Comprehensive analysis of lactate-related gene profiles and immune characteristics in lupus nephritis.

Objectives: The most frequent cause of kidney damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN), which is also a significant risk factor for morbidity and mortality. Lactate metabolism and protein lactylation might be related to the development of LN. However, there is still a lack of relative research to prove the hypothesis. Hence, this study was conducted to screen the lactate-related biomarkers for LN and analyze the underlying mechanism. Methods: To identify differentially expressed genes (DEGs) in the training set (GSE32591, GSE127797), we conducted a differential expression analysis (LN samples versus normal samples). Then, module genes were mined using WGCNA concerning LN. The overlapping of DEGs, critical module genes, and lactate-related genes (LRGs) was used to create the lactate-related differentially expressed genes (LR-DEGs). By using a machine-learning algorithm, ROC, and expression levels, biomarkers were discovered. We also carried out an immune infiltration study based on biomarkers and GSEA. Results: A sum of 1259 DEGs was obtained between LN and normal groups. Then, 3800 module genes in reference to LN were procured. 19 LR-DEGs were screened out by the intersection of DEGs, key module genes, and LRGs. Moreover, 8 pivotal genes were acquired via two machine-learning algorithms. Subsequently, 3 biomarkers related to lactate metabolism were obtained, including COQ2, COQ4, and NDUFV1. And these three biomarkers were enriched in pathways 'antigen processing and presentation' and 'NOD-like receptor signaling pathway'. We found that Macrophages M0 and T cells regulatory (Tregs) were associated with these three biomarkers as well. Conclusion: Overall, the results indicated that lactate-related biomarkers COQ2, COQ4, and NDUFV1 were associated with LN, which laid a theoretical foundation for the diagnosis and treatment of LN.

The role of B-cell ferroptosis in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested a potential role of ferroptosis, an iron-dependent form of regulated cell death, in the pathogenesis of SLE. Here, we demonstrate that B-cell ferroptosis occurs both in lupus patients and MRL/lpr mice. Treatment with liproxstatin-1, a potent ferroptosis inhibitor, could reduce autoantibody production, improve renal damage, and alleviate lupus symptoms in vivo. Furthermore, our results suggest that ferroptosis may regulate B cell differentiation and plasma cell formation, indicating a potential mechanism for its involvement in SLE. Taken together, targeting ferroptosis in B cells may be a promising therapeutic strategy for SLE.

Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor.

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.

LncRNA NEAT1 promotes IL-6 secretion in monocyte-derived dendritic cells via sponging miR-365a-3p in systemic lupus erythematosus.

Increasing evidence has uncovered the essential roles of long noncoding RNAs (lncRNAs) in biological and pathological functions of dendritic cells (DCs) among patients with systemic lupus erythematosus (SLE). However, whether lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) could modulate DCs, especially in the inflammation of SLE, remains largely unknown. Fifteen SLE patients and fifteen age-matched healthy controls were included, and their monocyte-derived dendritic cells (moDCs) were cultured in vitro. Our research identified that the expression of NEAT1 was significantly increased in moDCs of SLE patients and positively correlated with disease activity. Interleukin 6 (IL-6) from both plasma and secreted supernatants of moDCs was also elevated in the SLE group. In addition, regulation of NEAT1 in moDCs by transfection could lead to the corresponding change in IL-6 generation. While for miR-365a-3p, a micro-RNA that can bind with the 3' UTR region of IL6 and NEAT1, it may serve as a negative modulator since its overexpression could result in the reduction of IL-6 levels and vice versa. Additionally, the elevation in NEAT1 expression could increase the secretion of IL-6 by specifically binding to miR-365a-3p, reducing the negative modulatory effects of miR-365a-3p on the IL6 target gene, which suggested that elevated NEAT1 expression could function as the competing endogenous RNA (ceRNA). In conclusion, our findings indicate that NEAT1 can efficiently sponge miR-365a-3p to upregulate expression and secretion of IL-6 in moDCs, suggesting that the NEAT1/miR-365a-3p/IL6 axis may be involved in the development of SLE disease.

The Potential Role of Ferroptosis in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is accompanied with autoantibody production and inflammation. Other features of SLE pathogenesis include iron accumulation, oxidative stress, and lipid peroxidation, which are also major biochemical characteristics of ferroptosis, a novel non-apoptotic regulated form of cell death. To date, ferroptosis has been demonstrated to be an important driver of lupus progression, and several ferroptosis inhibitors have therapeutic effect in lupus-prone mice. Given the emerging link between ferroptosis and SLE, it can be postulated that ferroptosis is an integral component in the vicious cycle of immune dysfunction, inflammation, and tissue damage in SLE pathogenesis. In this review, we summarize the potential links between ferroptosis and SLE, with the aim of elucidating the underlying pathogenic mechanism of ferroptosis in lupus, and providing a new promising therapeutic strategy for SLE.

Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization.

Objectives: Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. Methods: The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. Results: The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factor-alpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). Conclusion: This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream.

Azithromycin alleviates systemic lupus erythematosus via the promotion of M2 polarisation in lupus mice.

Our previous study demonstrated that azithromycin could promote alternatively activated (M2) macrophages under lupus conditions in vitro, which might be beneficial for lupus treatment. Thus, the aim of this study was to further confirm whether azithromycin can drive M2 polarisation in lupus and ultimately alleviate systemic lupus erythematosus (SLE) in vivo. Lymphocyte-derived DNA (ALD-DNA)-induced mice (induced lupus model) and MRL-Faslpr mice (spontaneous lupus model) were both used in the experiment. First, we observed symptoms of lupus by assessing the levels of serum anti-dsDNA antibodies and serum creatinine and renal pathology. We found that both murine models showed increased levels of serum anti-dsDNA antibodies and creatinine, enhanced glomerular fibrosis and cell infiltration, basement membrane thickening and elevated IgG deposition. After azithromycin treatment, all these medical indexes were alleviated, and kidney damage was effectively reversed. Next, macrophage polarisation was assessed in the spleen and kidneys. Macrophage infiltration in the spleen was notably decreased after azithromycin treatment in both murine models, with a remarkably elevated proportion of M2 macrophages. In addition, the expression of interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), CD86, toll-like receptor (TLR)2 and TLR4 was extremely downregulated, while the expression of transforming growth factor (TGF)-ß, arginase-1 (Arg-1), chitinase-like 3 (Ym-1), found in inflammatory zone (Fizz-1) and mannose receptor (CD206) was significantly upregulated in the kidneys after azithromycin treatment. Taken together, our results indicated for the first time that azithromycin could alleviate lupus by promoting M2 polarisation in vivo. These findings exploited the newly discovered potential of azithromycin, a conventional drug with verified safety, affordability and global availability, which could be a novel treat-to-target strategy for SLE via macrophage modulation.

Bioinformatic analysis of key biomarkers and immune filtration of skin biopsy in discoid lupus erythematosus.

OBJECTIVE: Discoid lupus erythematosus (DLE) is the most common category of chronic cutaneous lupus erythematosus, where the pathological process is proved to be closely associated with immunity. This bioinformatic analysis sought to identify key biomarkers and to perform immune infiltration analysis in the skin biopsy samples of DLE. METHODS: GSE120809, GSE100093, GSE72535, GSE81071 were used as the data source of gene expression profiles, altogether containing 79 DLE samples and 47 normal controls (NC). Limma package was applied to identify differentially expressed genes (DEGs) and additional Gene Ontology (GO) together with The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were done. Protein-protein interaction network (PPI) was constructed using STRING and Cytoscape. Hub genes were selected by CytoHubba. Finally, immune filtration analysis was finished by the CIBERSORT algorithm, and comparisons between the two groups were accomplished. RESULTS: A total of 391 DEGs were identified, which were composed of 57 up-regulated genes and 334 down-regulated genes. GO and KEGG enrichment analyses revealed that DEGs were closely related with different steps in the immune response. Top 10 hub genes included GBP2, HLA-F, IFIT2, RSAD2, ISG15, IFIT1, IFIT3, MX1, XAF1 and IFI6. Immune filtration analysis from CIBERSORT had found that compared with NC, DLE samples had higher percentages of CD8+ T cells, T cells CD4 memory activated, T cells gamma delta, macrophages M1 and lower percentages of T cells regulatory, macrophages M2, dendritic cells resting, mast cells resting, mast cells activated. CONCLUSION: This bioinformatic study selected key biomarkers from the contrast between DLE and NC skin samples and is the first research to analyze immune cell filtration in DLE.

Correlation between circulating interleukin-18 level and systemic lupus erythematosus: a meta-analysis.

This study is a meta-analysis aimed at pooling reported data and clarifying the association between circulating level of interleukin-18 and systemic lupus erythematosus (SLE). We searched medical databases including Medline/Pubmed, Embase, Scopus, The Cochrane Library, and Web of Science thoroughly to obtain all related articles published before July 15th, 2020. We pooled computed standardized mean difference (SMD) and its 95% confidence interval using STATA 13.0 and exhibited in the form of forest graph. Meta-regression and subgroup analysis were also performed to explore the source of heterogeneity. Publication bias was first evaluated by the symmetry of the funnel plot and then Egger's linear regression test. Thirty eligible studies from eighteen regions were finally included and the relevant data from these studies were pooled. The analysis results displayed that SLE patients showed a significantly higher level of circulating IL-18 level in comparison with healthy controls (SMD = 1.56, 95% CI [1.20-1.93]; I2 = 94.9%, p < 0.01). The conclusion was equally applicable in subgroups divided based on sample type, mean age, disease duration, and testing method. Patients with SLEDAI score higher than five, or who were Asian, White, Arab, or mixed ethnicity had an elevated level of IL-18, while the others didn't. This meta-analysis has elucidated that compared with healthy people, the circulating level of IL-18 is considerably higher in SLE patients, which indicates the underlying role of IL-18 in SLE pathogenesis.

The Behavior of Amphibians Shapes Their Symbiotic Microbiomes.

Seasonal dynamics in symbiotic microbiomes have been investigated in a number of vertebrates and are mainly caused by changes in the diet (in the gut microbiome) or the living environment (in the skin microbiome). Most amphibian microbiome studies focus on the skin, whereas internal microbiome structure and dynamics are often overlooked. The present study investigated the seasonal dynamics in three types of symbiotic microbiomes (the skin, stomach, and gut) across four wild frog species, belonging to different families, in May and October. The frogs harbored more water source microbes in May than in October. On the contrary, the frogs harbored more soil source microbes in October than in May. The frog species investigated tend to live in a water environment in May to maintain body surface humidity at high environmental temperatures and to breed. In October, these four species prefer to live on the land, as the environmental temperature decreases, to prepare for hibernation in caves or under stones. Thus, seasonal changes in the wild amphibian symbiotic microbiome may be caused by the difference in microbe transmission from their living environment due to specific behaviors. This study demonstrated that the behavior and living environment of wild amphibians shape their symbiotic microbiome externally (on the skin) and internally (in the stomach and gut). We revealed the potential association between specific behaviors in poikilothermic animals and host symbiotic microbiomes.IMPORTANCE Understanding the interactions between host behavior and microbiome dynamics remains an outstanding priority in the field of microbial ecology. Here, we provide the reader with a simple example of how the behavior and living environment of wild amphibians shape their symbiotic microbiome externally (on the skin) and internally (in the stomach and gut).

Comparison of chemotherapy plus bevacizumab vs. chemotherapy alone as third-line treatment or beyond for advanced non-small cell lung cancer: A propensity score-matched analysis.

The addition of bevacizumab to chemotherapy has demonstrated efficacy as a first-line treatment for non-small cell lung cancer (NSCLC). Whether this combination is effective as a salvage treatment for patients with NSCLC remains unclear. The present retrospective study was designed to compare the efficacy and safety of chemotherapy plus bevacizumab with chemotherapy alone as a third-line, or continuing, treatment for patients with NSCLC. Between January 2011 and June 2016, a total of 38 patients with stage IV NSCLC who had received chemotherapy plus bevacizumab subsequent to failure of ≥2 prior regimens were matched with 38 patients who had received chemotherapy alone using propensity score matching from a dataset of 165 patients. The variables that were analyzed included age, sex, smoking history, histology, epithelial growth factor receptor mutation status, number of prior regimens and type of chemotherapy regimen. Univariate and multivariate analyses were used to evaluate the prognostic factors for survival outcomes and tumor response, and toxicity analyses were performed. The objective response rate (ORR) and disease control rate (DCR) were improved in patients who underwent chemotherapy-bevacizumab treatment compared with chemotherapy alone (ORR, 23.7 vs. 5.3%, P<0.001; DCR, 65.8 vs. 31.6%, P<0.001). Progression-free survival was prolonged in the chemotherapy-bevacizumab group compared with the chemotherapy-alone group (median, 3.9 vs. 2.2 months; HR, 0.54; 95% CI, 0.32-0.89, P=0.014). Incidence of ≥grade 3 adverse events was low and similar across the groups. The combination of chemotherapy and bevacizumab is a potentially effective and safe alternative salvage treatment for patients with NSCLC who have not received bevacizumab treatment previously.

Upregulated N-cadherin expression is associated with poor prognosis in epithelial-derived solid tumours: A meta-analysis.

BACKGROUND: N-cadherin is an important molecular in epithelial-mesenchymal transition (EMT) and has been reported to be associated with aggressive behaviours of tumours. However, prognostic value of N-cadherin in solid malignancies remains controversially. MATERIALS AND METHODS: The Pubmed/MELINE and EMBASE databases were used for a comprehensive literature searching. Pooled risk ratio (RR) and hazard ratio (HR) with their corresponding 95% confidence intervals (CIs) were employed to quantify the prognostic role. RESULTS: Involving 36 studies with 5705 patients were performed to investigate relationships between N-cadherin upregulation and clinicopathological features, survival. Results suggested upregulated N-cadherin was associated with lymph node metastasis (RR = 1.16, 95% CI [1.00, 1.35]), higher histological grade (RR = 1.36, 95%CI [1.14, 1.62]), angiolymphatic invasion (RR = 1.19, 95% CI [1.06, 1.34]) and advanced clinical stage (RR = 1.32, 95% CI [1.06, 1.64]), while upregulated N-cadherin was apt to be associated with distant metastasis (RR = 1.43, 95% CI [0.99, 2.05]). Moreover, N-cadherin was correlated with poor prognosis of 3-year survival (HR = 1.78, 95% CI [1.51, 2.10]), 5-year survival (HR = 1.57, 95% CI [1.17, 2.10]) and overall survival (OS) (HR = 1.32, 95% CI [1.20, 1.44]). Subgroup analyses according to cancer types were also conducted for applying these conclusions to some tumours more properly. No publication bias was found except subgroup analysis of distant metastasis (P = .652 for Begg's test and 0.023 for Egger's test). CONCLUSIONS: Taken together, upregulation of N-cadherin is associated with more aggressive behaviours of epithelial-derived solid malignancies and can be regarded as a predictor of poor survival.

Prognostic role of Gli1 expression in breast cancer: a meta-analysis.

Glioma-associated oncogene 1 (Gli1) is a critical transcriptional factor of Sonic hedgehog pathway which has been proved to participate in the initiation and progression of tumor in mammalians. However, its clinical value in breast cancer remains unknown. Thus, a meta-analysis was performed to clarify the association of Gli1 over-expression, clinic-pathological characteristics, molecular subtypes and prognosis in breast cancer. According to included criteria, 13 eligible studies containing 2816 patients all around the world were selected in this study. Our results indicated no significant association of Gli1 expression and histological grade (RR = 1.20, 95% CI: [0.98, 1.47]), T stage (RR = 1.05, 95% CI: [0.87, 1.27]), clinical stage (RR = 1.04, 95% CI: [0.93, 1.18]) and lymph node metastasis (RR = 1.12, 95% CI: [0.92, 1.37]). In addition, pooled RR showed no correlation of Gli1 expression and progesterone receptor (PR) (RR = 0.92, 95% CI: [0.70, 1.21]), estrogen receptor (ER) (RR = 1.03, 95% CI: [0.74, 1.42]), human epidermal growth factor receptor 2 (HER-2) (RR = 1.12, 95% CI: [0.90, 1.39]). Nonetheless, up-regulated Gli1 expression predicts shorter disease-free survival (DFS) (HR = 1.38, 95% CI: [1.05, 1.81]), 3-year survival (HR = 1.74, 95% CI: [1.28, 2.36]), 5-year survival (HR = 2.04, 95% CI: [1.62, 2.57]) and overall survival (OS) (HR = 2.05, 95% CI: [1.60, 2.64]). In conclusion, over-expression of Gli1 tends to progressive stages and is related to unfavorable prognosis of breast cancer, which may become a potential prognosis indicator and therapy target in breast cancer.