Non-genetic biomarkers for ankylosing spondylitis: An umbrella review.

OBJECTIVE: The objective of the study was to provide an overview of the existing evidence on non-genetic biomarkers for ankylosing spondylitis (AS). METHODS: In this umbrella review, we searched PubMed and Web of Science from database inception to October 31, 2020. Systematic reviews and meta-analyses of observational studies investigating the associations between any non-genetic biomarkers and AS were included. We estimated summary standardized mean difference (SMD) along with 95% confidence interval (CI), I2 statistic, 95% prediction interval (PI), and assessed small-study effects and excess significance bias. The study was registered in PROSPERO with registration number of CRD42020218240. RESULTS: A total of 1276 publications were identified, of which 21 articles covering 43 non-genetic biomarkers were eligible for inclusion. Evidence of 22 (51%) non-genetic biomarkers exhibited a nominally significant effect (p < 0.05) on AS, and 7 associations (14%) showed small-study effects. The associations of platelet count (SMD: 0.53, 95% CI: 0.36 to 0.71) and serum interleukin (IL)-23 levels (SMD = 2.03, 95% CI: 1.27 to 2.79) with AS presented highly suggestive evidence, while circulating IL-17 levels (SMD = 2.36, 95% CI: 1.71, 3.01) and Treg/PBMC ratio (SMD = -0.75, 95% CI: -1.06 to -0.44) presented suggestive evidence. However, these associations showed large or very large between-study heterogeneity, suggesting an indefinite direction for the effect when 95% PIs were considered. CONCLUSION: No convincing evidence supported the existence of a non-genetic biomarker for AS. Some highly suggestive associations might be affected by bias, therefore, promising non-genetic biomarkers for AS remain limited at least based on the current evidence from observational studies.

The Potential Protective Effect of Mesencephalic Astrocyte-Derived Neurotrophic Factor on Post-Operative Delirium via Inhibiting Inflammation and Microglia Activation.

BACKGROUND: The increased inflammation is closely correlated with post-operative delirium (POD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effect on inflammatory diseases. However, the relationship between MANF and POD is still undefined. This study aimed to explore the potential effect of MANF on POD. METHODS: Pre- and post-operative levels of MANF and inflammatory cytokines were measured in serum from POD and non-POD patients by ELISA, as well as endogenous MANF in serum from healthy individuals with different ages. Endogenous MANF in mice brain from different ages was also measured. Abdominal surgery was performed for POD mice model. POD-like behavior changes in mice were evaluated using buried food test, open field test and Y maze test. RESULTS: Endogenous MANF was decreased in age-dependent manner in both humans and mice. The pre-operative level of MANF in serum from POD patients was lower compared with that in non-POD patients (p=0.016). MANF increase in serum after surgery was less in POD patients than that in non-POD patients (p<0.001). In mice, recombinant human MANF reversed the surgery-induced elongation of latency to eat food, increase in latency to center and increase in time in center in open field test, and also increase in duration in novel arm in Y maze test. In addition, MANF inhibited surgery-induced inflammation, microglial activation and M1 polarization in mice. CONCLUSION: The relative low MANF level may contribute to POD in the elderly. MANF has a protective role against POD-like behavior changes in mice.

Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice.

BACKGROUND: Endoplasmic reticulum (ER) perturbations are novel subcellular effectors involved in the ischaemia-reperfusion injury. As an ER stress-inducible protein, mesencephalic astrocyte-derived neurotrophic factor (MANF) has been proven to be increased during ischaemic brain injury. However, the role of MANF in liver ischaemia reperfusion (I/R) injury has not yet been studied. METHODS: To investigate the role of MANF in the process of liver ischaemia-reperfusion, Hepatocyte-specific MANF knockout (MANFhep-/- ) mice and their wild-type (WT) littermates were used in our research. Mice partial (70%) warm hepatic I/R model was established by vascular occlusion. We detected the serum levels of MANF in both liver transplant patients and WT mice before and after liver I/R injury. Recombinant human MANF (rhMANF) was injected into the tail vein before 1 hour occlusion. AST, ALT and Suzuki score were used to evaluate the extent of I/R injury. OGD/R test was performed on primary hepatocytes to simulate IRI in vitro. RNA sequence and RT-PCR were used to detect the cellular signal pathway activation while MANF knockout. RESULTS: We found that MANF expression and secretion are dramatically up-regulated during hepatic I/R. Hepatocyte-specific MANF knockout aggravates the I/R injury through the over-activated ER stress. The systemic administration of rhMANF before ischaemia has the potential to ameliorate I/R-triggered UPR and liver injury. Further study showed that MANF deficiency activated ATF4/CHOP and JNK/c-JUN/CHOP pathways, and rhMANF inhibited the activation of the two proapoptotic pathways caused by MANF deletion. CONCLUSION: Collectively, our study unravels a previously unknown relationship among MANF, UPR and hepatic I/R injury.

Dexmedetomidine alleviates non-ventilation associated lung injury via modulating immunology phenotypes of macrophages.

AIMS: We aimed to evaluate the effect of Dexmedetomidine (Dex) on immunology function of macrophages and inflammatory reactions in non-ventilated lung tissues from both humans and rats. MAIN METHODS: Patients scheduled for lung lobectomy were randomly assigned to traditional anesthesia group or Dex anesthesia group, 15 subjects in each group. CD68, CD86 and CD206 were used to mark activate and polarized macrophages using immunofluorescence staining in human lung tissues. Sprague-Dawley rats were used to set lung injury model and randomly divided into Control group, one-lung ventilation group (CLI group) and CLI + Dex group. Lung tissues and bronchoalveolar lavage fluid (BALF) from non-ventilated lungs were collected. The acquired lung tissues were subjected to hematoxylin-eosin (H&E) staining and the inflammatory cells in BALF were calculated. Levels of cytokines and chemokines were detected by enzyme-linked immunosorbent assays (ELISA). KEY FINDINGS: Results from humans showed that anesthesia with Dex decreased the number of both CD68 positive cells and CD86 positive cells and down-regulated level of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1) in human lung. Results from rats demonstrated that treatment with Dex reversed the increased inflammatory cells in lung and the increased levels of TNF-α, interleukin-1ß (IL-ß), MCP-1 and chemokine (C-X-C motif) ligand 1 (CXCL1) resulted from non-ventilation; Dex increased the anti-inflammatory cytokine interleukin-10 (IL-10) in BALF from non-ventilated lung. SIGNIFICANCE: This study showed that Dex modulated the activation and immunological function of macrophages in non-ventilated lung and revealed a protective role in collapsed lung injury.

Sevoflurane modulates AQPs (1,5) expression and endoplasmic reticulum stress in mice lung with allergic airway inflammation.

Sevoflurane was found to show protective roles in mice with asthma, however, the mechanism of which needs further exploring. Aquaporins (AQPs) have been demonstrated to be involved in the pathogenesis of asthma, while endoplasmic reticulum stress has been reported to be related to many inflammatory diseases and involved in protein processing, including AQPs. The present study aimed to determine the role of sevoflurane in AQPs (AQP1,3,4,5) expression in mice with allergic airway inflammation and the probable mechanism. The increased number of inflammatory cells infiltrating the lung tissue, and the elevated levels of tumor necrosis factor-α (TNF-α) and interleukin (IL) 13 (IL-13) were all decreased after sevoflurane treatment (all P<0.05). Meanwhile, mRNA levels of AQP1 and AQP5 but not AQP3 and AQP4 were decreased in ovalbumin (OVA)-induced allergic mice lung. Both the decreased mRNA expression and protein levels of AQP1 and AQP5 in allergic lung tissues were reversed by sevoflurane treatment. Furthermore, we established that sevoflurane inhibited the OVA-induced protein increase in the endoplasmic reticulum (ER) stress markers BiP and C/EBP homologous protein (CHOP). Collectively, these findings suggested that sevoflurane modulated the expression and protein level of AOPs (AQP1, AQP5) as well as inhibited ER stress response in OVA-induced allergic airway inflammation of mice.