upregulation of class A scavenger receptor (SRA) which mediated AuNPs uptake and triggered activation of extracellular regulated protein kinase (ERK) and p38. Blocking SRA or inhibiting ERK and p38 activation remarkably abrogated the effect of AuNPs and LPS to induce NETs formation. Further experiments demonstrated that AuNPs and LPS augmented the production of cytosolic reactive oxygen species (ROS) in p38 and ERK dependent manner, through upregulating and activating NADPH oxidase 2 (NOX2). Accordingly, scavenging of ROS or inhibiting the NOX2 dampened NETs release induced by combined AuNPs and LPS treatment. AuNPs and LPS also synergized to upregulate reactive oxygen species modulator 1 (ROMO1) via activating ERK, thereby increasing mitochondrial ROS generation and promoting the release of NETs. In summary, we provide new evidences about the synergy of AuNPs and LPS to augment cellular responses in neutrophils, which implicates the need to consider the amplifying effect by pathogenic stimuli when utilizing nanomaterials in infectious or inflammatory conditions.

Stimulation of the class-A scavenger receptor induces neutrophil extracellular traps (NETs) by ERK dependent NOX2 and ROMO1 activation.

Neutrophil extracellular traps (NETs) play a critical role in host antimicrobial response whereas they are also implicated in the pathogenesis of inflammatory and autoimmunediseases. Generation of reactiveoxygen species (ROS) is key to NETs formation. A variety of stimulatory ligands have been found to enhance ROS production and thus trigger NETs. However, the mechanisms that connect receptor stimuli with ROS production and NETs formation remain unclear. In this study, we described a new mechanism of NETs generation in neutrophils triggered by stimulation of the class A scavenger receptor (SRA), a major subtype of scavenger receptors in response to various stimuli during infection and inflammatory disorders. By using polyinosinic acid (Poly I), a ribonucleotide ligand of SRA, we demonstrated that SRA stimulation lead to selective ERK phosphorylation, which upregulated cytosol ROS levels and induced canonical NETs formation by activating NADPH oxidase 2 (NOX2). Interestingly, our results showed that mitochondrial ROS (mtROS) production was also enhanced by the SRA dependent ERK activation through upregulation and activation of reactive oxygen species modulator 1(ROMO1), a mitochondrial membrane protein and a key mediator of mtROS. Moreover, inhibition of the SRA elicited ROMO1 activation dampened NETs release upon SRA stimulation. Overall, our study describes a new insight into the NETs release triggered by membrane SRA stimulation and mediated by ERK dependent NOX2 and ROMO1 activation.

Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation.

A growing body of literature suggests that most chronic autoimmune diseases are associated with inappropriate inflammation mediated by Toll-like receptor (TLR) 3, TLR7/8, or TLR9. Therefore, research into blocking TLR activation to treat these disorders has become a hot topic. Here, we report the immunomodulatory properties of a nonstimulatory CpG-containing oligodeoxynucleotide (CpG-ODN), CpG-c41, which had previously only been known as a TLR9 antagonist. In this study, we found that both in vitro and in vivo CpG-c41 decreased levels of various proinflammatory factors that were induced by single activation or coactivation of intracellular TLRs, but not membrane-bound TLRs, no matter what downstream signal pathways the TLRs depend on. Moreover, CpG-c41 attenuated excessive inflammation in the imiquimod-induced psoriasis-like mouse model of skin inflammation by suppressing immune cell infiltration and release of inflammatory factors. We also found evidence that the immunosuppressive effects of CpG-c41 on other intracellular TLRs are mediated by a TLR9-independent mechanism. These results suggest that CpG-c41 acts as an upstream of signaling cascades, perhaps on the processes of ligand internalization and transfer. Taken together, these results suggest that CpG-c41 disrupts various aspects of intracellular TLR activation and provides a deeper insight into the regulation of innate immunity.

The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock.

Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1ß and IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1ß, IL-18, and Nlrp3 in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1ß and IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock.

Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases.

AIMS: To clarify the imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases (AITDs) including Graves' disease(GD), Hashimoto's thyroiditis(HT) and Graves' ophthalmopathy (GO). METHODS: 47 patients with AITD (including 16 GD, 15 HT, and 16 GO) and 12 healthy controls were enrolled in this study. The percentages of Th17 and Treg cells, the ratio of Th17/Treg, as well as their related transcription factors RORγt and Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry and real-time quantitative PCR Results: Compared with those in control group, the percentage of CD4+IL-17+T cell(Th17) and the mRNA expression of its transcription factor RORγt were higher in PBMCs of AITDs (P<0.05), particularly in HT subgroup (P<0.01). The percentage of CD4+Foxp3+T (Treg) cells and its transcription factor Foxp3 mRNA were significantly decreased in PBMCs of GD (P<0.05). In addition, the ratio of Th17/Treg was elevated in AITD group and GO subgroup (P<0.01). In GO subgroup, the patients with clinical activity score (CAS) above 4.5 had higher percentages of Th17 than those with CAS ranging from 3 to 4.5 (P<0.05). CONCLUSION: Increased Th17 lymphocytes may play a more important role in the pathogenesis of HT and GO while decreased Treg may be greatly involved in GD.

Extracellular calcium influx promotes antibacterial autophagy in Escherichia coli infected murine macrophages via CaMKKß dependent activation of ERK1/2, AMPK and FoxO1.

Autophagy induction has been found as an alternative mechanism for ultimate elimination of invaded bacteria in innate immune cells. However, underlying mechanisms for the regulation of antibacterial autophagy require further elucidation. The present study mainly explores calcium dependent regulation of autophagy and its contribution to bactericidal activity in Escherichia coli (E. coli) infected murine macrophages. In this study, E. coli was shown to increase cellular calcium levels by triggering extracellular calcium influx in murine bone marrow derived macrophages. The elevated calcium was required for autophagy and bactericidal activity against E. coli, as extracellular calcium depletion or inhibition of calcium influx suppressed E. coli induced Beclin1 and LC3B expression, dampened LC3B puncta or LC3I to LC3II conversion and impaired intracellular E. coli degradation. Then CaMKKß was identified as activated by E. coli induced calcium influx and chemical inhibition or RNAi knockdown of CaMKKß abolished calcium mediated antibacterial autophagy. CaMKKß was demonstrated to activate signaling pathways involving ERK, AMPK and FoxO1 and RNAi knockdown of these molecules also dampened the antibacterial autophagy against E. coli. In summary, we demonstrate a new mechanism of calcium dependent antibacterial strategy in E. coli infected macrophages, which requires autophagy enhancement mediated by activation of CaMKKß, ERK, AMPK and FoxO1.

The haplotype of UBE2L3 gene is associated with Hashimoto's thyroiditis in a Chinese Han population.

BACKGROUND: The ubiquitin conjugating enzyme E2L3 (UBE2L3) gene is associated with susceptibility to many autoimmune diseases. The aim of this study was to investigate the association between UBE2L3 gene and autoimmune thyroid diseases (AITDs) and their clinical phenotypes. METHODS: We genotyped five single-nucleotide polymorphisms (SNPs) rs131654, rs5754217, rs2298428, rs140489 and rs5998672 of UBE2L3 gene in case groups including 1028 patients with AITDs [676 cases of Graves' disease (GD) and 352 cases of Hashimoto's thyroiditis (HT)] and control group including 897 healthy individuals. The genotyping was performed with the method of polymerase chain reaction-ligase detection reaction (PCR-LDR). RESULTS: The frequencies of allele and genotype of five SNPs in gene UBE2L3 showed no statistically significant difference between case groups and control group, respectively. Moreover, no significant differences in frequencies of allele and genotype of five SNPs of the gene were found between clinical subphenotypes of AITDs and control group. Such subphenotypes included GD, HT, and thyroid associated ophthalmopathy (TAO). The negative results were also found in the frequency of other haplotypes of the gene except the haplotype of TCGGC, which was significantly higher in HT group than in control group (P = 0.031, OR = 1.441). CONCLUSIONS: The present findings indicate that TCGGC haplotype is associated with an increased risk of HT and UBE2L3 gene is likely to be a susceptibility factor to HT in a Chinese Han population.

Inhibition of Extracellular Calcium Influx Results in Enhanced IL-12 Production in LPS-Treated Murine Macrophages by Downregulation of the CaMKKß-AMPK-SIRT1 Signaling Pathway.

Activated macrophages are the primary sources of IL-12, a key cytokine bridging innate and adaptive immunity. However, macrophages produce low amounts of IL-12 upon stimulation and the underlying regulatory mechanism remains unclear. In this study, we found a new calcium-dependent mechanism that controlled IL-12 production in LPS-treated murine macrophages. First, LPS was demonstrated to induce extracellular calcium entry in murine peritoneal macrophages and inhibition of calcium influx resulted in marked enhancement in IL-12 production. Then, withdrawal of extracellular calcium was found to suppress CaMKKß and AMPK activation triggered by LPS while chemical inhibition or genetic knockdown of these two kinases augmented LPS induced IL-12 production. AMPK activation increased the NAD(+)/NADH ratio and activated Sirtuin 1 (SIRT1), a NAD(+)-dependent deacetylating enzyme and negative regulator of inflammation. Chemical inhibitor or siRNA of SIRT1 enhanced IL-12 release while its agonist suppressed IL-12 production. Finally, it was found that SIRT1 selectively affected the transcriptional activity of NF-κB which thereby inhibited IL-12 production. Overall, our study demonstrates a new role of transmembrane calcium mobilization in immunity modulation such that inhibition of calcium influx leads to impaired activation of CaMKKß-AMPK-SIRT1 signaling pathway which lifts restriction on NF-κB activation and results in enhanced IL-12 production.

Antisaccadic eye movements in middle-aged individuals with a family history of Alzheimer's disease.

Background: Antisaccade is closely associated with cognitive ability in Alzheimer's disease (AD). However, studies regarding antisaccade in the early stages of AD are scarce. Considering that first-degree family history is a well-established risk factor for AD, we explored the influence of family history on the performance of antisaccade tasks in individuals with normal cognition. Methods: In total, 44 participants (aged 50-66 years) with a family history of AD (FH+) and 44 age-, gender-, and educational level-matched controls (FH-) were enrolled in our study. After cognitive assessment using the Montreal Cognitive Assessment and Mini-mental State Examination, participants underwent antisaccade trials, and all parameters were recorded using an eye tracker. Results: While the average velocity was relatively lower in FH+ individuals than in FH- individuals (107.9 ± 14.3°/s vs. 132.9 ± 23.7°/s, p < 0.001), FH+ individuals surprisingly showed relatively fewer uninhibited reflexive saccades (44.7 ± 26.0% vs. 56.2 ± 24.7%, p = 0.037) than the control group. They also required a relatively shorter time to detect and correct false saccades (121.6 ± 40.7 ms vs. 143.9 ± 37.0 ms, p = 0.023). Conclusions: This study showed that family history is associated with alterations in antisaccadic parameters, suggesting that eye tracking can be used to assess oculomotor control and executive function in individuals at risk of developing dementia.

Glutamine alleviates intestinal injury in a murine burn sepsis model by maintaining intestinal intraepithelial lymphocyte homeostasis.

Intestinal intraepithelial lymphocytes (IELs) play a sentinel role in the mucosal immune system because of their unique anatomical location in the epithelial layer. The disruption of IEL homeostasis is implicated in driving the intestinal injury of many typical inflammatory disorders, such as inflammatory bowel disease (IBD) and sepsis. Therefore, it is meaningful to alleviate intestinal injury by restoring IEL homeostasis in disease conditions. This study explores the effects of glutamine on intestinal IEL homeostasis in a murine model of burn sepsis. We report that glutamine inhibits inflammatory response and reduces injury in the small intestine of burn septic mice. This effect is attributed to the maintaining of IEL homeostasis by suppressing apoptosis and restoring the disrupted subpopulation balance induced by burn sepsis. Mechanistically, we show that glutamine does not affect the IL-15 dependent mechanisms that drive the maintenance and differentiation of IELs. Instead, glutamine sustains IEL homeostasis by upregulate aryl hydrocarbon receptor (AHR) and interleukin (IL)-22 transcription and expression. Consistently, the protective roles of glutamine in burn septic mice were repressed by further supplement with an AHR antagonist CH-223191. Collectively, our study reveals a new role of glutamine to maintain IEL homeostasis by activating the AHR signaling pathway, which in turn ameliorates intestinal injury in burn sepsis.

Association between thyroid stimulating hormone receptor gene intron polymorphisms and autoimmune thyroid disease in a Chinese Han population.

Autoimmune thyroid disease (AITD) is a multifactorial disease with a genetic susceptibility and environmental factors. The thyroid stimulating hormone receptor gene (TSHR) which is expressed on the surface of the thyroid epithelial cell is thought to be the main auto-antigen and a significant candidate for genetic susceptibility to AITD. This case-control study aimed at evaluating the association between single nucleotide polymorphisms (SNP) of TSHR and AITD in a Chinese Han population. We recruited 404 patients with Graves' disease (GD), 230 patients with Hashimoto's thyroiditis (HT) and 242 healthy controls. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was used to detect five SNPs (rs179247, rs12101255, rs2268475, rs1990595, and rs3783938) in TSHR gene. The frequencies of allele T and TT genotype of rs12101255 in GD patients were significantly increased compared with those of the controls (P=0.004/0.015, OR=1.408/1.446). The allele A frequency of rs3783938 was greater in HT patients than in the controls (P=0.025, OR=1.427). The AT haplotype (rs179247-rs12101255) was associated with an increased risk of GD (P=0.010, OR=1.368). The allele A of rs179247 was associated with ophthalmopathy in GD patients. These data suggest that the polymorphisms of rs12101255 and rs3783938 are associated with GD and HT, respectively.

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond.

Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.

Glutamine mitigates murine burn sepsis by supporting macrophage M2 polarization through repressing the SIRT5-mediated desuccinylation of pyruvate dehydrogenase.

Background: Alternative (M2)-activated macrophages drive the anti-inflammatory response against sepsis, a leading cause of death in patients suffering from burn injury. Macrophage M2 polarization is intrinsically linked with dominant oxidative phosphorylation (OXPHOS). Glutamine serves as a major anaplerotic source to fuel OXPHOS, but it remains unknown whether glutamine can modulate metabolic checkpoints in OXPHOS that favour M2 polarization. The study aims to explore whether glutamine essentially supports M2 polarization in IL-4-stimulated murine macrophages by sustaining the activity of PDH and whether glutamine augments macrophage M2 polarization and thus alleviates inflammation and organ injury in a murine burn sepsis model. Methods: To understand how glutamine promotes M2 activation in interleukin (IL-4)-treated murine macrophages, we detected glutamine-dependent M2 polarization and its relationship with the pyruvate dehydrogenase (PDH) complex by RT-PCR, flow cytometry and western blot. To explore how glutamine modulates PDH activity and thus supports M2 polarization, we compared the expression, phosphorylation and succinylation status of PDHA1 and then examined sirtuin SIRT5-dependent desuccinylation of PDHA1 and the effects of SIRT5 overexpression on M2 polarization by RT-PCR, flow cytometry and western blot. To determine whether glutamine or its metabolites affect M2 polarization, macrophages were cocultured with metabolic inhibitors, and then SIRT5 expression and M2 phenotype markers were examined by RT-PCR, flow cytometry and western blot. Finally, to confirm the in vivo effect of glutamine, we established a burn sepsis model by injecting Pseudomonas aeruginosa into burn wounds and observing whether glutamine alleviated proinflammatory injuries by RT-PCR, flow cytometry, western blot, immunofluorescent staining, hematoxylin-eosin staining and enzyme-linked immuno sorbent assay. Results: We showed that consumption of glutamine supported M2 activation in IL-4-treated murine macrophages by upregulating the activity of PDH. Mechanistically, glutamine did not affect the expression or alter the phosphorylation status of PDHA1 but instead downregulated the expression of SIRT5 and repressed SIRT5-dependent desuccinylation on PDHA1, which in turn recovered PDH activity and supported M2 polarization. This effect was implemented by its secondary metabolite α-ketoglutarate (αKG) rather than glutamine itself. Finally, we demonstrated that glutamine promoted macrophage M2 polarization in a murine burn sepsis model, thereby repressing excessive inflammation and alleviating organ injury in model mice. Conclusions: Glutamine mitigates murine burn sepsis by essentially supporting macrophage M2 polarization, with a mechanism involving the repression of the SIRT5-mediated desuccinylation of pyruvate dehydrogenase that replenishes OXPHOS and sustains M2 macrophages.

Traditional processing, uses, phytochemistry, pharmacology and toxicology of Aconitum sinomontanum Nakai: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: As a folk medicine, Aconitum sinomontanum Nakai (Ranunculaceae) a perennial herbaceous flowering plant, is a widely used traditional Chinese medicine. Its rhizomes and roots are known as 'Gaowutou' in China, and it has been traditionally used for the treatment of rheumatoid arthritis, painful swelling of joints, bruises and injuries and has been known to grow well in regions of high altitude such as Gansu, Tibet etc. THE AIM OF THE REVIEW: This systematic review the comprehensive knowledge of the A. sinomontanum, including its traditional processing and uses, chemical constituents, pharmacological activities, toxicity assessment, pharmacokinetics and metabolism, and its use in clinical settings to emphasize the benefits of this species. We also discuss expectations for prospective research and implementation of this herb. This work lays a solid foundation for further development of A. sinomontanum. MATERIALS AND METHOD: Information on the studies of A. sinomontanum was collected from scientific journals, books, and reports via library and electronic data search (PubMed, Elsevier, Scopus, Google Scholar, Springer, Science Direct, Wiley, ACS, EMBASE, Web of Science and CNKI). Meanwhile, it was also obtained from published works of material medica, folk records, ethnopharmacological literatures, Ph.D. and Masters dissertation. RESULTS: As a member of the Ranunculaceae family, A. sinomontanum possesses its up-and-coming biological characteristics. It is widely reported for treating rheumatoid arthritis, painful swelling of joints, bruises and injuries. Currently, over 71 phytochemical ingredients have been obtained and identified from different parts of A. sinomontanum. Among them, alkaloids, flavonoids, steroids, glycosides are the major bioactive constituents. Activities such as antinociceptive, anti-inflammatory, antitumor, antiarrhythmic, local anesthetic, antipyretic, antimicrobial, insecticidal and others have been corroborated in vivo and in vitro. These properties are attributed to different alkaloids. In addition, many of the active ingredients, such as lappaconitine, ranaconitine and total alkaloids have been used as quality markers. CONCLUSION: This work contributes to update the ethnopharmacological uses, chemical constituents, pharmacological activities, toxicity assessment, pharmacokinetics and metabolism, and clinical settings information for A. sinomontanum, which provide basic information to help better understand the pharmacological and toxicological activities of A. sinomontanum in human. However, further in-depth studies are needed to determine the medical uses of this herb and its chemical constituents, pharmacological activities, clinical applications and toxicology.

Association between patent foramen ovale and migraine without aura: a community-based cross-sectional study in China.

OBJECTIVES: To assess the influence of patent foramen ovale (PFO) on the prevalence of migraine without aura based on propensity score-matched samples in Southwest China. DESIGN: Propensity-matched cross-sectional study. PARTICIPANTS: Residents over 20 years of age were recruited from 15 communities of Western China from July 2020 to October 2020. A total of 3741 residents having accepted to undergo contrast-transthoracic echocardiography and a standard structured questionnaire was assessed for the relationship between PFO and migraine without aura. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were the prevalence of migraine without aura across different degrees of right-left shunts. RESULTS: A total of 3741 participants were included. Among them, 881 participants were diagnosed with PFO. The prevalence of migraine without aura in the PFO group was 12.83%, significantly higher than the other group (7.83%, p<0.0001). Analyses of the matched samples showed that the presence of a PFO increased the morbidity risk of migraine without aura (p < 0.001; OR=1.71, 95% CI 1.19 to 2.47). CONCLUSION: This community-based cross-sectional study pointed to a strong association between PFO and migraine without aura, especially when the shunt is large. TRIAL REGISTRATION NUMBER: ChiCTR1900024623.

Sorbent and solvent co-enhanced direct analysis in real time-mass spectrometry for high-throughput determination of trace pollutants in water.

A sorbent and solvent co-enhanced direct analysis in real-time mass spectrometry (SSE-DART-MS) method was developed for high-throughput determination of trace pollutants in water. The use of sorbent for preconcentration and solvents for assisting desorption and ionization synergistically enhanced the signals from the trace pollutants detected by DART-MS. Phthalic acid esters (PAEs) were used as model analytes to validate the SSE-DART-MS method. Graphitic carbon nitride (g-C3N4)-based materials with two morphologies and six organic solvents were used to systematically evaluate the enhancement effect by the sorbent and solvent. A better analytical performance was achieved with the two-dimensional (2D) g-C3N4, compared to three-dimensional (3D) g-C3N4/C, indicating that the morphologies of sorbents played a key role in SSE-DART-MS analysis. The MS signals of all the analytes were increased by 10-100 times for the two materials in the presence of the selected solvents. With the SSE-DART-MS method, concentration limits of detection for water samples in the range 0.07-0.94 ng L-1, and recovery in the range 82.8-119% using g-C3N4, were obtained for the PAEs. This work not only provides a reliable method for the coupling of solid phase extraction technique with DART-MS, but also presents valuable information for conducting other DART-MS analyses.