The stimulator of interferon genes (STING) in macrophages plays a crucial role in nonalcoholic fatty liver disease (NAFLD) progression. However, there is a lack of evidence from large samples of ...patients to validate a deleterious role for STING in NAFLD. Moreover, sources of STING-expressing cells that are related to NAFLD remain to be definitively characterized. To investigate STING expression and explore its correlation with NAFLD progression in human subjects, our study involved liver samples from 98 NAFLD subjects and 8 controls. STING and p-TBK1 expression in nonparenchymal liver cells was analyzed and correlated with NAFLD pathological features. Numbers of STING+ cells were increased in livers from nonalcoholic steatohepatitis (NASH) patients compared with controls, especially in the liver portal tract of NASH patients with fibrosis (p < 0.05). Moreover, numbers of STING+ cells in livers of NASH patients were increased with aggravation of inflammation grade and fibrosis stage (p < 0.05). STING was mainly expressed in macrophages, including monocyte-derived macrophages (CCR2+, S100A9+), Kupffer cells (CD68+) and CD163+ macrophages. Compared with controls, numbers of STING+/CCR2+ and STING+/S100A9+ cells were significantly increased in livers from NASH patients with fibrosis and positively correlated with liver inflammation grade and fibrosis stage (p < 0.05). However, numbers of STING+/CD68+ and STING+/CD163+ cells were significantly increased in livers from NASH patients with advanced fibrosis and correlated only with aggravation of fibrosis stage (p < 0.05). Furthermore, compared with controls, NASH patients exhibited significantly increased STING+/p-TBK1+ cell numbers. In a coculture system, the amount of p-TBK1 and the mRNAs of IL1β and IL6 in THP1 macrophages, as well as the amount of α-SMA and the mRNAs of Col1a1, Fn and TGFβ1 in LX2 cells were significantly increased upon STING activation in macrophages (p < 0.05). Therefore, increased STING expression in MoMFs appears to be indicative of NAFLD progression, and STING could be a new target for NAFLD therapy.
Due to the unknown Triassic volcanism in the Junggar Basin, the Middle-Late Triassic sedimentary provenance in the southern Junggar Basin (SJB) has long been controversial. Detrital zircon grains ...from 13 samples of the Middle-Upper Triassic Xiaoquangou Group in the SJB were analyzed using zircon U-Pb geochronology to constrain the provenance of Triassic sedimentary rocks and to further understand their source-to-sink system. Comparison of detrital zircon U-Pb age distributions for 13 samples reveals that the Triassic age populations predominate in sediments of the northern Bogda Mountains, with subordinate in the southern Bogda Mountains, and no or minimal in the North Tianshan (NTS). Coupled with sandstone petrological, sedimentary geochemical and paleocurrent data, the Triassic detrital zircon grains of the Xiaoquangou Group in the SJB were probably input from the Bogda Mountains. As Pennsylvanian and Mississippian zircon grains are mainly derived from the NTS and Central Tianshan (CTS), the provenance of the Xiaoquangou Group includes the NTS, CTS and Bogda Mountains. But the different samples in different sink areas have different provenances, originating from at least four source-to-sink systems. The supply of sediments from the Bogda Mountains started in the Late Triassic, suggesting initial uplift of the Bogda Mountains.
Field-based mapping, sandstone petrology, palaeocurrent measurements and zircon cathodoluminescence images, as well as detrital zircon U–Pb geochronology were integrated to investigate the provenance ...of the Upper Carboniferous – Upper Triassic sedimentary rocks from the northern Bogda Mountains, and further to constrain their tectonic evolution. Variations in sandstone composition suggest that the Upper Carboniferous – Lower Triassic sediments displayed less sedimentary recycling than the Middle–Upper Triassic sediments. U–Pb isotopic dating using the LA-ICP-MS method on zircons from 12 sandstones exhibited similar zircon U–Pb age distribution patterns with major age groups at 360–320 Ma and 320–300 Ma, and with some grains giving ages of > 541 Ma, 541–360 Ma, 300–250 Ma and 250–200 Ma. Coupled with the compiled palaeocurrent data, the predominant sources were the Late Carboniferous volcanic rocks of the North Tianshan and Palaeozoic magmatic rocks of the Yili–Central Tianshan. There was also input from the Bogda Mountains in Middle–Late Triassic time. The comprehensive geological evidence indicates that the Upper Carboniferous – Lower Permian strata were probably deposited in an extensional context which was related to a rift or post-collision rather than arc-related setting. Conspicuously, the large range of U–Pb ages of the detrital zircons, increased sedimentary lithic fragments, fluvial deposits and contemporaneous Triassic zircon ages argue for a Middle–Late Triassic orogenic movement, which was considered to be the initial uplift of the Bogda Mountains.
In a complex, diverse intestinal environment, commensal microbiota metabolizes excessive dietary tryptophan to produce more bioactive metabolites connecting with kinds of diverse process, such as ...host physiological defense, homeostasis, excessive immune activation and the progression and outcome of different diseases, such as inflammatory bowel disease, irritable bowel syndrome and others. Although commensal microbiota includes bacteria, fungi, and protozoa and all that, they often have the similar metabolites in tryptophan metabolism process via same or different pathways. These metabolites can work as signal to activate the innate immunity of intestinal mucosa and induce the rapid inflammation response. They are critical in reconstruction of lumen homeostasis as well. This review aims to seek the potential function and mechanism of microbiota‐derived tryptophan metabolites as targets to regulate and shape intestinal immune function, which mainly focused on two aspects. First, analyze the character of tryptophan metabolism in bacteria, fungi, and protozoa, and assess the functions of their metabolites (including indole and eight other derivatives, serotonin (5‐HT) and d‐tryptophan) on regulating the integrity of intestinal epithelium and the immunity of the intestinal mucosa. Second, focus on the mediator and pathway for their recognition, transfer and crosstalk between microbiota‐derived tryptophan metabolites and intestinal mucosal immunity. Disruption of intestinal homeostasis has been described in different intestinal inflammatory diseases, available data suggest the remarkable potential of tryptophan‐derived aryl hydrocarbon receptor agonists, indole derivatives on lumen equilibrium. These metabolites as preventive and therapeutic interventions have potential to promote proinflammatory or anti‐inflammatory responses of the gut.
The Ediacaran–Cambrian transition was characterized by profound climatic, tectonic, and oceanographic fluctuations, followed by the remarkable radiation of metazoans. To further understand the ...paleoclimatic and paleoenvironmental conditions during this interval, comprehensive mineralogical and geochemical analyses were performed on Ediacaran–Cambrian shales (in the Doushantuo through Jiumenchong to Bianmachong formations) at Daotuo, South China. Their major and trace element compositions and ratios indicate that all of the studied shales were derived from basically uniform source rocks that were similar to granodiorite. The chemical index of alteration (CIA) values in the Doushantuo and Bianmachong formations mostly range from 65 to 80, indicating that they experienced a moderate degree of chemical weathering and were thus deposited in a warm and humid climate. In contrast, a sharp drop in CIA values (~60–70) in the lower Jiumenchong Formation, together with decreased Al/Ti ratios that are indicative of increased eolian inputs, are suggestive of a relatively cold and arid climate for the Early Cambrian Yangtze Block. In this scenario, eolian fluxes could have supplied nutrients to the marine environment; increased upwelling, along with a rising thermocline and nutricline during the extensive marine transgression, could have returned abundant nutrients to the surface seawater, thus greatly stimulating primary productivity and intensifying anoxic conditions, which would ultimately have resulted in a high degree of organic burial in the sediments. Therefore, the negative correlation between the corrected CIA values and the total organic carbon (TOC) content may imply that climate-related changes played a role in the enrichment of organic matter during the Early Cambrian.
•Provenances of the Ediacaran-Cambrian shales on the Yangtze Platform are uniformly close to granodiorite.•CIA values in the lower Cambrian shales indicate weak chemical weathering and arid climatic conditions.•Increased eolian fluxes and enhanced upwelling greatly stimulated primary productivity in the early Cambrian.
The late Ediacaran to early Cambrian transition was a critical interval in Earth history, during which both the environment and life experienced dramatic change. Relationships between these events, ...however, are widely debated. This time interval also witnessed the occurrence of massive phosphate deposits. Studies on the characteristics, origins, and depositional context of this geochemical archive may provide important insights into not only the ore-forming process but also the coevolution of the Earth surface system. Here, phosphate nodules from two sections (Jinsha and Songtao) are investigated using in-situ LA-ICP-MS mapping and solution ICP-MS methods. Elemental images and factor analyses of the LA-ICP-MS dataset show that Ca, P, and Sr are evenly distributed and co-enriched within the nodule, whereas iron-related elements (Fe, As, and Mo) are roughly present as concentric layers. The PAAS-normalized REE patterns of the Jinsha samples exhibit moderately negative Ce anomalies and pronounced MREE enrichments, possibly related to uptake of REE released by iron oxyhydroxides during early diagenesis. In contrast, the Songtao samples are characterized by more seawater-like signals with significantly lower Ce/Ce* and higher Eu/Eu* values. These positive Eu anomalies are ascribed to active submarine hydrothermal vents along the Yangtze Platform margin. Based on a compilation of published Ce/Ce* data, we suggest that the prominent negative Ce anomalies during the Ediacaran–Cambrian phosphogenesis give evidence of possible link between P dynamics and ocean oxygenation.
•A combination of LA- and solution ICP-MS was used to study phosphate geochemistry.•Different rare earth element patterns point to different sources.•Marked Ce anomalies in the lower Cambrian indicate significant environmental change.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, ...fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression.
Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of ...stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function.
We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223(-/-) mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic proinflammatory pathways and enhances the alternative antiinflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization.
For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing proinflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.
•Decoupled Mo–U pattern points to expanded marine anoxia during the Cryogenian interglaciation.•The post-Sturtian period was not characterized by a significant rise in oxygen levels.•Oxygen demands ...for early animals may have been met well before animals evolved.
Paleoredox reconstructions of Neoproterozoic successions have been the subject of long-standing debates, especially concerning the precise timing of ocean ventilation and its causal relationship, if any, with the evolution of early animal life. Sponge biomarkers and putative sponge-like body fossils have been found from rocks in the Cryogenian Period, yet the contemporaneous deep-water conditions remain poorly understood. To fill this gap, we report pyrite morphology, trace metal enrichments, and total organic carbon data from interglacial black shales of the lower Datangpo Formation at Daotuo area, northeast Guizhou Province, South China. A contrasting Mo–U enrichments pattern emerges from the basal Datangpo black shales, despite the persistently euxinic local environment as testified by the presence of abundant tiny pyrite framboids. Molybdenum is markedly enriched in the basal interval and its concentration decreases sharply up section, while uranium stays relatively constant at crustal concentrations throughout the entire profile. This decoupled Mo–U signature, integrated with a simple mass balance model, suggests that euxinia only covered a small proportion of the dominantly ferruginous global seafloor, thus allowing dissolved Mo to accumulate to significant level in seawater. The enrichment degrees of Mo, although nontrivial, are still much lower than those from Phanerozoic equivalents. Contrarily, they are quite close to the total mean abundance for Mesoproterozoic euxinic shales. Such a mild increase of marine Mo–U inventory is therefore inferred as recording no dramatic rise in oxygen levels following the Sturtian glaciation. A drop of Mo contents after the basal interval could represent either limited Mo availability or inadequate hydrogen sulfide supply.
Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator ...6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.
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