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Abstract Background The aim of this study was to explore the mechanism whereby LACC1 regulates the intestinal flora in a mouse model of inflammatory bowel disease (IBD). Methods C57BL/6 and Lacc1 −/− mice were used to establish a mouse model of IBD induced by dextran sodium sulfate (DSS). The effects of Lacc1 deletion in mice were evaluated. Changes in the body weight and stool blood were recorded daily. After 7 days of successful modeling, the mice were sacrificed, blood was collected from the eyeballs, the entire colon was dissected and separated, and the length of the colon was measured. Results Compared with the wild-type (WT) DSS model group, the Lacc1 −/− DSS model group showed a significantly higher disease activity index score (P 3 or

目的 探讨漆酶基因LACC1对脑梗死后缺血再灌注损伤的影响及其机制。 方法 ①采购C57BL/6J LACC1基因敲除（LACC1-/-）小鼠20只，野生型小鼠20只，建立大脑中动脉闭塞/再灌注（middle cerebral artery occlusion/reperfusion，MCAO/R）模型各15只，比较两组小鼠的脑梗死体积。采用蛋白质免疫印迹实验检测脑组织中磷酸化腺苷酸活化蛋白激酶（phosphorylate AMP-activated protein kinase，p-AMPK）及NOD样受体热蛋白结构域相关蛋白3（nucleotide-binding oligomerization domain-like receptor protein 3，NLRP3）水平，采用微阵列分析外周血中长链非编码RNA（long noncoding RNA，lncRNA）表达谱及探讨可能涉及的信号转导通路。②制备小鼠小胶质细胞氧糖剥夺/再灌注（oxygen glucose deprivation/reoxygenation，OGD/R）模型，并通过小干扰RNA（siRNA）转染技术上调及抑制LACC1的表达，明确LACC1对脑梗死体外模型炎症和氧化应激的调节作用。采用蛋白质免疫印迹实验检测p-AMPK、NLRP3水平，采用酶联免疫吸附测定法检测血清过氧化氢酶（catalase，CAT）、超氧化物歧化酶（superoxide dismutase，SOD）、丙二醛（malondialdehyde，MDA）、活性氧（reactive oxygen species，ROS）、IL-1β、IL-6、干扰素-γ（interferon-γ，IFN-γ）、TNF-α水平。 结果 MCAO/R模型野生型小鼠组脑梗死体积比例为（21.38%±4.06%），LACC1-/-小鼠组脑梗死体积比例为（19.07%±2.86%），差异有统计学意义（P=0.041），同时LACC1-/-小鼠脑组织中p-AMPK的蛋白表达水平增加，NLRP3蛋白表达水平受到抑制。OGD/R细胞模型中，LACC1的下调抑制了NLRP3蛋白的表达、增加了p-AMPK蛋白的表达。OGD/R细胞模型中，LACC1的过度表达增加了IL-1β、IL-6、INF-γ、TNF-α、MDA和ROS生成，降低了CAT和SOD的水平（P＜0.05）。 结论 LACC1可能通过AMPK/NLRP3途径加重小鼠缺血再灌注后的炎症反应，这可能为脑梗死或其他神经系统疾病及其相关并发症提供一种新的治疗方案。 Abstract: Objective To investigate the effect and mechanism of laccase gene LACC1 on ischemic reperfusion after cerebral infarction. Methods ①Purchase 20 C57BL/6J LACC1 knockout (LACC1-/-) mice and 20 wild-type (WT) mice, and establish middle cerebral artery occlusion/reperfusion (MCAO/R) model with 15 mice each, the volume of cerebral infarction was compared between the two groups, and western blot was performed to detect phosphorylate AMP-activated protein kinase (p-AMPK) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in brain tissue. Microarray analysis of long noncoding RNA (lncRNA) expression profiles in peripheral blood and exploration of possible signal transduction pathways involved. ②Preparation of a mouse microglia oxygen glucose deprivation/reperfusion (OGD/R) model and upregulation and inhibition of LACC1 expression by siRNA transfection technique to clarify the regulatory effects of LACC1 on inflammation and oxidative stress in an in vitro model of cerebral infarction, western blot detection levels of p-AMPK and NLRP3. Serum catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS), IL-1β, IL-6, interferon-γ (INF-γ), TNF-α levels were measured by enzyme linked immunosorbent assay (ELISA). Results The proportion of cerebral infarction volume in WT mouse group of MCAO/R model was (21.38%±4.06%) and that in LACC1-/- mouse group was (19.07%±2.86%), the difference was statistically significant (P=0.041). Meanwhile, the expression level of p-AMPK protein in brain tissue of LACC1-/- mice was increased. NLRP3 protein expression was inhibited. Down-regulation of LACC1 inhibited the expression of NLRP3 protein and increased the expression of p-AMPK protein in OGD/R cell models. In OGD/R cell model, over expression of LACC1 increased the production of IL-1β, IL-6, INF-γ, TNF-α, MDA and ROS, and decreased the levels of CAT and SOD (P

Background: The aim of this study was to explore the mechanism whereby LACC1 regulates the intestinal flora in a mouse model of inflammatory bowel disease (IBD). Methods: C57BL/6 and Lacc1−/− mice were used to establish a mouse model of IBD induced by dextran sodium sulfate (DSS). The effects of Lacc1 deletion in mice were evaluated. Changes in the body weight and stool blood were recorded daily. After 7 days of successful modeling, the mice were sacrificed, blood was collected from the eyeballs, the entire colon was dissected and separated, and the length of the colon was measured. Results: Compared with the wild-type (WT) DSS model group, the Lacc1−/− DSS model group showed a significantly higher disease activity index score (P < 0.05), significantly faster weight loss (P < 0.05), and a significantly shorter colon (P < 0.05), indicating that the colonic mucosal tissue was seriously damaged in the Lacc1−/− DSS model group (P < 0.05). Serum IL-1β, IL-6, TNF-α, and IFN-γ levels were significantly higher in the Lacc1−/− DSS model group than the WT DSS model group. Principal coordinate analysis showed that there were significant microbiome differences between the WT, Lacc1−/−, WT DSS model, and Lacc1−/− DSS model groups (P < 0.05). Linear discriminant analysis effect size analysis showed that under natural conditions, Lacc1−/− mice had significant changes in their intestinal flora compared with control mice (LDA value > 3 or < 3, P < 0.05). Conclusions: Lacc1 deletion aggravates DSS-induced IBD in mice. [ABSTRACT FROM AUTHOR]

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Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Transcription (STAT) pathways, which could then prevent the activity of several proinflammatory cytokines. They may provide a useful alternative in these cases of JIA or in patients actually affected by Mendelian disorders mimicking JIA, such as type I interferonopathies with joint involvement, and might be the bridge for haematopoietic stem cell transplantation in these disabling conditions. As these treatments may have side effects that should not be ignored, ongoing and further controlled studies are still needed to provide data underlying long-term safety considerations in children and delineate subsets of JIA patients that will benefit from these promising treatments. [ABSTRACT FROM AUTHOR]

Background: Some juvenile idiopathic arthritis (JIA) patients have a familial aggregation of the disease, and a few have been found to have a juvenile arthritis (JA) phenotype caused by a genetic mutation. JA due to LACC1 defects is a rare condition and it was never reported in China. Methods: The clinical and molecular characteristics of a child with LACC1 gene mutation‐related juvenile arthritis, diagnosed by high‐throughput sequencing in Wuhan children's Hospital in 2021 were analyzed retrospectively; The literature and database were reviewed to summarize the clinical data and genotype characteristics of patients with JA caused by LACC1 gene mutation. Results: Here, we report a 19‐month‐old Chinese male patient who presented with bilateral limb edema without a history of fever. Laboratory tests showed had moderate anemia and signs of inflammation: hemoglobin of 76 g/L, white blood cell count of 20.53 × 109, and platelet count of 1194 × 109; MRI showed the patient had synovitis and tenosynovitis in bilateral hands and wrists. Whole‐exome sequencing (WES) detected compound heterozygous variants, novel c.446_449dupTAAA and c.889T>C, in the LACC1 gene. Of the 52 patients reported in the literature (including this case), 38.9% had clinical symptoms of systemic juvenile idiopathic arthritis (sJIA), which tended to be caused by loss‐of‐function (LOF) mutation. Findings in this study expanded the spectrum of pathogenic variants and reveal the phenotypic heterogeneity of LACC1‐JA. Conclusions: Our study reported a rare case of juvenile arthritis, which is due to the compound heterozygous mutation of LACC1, including a new novel frameshift mutation c.446_449dupTAAA, and LACC1 C297R variant causes disease by potentially modifying the local conformation of proteins. The clinical and genetic findings in our study show that LACC1‐JA is highly heterogeneous, and gene testing is required for juvenile arthritis patients with a high inflammatory response at a young onset age. [ABSTRACT FROM AUTHOR]

Laccase domain‐containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages, and studies have shown that it has a key role in diseases such as inflammatory bowel disease, arthritis, and microbial infections. Therefore, in this review, we focus on LACC1‐mediated catalysis. In detail, LACC1 converts l‐CITrulline (l‐CIT) to l‐ORNithine (l‐ORN) and isocyanic acid in mice and humans and acts as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism, thus exerting anti‐inflammatory and antibacterial effects. Considering the actions of LACC1, targeting LACC1 may be a potent therapeutic avenue for inflammation‐related diseases and microbial infection diseases. [ABSTRACT FROM AUTHOR]

Fungal laccases play important roles in the degradation of lignocellulose. In this study, the laccase producing cotton straw medium for Pleurotus ostreatus was optimized by single-factor and orthogonal experiments, and to investigate the role of Lacc1 gene, one of the laccase-encoding genes, in the degradation of cotton straw lignin, an overexpression strain of Lacc1 gene was constructed, which was analyzed for the characteristics of lignin degradation. The results demonstrated that the culture conditions with the highest lignin degradation efficiency of the P. ostreatus were the cotton straw particle size of 0.75 mm, a solid–liquid ratio of 1:3 and containing 0.25 g/L of Tween in the medium, as well as an incubation temperature of 26 °C. Two overexpression strains (OE L1-1 and OE L1-4) of Lacc1 gene were obtained, and the gene expression increased 12.08- and 33.04-fold, respectively. The results of 1H-NMR and FTIR analyses of significant changes in lignin structure revealed that Lacc1 gene accelerated the degradation of lignin G-units and involved in the cleavage of β-O-4 linkages and the demethylation of lignin units. These findings will help to improve the efficiency of biodelignification and expand our understanding of its mechanism. [ABSTRACT FROM AUTHOR]

Objective To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1. Methods Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1 -knockout macrophages (Mϕ). Results A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter- LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter- LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1 -associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1 -disrupted as compared with wild-type Mϕ. Conclusions Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways. [ABSTRACT FROM AUTHOR]

Leprosy is a much‐feared incapacitating infectious disease caused by Mycobacterium leprae or M lepromatosis, annually affecting roughly 200,000 people worldwide. During host‐pathogen interaction, M leprae subverts the immune response, leading to development of disease. Throughout the last few decades, the impact of energy metabolism on the control of intracellular pathogens and leukocytic differentiation has become more evident. Mitochondria play a key role in regulating newly‐discovered immune signaling pathways by controlling redox metabolism and the flow of energy besides activating inflammasome, xenophagy, and apoptosis. Likewise, this organelle, whose origin is probably an alphaproteobacterium, directly controls the intracellular pathogens attempting to invade its niche, a feature conquered at the expense of billions of years of coevolution. In the present review, we discuss the role of reduced host cell mitochondrial activity during M leprae infection and the consequential fates of M leprae and host innate immunity. Conceivably, inhibition of mitochondrial energy metabolism emerges as an overlooked and novel mechanism developed by M leprae to evade xenophagy and the host immune response. [ABSTRACT FROM AUTHOR]

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1–12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1–10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A , as contributing to leprosy risk (p = 4.95 × 10 −9 , odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31 ) and leprosy (p = 6.11 × 10 −18 , OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae -stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis. [ABSTRACT FROM AUTHOR]

This study aims to explore the mechanism of miR-211–5p in extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) in improving frozen shoulder (FS) in rat models. Rat BMSCs and EVs derived from rat BMSCs were isolated, identified, and then injected into rats to assess the expression of TGF-β, MMP1, MMP3, MMP12, GAP43, and PGP9.5 in shoulder capsule tissues. The range of motion of bilateral glenohumeral joints was assessed and pathological changes of shoulder capsule tissues were observed after hematoxylin-eosin staining. The binding sites of miR-211–5p to KDM2B and LACC1 to H3K4me3 were measured. FS rat models with LACC1 highly expressed were established to assess the motion of bilateral glenohumeral joints and expression of arthritis related factors in rats. EVs were successfully extracted from BMSCs. Injection of BMSCs-EVs could improve the activity of bilateral glenohumeral joints and the pathological condition of joint capsule in rats. Elevated expression of miR-211–5p was found in rats injected with BMSCs-EVs. Dual luciferase assay showed that miR-211–5p had a binding site with KDM2B. ChIP, qRT-PCR, and western blot experiments showed BMSCs-EVs injection resulted in elevated enrichment of LACC1 promoter in shoulder capsule tissues of FS rats, and decreased mRNA and protein expression of KDM2B and increased H3K4me3 methylation. Overexpression of LACC1 could also improve the pathological condition of joint capsule tissue. miR-211–5p in EVs derived from BMSCs increased H3K4me3 methylation in shoulder capsule tissue of rats by binding KDM2B, resulting in up-regulated transcription level of LACC1 and improving FS. The datasets used or analyzed during the current study are available from the corresponding author on reasonable request. • miR-211–5p in BMSCs-EVs facilitates the repair of rat FS. • miR-211–5p targets KDM2B. • miR-211–5p in BMSCs-EVs reduces the expression of KDM2B in FS rats. • miR-211–5p in BMSCs-EVs increases the expression of LACC1 in FS rats. • Overexpressed LACC1 improves the repair of rat FS. [ABSTRACT FROM AUTHOR]

Background: The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production. Case presentation: We describe two siblings with severe familial forms of juvenile arthritis in which whole-exomesequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delÇ. p.(T276fs*2) in FAMIN. Conclusions: The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis. [ABSTRACT FROM AUTHOR]

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H + and phosphate recycling., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)