Gut microbiota-induced CXCL1 elevation triggers early neuroinflammation in the substantia nigra of Parkinsonian mice.

Gut microbiota disturbance and systemic inflammation have been implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD). How the alteration of gut microbiota results in neuropathological events in PD remains elusive. In this study, we explored whether and how environmental insults caused early neuropathological events in the substantia nigra (SN) of a PD mouse model. Aged (12-month-old) mice were orally administered rotenone (6.25 mg·kg-1·d-1) 5 days per week for 2 months. We demonstrated that oral administration of rotenone to ageing mice was sufficient to establish a PD mouse model and that microglial activation and iron deposition selectively appeared in the SN of the mice prior to loss of motor coordination and dopaminergic neurons, and these events could be fully blocked by microglial elimination with a PLX5622-formulated diet. 16 S rDNA sequencing analysis showed that the gut microbiota in rotenone-treated mice was altered, and mice receiving faecal microbial transplantation (FMT) from ageing mice treated with rotenone for 2 months exhibited the same pathology in the SN. We demonstrated that C-X-C motif chemokine ligand-1 (CXCL1) was an essential molecule, as intravenous injection of CXCL1 mimicked almost all the pathology in serum and SN induced by oral rotenone and FMT. Using metabolomics and transcriptomics analyses, we identified the PPAR pathway as a key pathway involved in rotenone-induced neuronal damage. Inhibition of the PPARγ pathway was consistent in the above models, whereas its activation by linoleic acid (60 mg·kg-1·d-1, i.g. for 1 week) could block these pathological events in mice intravenously injected with CXCL1. Altogether, these results reveal that the altered gut microbiota resulted in neuroinflammation and iron deposition occurring early in the SN of ageing mice with oral administration of rotenone, much earlier than motor symptoms and dopaminergic neuron loss. We found that CXCL1 plays a crucial role in this process, possibly via PPARγ signalling inhibition. This study may pave the way for understanding the "brain-gut-microbiota" molecular regulatory networks in PD pathogenesis. The aged C57BL/6 male mice with rotenone intragastric administration showed altered gut microbiota, which caused systemic inflammation, PPARγ signalling inhibition and neuroinflammation, brain iron deposition and ferroptosis, and eventually dopaminergic neurodegeneration in PD.

Cell senescence induced by toxic interaction between α-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson's disease.

Cell senescence has been implicated in the pathology of Parkinson's disease (PD). Both abnormal α-synuclein aggregation and iron deposition are suggested to be the triggers, facilitators, and aggravators during the development of PD. In this study, we investigated the involvement of α-synuclein and iron in the process of cell senescence in a mouse model of PD. In order to overexpress α-syn-A53T in the substantia nigra pars compacta (SNpc), human α-syn-A53T was microinjected into both sides of the SNpc in mice. We found that overexpression of α-syn-A53T for one week induced significant pro-inflammatory senescence-associated secretory phenotype (SASP), increased cell senescence-related proteins (ß-gal, p16, p21, H2A.X and γ-H2A.X), mitochondrial dysfunction accompanied by dysregulation of iron-related proteins (L-ferritin, H-ferritin, DMT1, IRP1 and IRP2) in the SNpc. In contrast, significant loss of nigral dopaminergic neurons and motor dysfunction were only observed after overexpression of α-syn-A53T for 4 weeks. In PC12 cells stably overexpressing α-syn-A53T, iron overload (ferric ammonium citrate, FAC, 100 µM) not only increased the level of reactive oxygen species (ROS), p16 and p21, but also exacerbated the processes of oxidative stress and cell senescence signalling induced by α-syn-A53T overexpression. Interestingly, reducing the iron level with deferoxamine (DFO) or knockdown of transferrin receptor 1 (TfR1) significantly improved both the phenotypes and dysregulated proteins of cell senescence induced by α-syn-A53T overexpression. All these evidence highlights the toxic interaction between iron and α-synuclein inducing cell senescence, which precedes nigral dopaminergic neuronal loss in PD. Further investigation on cell senescence may yield new therapeutic agents for the prevention or treatment of PD.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid ß-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.

Prognostic analysis of different morphology of the necrotic-viable interface in osteonecrosis of the femoral head.

PURPOSE: The purpose of this study was to investigate the collapse progression in different morphologies of the necrotic-viable interface in osteonecrosis of the femoral head (ONFH). METHODS: A total of 168 patients (202 hips) with Association Research Circulation Osseous (ARCO) stage II ONFH were included. Ending with the collapse of the femoral head, all patients received conservative treatment but without surgical intervention and were followed for three to 91 months. Bilateral hip-joint radiographs and magnetic resonance imaging (MRI) were examined, and the largest layer of necrosis within the coronal section of MRI images was selected together with its anteroposterior radiograph to observe the morphology of the necrotic-viable interface. The morphology was divided into four types: I, type transverse; II, type "V"; III, type zigzag; IV, type closed. The collapse rate and the time to collapse in different morphologies were assessed. RESULTS: A total of 120 hips collapsed in two years or less, 61 were type-I, 51 were type-II, and 8 were type-III. Non-collapse occurred in all 17 hips with type-IV ONFH during long-term follow-up. In 202 hips with ARCO stage-II ONFH, the collapse rate in type-I ONFH was significantly higher than that of type-II and type-III ONFH (P < 0.01 for both). The time to collapse was markedly shortened. CONCLUSIONS: The risk of ONFH-induced collapse is influenced by the morphology of the necrotic-viable interface. Effective mechanical support for preventing the collapse of the femoral head is necessary when the morphology of the necrotic-viable interface is type transverse.

LC-MS-based urinary metabolite signatures in idiopathic Parkinson's disease.

Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). These body fluids include urine; however, the relationship between, specifically, urinary metabolic phenotypes and PD is not fully understood. In this study, urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Our study revealed significant correlation between clinical phenotype and urinary metabolite profile. Metabolic profiles of idiopathic PD patients differed significantly and consistently from normal controls, with related metabolic pathway variations observed in steroidogenesis, fatty acid beta-oxidation, histidine metabolism, phenylalanine metabolism, tryptophan metabolism, nucleotide metabolism, and tyrosine metabolism. In the fruit fly Drosophila melanogaster, the alteration of the kynurenine pathway in tryptophan metabolism corresponded with pathogenic changes in the alpha-synuclein overexpressed Drosophila model of PD. The results suggest that LC-MS-based urinary metabolomic profiling can reveal the metabolite signatures and related variations in metabolic pathways that characterize PD. Consistent PD-related changes across species may provide the basis for understanding metabolic regulation of PD at the molecular level.

Metabolite regulation of epigenetics in cancer.

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy.

Itaconate in host inflammation and defense.

Immune cells undergo rapid and extensive metabolic changes during inflammation. In addition to contributing to energetic and biosynthetic demands, metabolites can also function as signaling molecules. Itaconate (ITA) rapidly accumulates to high levels in myeloid cells under infectious and sterile inflammatory conditions. This metabolite binds to and regulates the function of diverse proteins intracellularly to influence metabolism, oxidative response, epigenetic modification, and gene expression and to signal extracellularly through binding the G protein-coupled receptor (GPCR). Administration of ITA protects against inflammatory diseases and blockade of ITA production enhances antitumor immunity in preclinical models. In this article, we review ITA metabolism and its regulation, discuss its target proteins and mechanisms, and conjecture a rationale for developing ITA-based therapeutics to treat inflammatory diseases and cancer.

[Retracted] Association between vascular endothelial growth factor gene polymorphisms and the risk of osteonecrosis of the femoral head: Systematic review.

[This retracts the article DOI: 10.3892/br.2015.527.].

Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking.

BACKGROUND: Hypertrophic scar (HTS) is dermal fibroproliferative disorder, which may cause physiological and psychological problems. Currently, the potential mechanism of WuFuYin (WFY) in the treatment of HTS remained to be elucidated. AIM: To explore the potential mechanism of WFY in treating HTS. METHODS: Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. HTS-related genes were obtained from the GeneCards, DisGeNET, and National Center for Biotechnology Information. The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome (KEGG) enrichment analysis. A protein + IBM-protein interaction (PPI) network was developed using STRING database and Cytoscape. To confirm the high affinity between compounds and targets, molecular docking was performed. RESULTS: A total of 65 core genes, which were both related to compounds and HTS, were selected from multiple databases. PPI analysis showed that CKD2, ABCC1, MMP2, MMP9, glycogen synthase kinase 3 beta (GSK3B), PRARG, MMP3, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the hub targets and MOL004941, MOL004935, MOL004866, MOL004993, and MOL004989 were the key compounds of WFY against HTS. The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway. Moreover, by performing molecular docking, we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity. CONCLUSION: The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941, MOL004989, and MOL004993 were the main compounds of WFY in HTS treatment.

[The impact of dietary methionine-restriction on tight junction expression and function in a rat colonitis model].

OBJECTIVE: To study the impact of methionine restriction (MetR) on mucosal histopathology, permeability and tight junction composition in a dextran sulfate sodium (DSS)-induced colitis model, and to explore its underlying mechanism. METHODS: SD rats were randomly divided into 4 groups: normal rats fed by a complete amino acid (AA group) diet, normal rats fed by MetR diet (MetR group), DSS treated rats fed by a complete amino acid (DSS+AA group) and DSS treated rats fed by MetR diet (DSS+MetR group), each group had 15 rats.Abdominal aorta blood sampling was taken at day 21 after DSS model been established to analyze blood routine examination, liver and kidney function and level of electrolyte. Morphological changes in colonic mucosa were evaluated and scored by light microscopy. Myeloperoxidase (MPO) activity was measured. The effect of MetR on mucosal permeability of colon strips was detected by Ussing chamber. Claudin2, occludin, claudin3, ZO-1 expression were quantified by Western blot. RESULTS: The early clinical manifestation in the DSS treated rats were loose stool or diarrhea, hematochezia positive and bleeding, and weight losing. HE observation showed prominent colitis in distal colon with manifestations of crypt abscess and infiltration of inflammatory cells. Although MPO activity and WBC account between the DSS+MetR and DSS+AA group did not significantly changed, treatment with MetR diet significantly decreased the extent and severity of epithelial injury of DSS+MetR group (10.55 ± 3.62 vs 15.00 ± 4.89, P = 0.003). There were no significant difference in PCNA immunohistochemical result between the DSS+MetR group and DSS+AA group. Compared to the rats on AA diet, transepithelial electrical resistance (TEER) in DSS+AA group was obvious lower [(28.40 ± 6.78) Ω·cm² vs (46.53 ± 4.03) Ω·cm², P < 0.05], and TEER in MetR group were obviously higher [(60.64 ± 8.40) Ω·cm² vs (46.53 ± 4.03) Ω·cm², P < 0.05]. However, short-circuit current (Isc) in DSS+MetR group was obviously higher that of DSS+AA group [(35.01 ± 2.19) µA/cm² vs (29.61 ± 1.19) µA/cm², P < 0.05]. Western blot suggested that colon claudin2 expression was not found in colon epithelium of normal rats, and an obviously increase expression of claudin3 protein was found in the MetR group, compared to AA group; and an significantly increase in the abundance of claudin3 was found in the DSS+MetR group, but amount of claudin2 was decreased, compared with the DSS+MetR group. CONCLUSION: The MetR diet has obvious therapeutic effect on ulcerative colitis model rats induced by DSS, and its mechanism may not by regulating inflammatory cell infiltration and the way of promoting intestinal cell growth to alleviate inflammatory injury, but probably by changing the structure and function of tight junction protein and improve the intestinal mucosal barrier function, and promote the repair of damaged intestinal mucosa.

[Initial experience of percutaneous coronary intervention guided by computed tomography coronary angiography derived roadmap and magnetic navigation system].

OBJECTIVE: To evaluate the feasibility, efficacy and safety of the percutaneous coronary intervention (PCI)guided by computed tomography (CT) coronary angiography derived roadmap and magnetic navigation system (MNS). METHODS: During June 2011 and May 2012, thirty consecutive patients receiving elective PCI were enrolled, coronary artery disease was primarily diagnosed by dual-source CT coronary angiography (DSCT-CA) at outpatient clinic and successively proved by coronary artery angiography in the hospital. Target vessels from pre-procedure DSCT-CA were transferred to the magnetic navigation system, and consequently edited, reconstructed, and projected onto the live fluoroscopic screen as roadmap. Parameters including characters of the target lesions, time, contrast volume, radiation dosage for guidewire crossing, and complications of the procedure were recorded. RESULTS: Thirty patients with 36 lesions were recruited and intervened by PCI. Among the target lesions, sixteen were classified as type A, 11 as type B1, 8 as type B2, 1 as type C. The average length of the target lesions was (22.0 ± 9.8) mm, and the average stenosis of the target lesions was (81.3 ± 10.3)%. Under the guidance of CT roadmap and MNS, 36 target lesions were crossed by the magnetic guidewires, with a lesion crossing ratio of 100%. The time of placement of the magnetic guidewires was 92.5 (56.6 - 131.3) seconds. The contrast volume and the radiation dosage for guidewire placement were 0.0 (0.0 - 3.0) ml and 235.0 (123.5 - 395.1) µGym(2)/36.5 (21.3 - 67.8) mGy, respectively. Guidewires were successfully placed in 21 (58.3%) lesions without contrast agent. All enrolled vessels were successfully treated, and there were no MNS associated complications. CONCLUSIONS: It is feasible, effective and safe to initiate PCI under the guidance of CT derived roadmap and MNS. This method might be helpful for the guidewire placement in the treatment of total occlusions.

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes.

AIM: To investigate the effects of rapamycin on glutamate uptake in cultured rat astrocytes expressing N-terminal 552 residues of mutant huntingtin (Htt-552). METHODS: Primary astrocyte cultures were prepared from the cortex of postnatal rat pups. An astrocytes model of Huntington's disease was established using the astrocytes infected with adenovirus carrying coden gene of N-terminal 552 residues of Huntingtin. The protein levels of glutamate transporters GLT-1 and GLAST, the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the autophagy substrate p62 in the astrocytes were examined using Western blotting. The mRNA expression levels of GLT-1 and GLAST in the astrocytes were determined using Real-time PCR. [(3)H]glutamate uptake by the astrocytes was measured with liquid scintillation counting. RESULTS: The expression of mutant Htt-552 in the astrocytes significantly decreased both the mRNA and protein levels of GLT-1 but not those of GLAST. Furthermore, Htt-552 significantly reduced [(3)H]glutamate uptake by the astrocytes. Treatment with the autophagy inhibitor 3-MA (10 mmol/L) significantly increased the accumulation of mutant Htt-552, and reduced the expression of GLT-1 and [(3)H]glutamate uptake in the astrocytes. Treatment with the autophagy stimulator rapamycin (0.2 mg/mL) significantly reduced the accumulation of mutant Htt-552, and reversed the changes in GLT-1 expression and [(3)H]glutamate uptake in the astrocytes. CONCLUSION: Rapamcin, an autophagy stimulator, can prevent the suppression of GLT-1 expression and glutamate uptake by mutant Htt-552 in cultured astrocytes.

[Changes in tight junction protein expression and permeability of colon mucosa in rats with dextran sulfate sodium-induced inflammatory bowel disease].

OBJECTIVE: To develop an experimental rat model of inflammatory bowel disease (IBD) by administration of dextran sulfate sodium (DSS), and to observe changes in the tight junction protein expression and permeability of colon mucosa. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into control (n=27) and IBD model groups (n=27). In the IBD model group, IBD was induced by 6-day administration of 3% DSS in water followed by 14-day administration of water only. The control group was fed with water only. Pathological changes in colon mucosae were observed on days 7, 14 and 21 after DSS administration. Colon tissue specimens were collected on day 21 for measuring myeloperoxidase (MPO) activity. The transepithelial electric resistance (TEER), transepithelial potential difference (TEPD) and short circuit current (Isc) of the specimens were measured by Ussing chamber. Real-time PCR and Western blot were used to measure the mRNA and protein expression of tight junction proteins in colon epithelia. RESULTS: In the IBD model group, diarrhea, hemafecia and weight loss were seen. Inflammation occurred mainly in the distal colon and was characterized by crypt abscess and inflammatory cell infiltration. The IBD model group showed significantly increased MPO activity (P<0.01), significantly decreased TEER (P<0.01) and TEPD (P<0.01), and significantly increased Isc (P<0.01) compared with the control group. No claudin 2 expression of mRNA and protein was detected in the control group, and they were expressed in the IBD model group. The expression levels of claudin 3, occludin and ZO-1 in the IBD model group were significantly decreased compared with in the control group (P<0.01). CONCLUSIONS: IBD rats show colonic barrier dysfunction and changes in the expression of tight junction proteins. The changes in the expression of tight junction proteins may contribute to colonic barrier dysfunction in cases of IBD in the chronic recovery stage.

Ursodeoxycholic acid prevention on cholestasis associated with total parenteral nutrition in preterm infants: a randomized trial.

BACKGROUND: Preterm infants with long-term parenteral nutrition (PN) therapy are at risk for cholestasis associated with total parenteral nutrition (PNAC). This study examined the safety and efficacy of ursodeoxycholic acid (UDCA) in preventing PNAC in preterm infants. Our research aimed to investigate the prophylactic effect of preventive oral UDCA on PNAC in preterm infants. METHODS: We compared oral administration of UDCA prophylaxis with no prophylaxis in a randomized, open-label, proof-of-concept trial in preterm neonates with PN therapy. The low-birth-weight preterm infants (< 1800 g) who were registered to the neonatal intensive care unit (NICU) within 24 hours after birth were randomized. The main endpoint was the weekly values of direct bilirubin (DB) of neonates during the NICU stay. RESULTS: Eventually, a total of 102 preterm neonates from January 2021 to July 2021 were enrolled in this prospective study (42 in the UDCA group and 60 in the control group). Notably, the peak serum level of DB [13.0 (12-16) vs. 15.2 (12.5-19.6) µmol/L, P < 0.05)] was significantly lower in the UDCA group than that in the control group without prevention. The peak serum level of total bilirubin (101.1 ± 34 vs. 116.5 ± 28.7 µmol/L, P < 0.05) was also significantly lower in the UDCA group than in the control group. Furthermore, the proportion of patients who suffered from neonatal cholestasis (0.0% vs. 11.7%, P < 0.05) in the UDCA group was significantly lower. CONCLUSION: UDCA prophylaxis is beneficial in preventing PNAC in NICU infants receiving prolonged PN.

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Chronic active Epstein-Barr virus infection treated with PEG-aspargase: A case report.

BACKGROUND: Chronic active Epstein-Barr virus infection (EBV) is a systemic EBV-positive lymphoproliferative disease, which may lead to fatal illness. There is currently no standard treatment regimen for chronic active EBV (CAEBV), and hematopoietic stem cell transplantation is the only effective treatment. We here report a CAEBV patient treated with PEG-aspargase, who achieved negative EBV-DNA. CASE SUMMARY: A 33-year-old female Chinese patient who had fever for approximately 3 mo was admitted to our hospital in December 2017. EBV-DNA was positive with a high copy number. She was diagnosed with chronic active EB virus infection. PEG-aspargase was administered at a dose of 1500 U/m2 at a 14-d interval, resulting in eradication of EBV for more than 6 mo. The effect of PEG-aspargase in this patient was excellent. CONCLUSION: A chemotherapy regimen containing PEG-aspargase for CAEBV may be further considered.

Brown Adipose Tissue Activation Is Involved in Atherosclerosis of ApoE-/- Mice Induced by Chronic Intermittent Hypoxia.

Background: Obstructive sleep apnea is an atherogenesis factor of which chronic intermittent hypoxia is a prominent feature. Chronic intermittent hypoxia (CIH) exposure can sufficiently activate the sympathetic system, which acts on the ß3 adrenergic receptors of brown adipose tissue (BAT). However, the activity of BAT and its function in CIH-induced atherosclerosis have not been fully elucidated. Methods: This study involved ApoE-/- mice which were fed with a high-fat diet for 12 weeks and grouped into control and CIH group. During the last 8 weeks, mice in the CIH group were housed in cages to deliver CIH (12 h per day, cyclic inspiratory oxygen fraction 5-20.9%, 180 s cycle). Atherosclerotic plaques were evaluated by Oil Red O, hematoxylin and eosin, Masson staining, and immunohistochemistry. Afterward, we conducted immunohistochemistry, western blotting, and qRT-PCR of uncoupling protein 1 (UCP1) to investigate the activation of BAT. The level of serum total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and free fatty acid (FFA) were measured. Finally, RNA-Sequencing was deployed to explore the differentially expressed genes (DEGs) and their enriched pathways between control and CIH groups. Results: Chronic intermittent hypoxia exposure promoted atherosclerotic plaque area with increasing CD68, α-SMA, and collagen in plaques. BAT activation was presented during CIH exposure with UCP1 up-regulated. Serum TC, triglyceride, LDL-c, and FFA were increased accompanied by BAT activation. HDL-c was decreased. Mechanistically, 43 lipolysis and lipid metabolism-associated mRNA showed different expression profiling between the groups. Calcium, MAPK, and adrenergic signaling pathway included the most gene number among the significantly enriched pathways. Conclusion: This study first demonstrated that BAT activation is involved in the progression of CIH-induced atherosclerosis, possibly by stimulating lipolysis.