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ObjectiveEmerging evidence links perturbations in the microbiome to neurodegeneration in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) and to surgical stress. In this study, we attempted to identify preoperative differences intestinal microbiota (IM) and barrier function between pAD [prodromal AD: Subjective cognitive decline (SCD) and aMCI] patients and normal neurocognition (NC) patients. Additionally, the potential associations between IM and barrier function, inflammation, and the clinical characteristics of pAD were evaluated.DesignEighty elderly patients scheduled to undergo orthopedic surgery were consecutively enrolled and grouped as NC, SCD, and aMCI following neuropsychological assessment. IM was determined by 16S rRNA MiSeq sequencing, and PICRUSt was used to predict functional shifts in IM. Furthermore, we investigated the association between IM and plasma claudin-1, occludin, LPS, systemic inflammatory cytokines, neuropsychological assessment, and clinical characteristics.ResultsThere was a lower Chao1 index in the SCD group (P = 0.004) and differences in beta diversity among the three groups (PCA: P = 0.026, PCoA: P= 0.004). The relative abundance of Bacteroidetes was higher in the SCD group (P = 0.016, P = 0.008), and Firmicutes were more enriched in the aMCI group than in the SCD group (P= 0.026). At the family level, the total abundance of Gram-negative bacteria was higher in the SCD group than in the aMCI group (P = 0.047), and the Christensenellaceae family was detected at lower levels in the SCD and aMCI groups than in the NC group (P= 0.039). At the genus level, the eleven short-chain fatty acid (SCFA)-producing bacteria exhibited differences among the three groups. PICRUSt analysis showed that the pathways involved in SCFA catabolism, biosynthesis, and adherent junctions were reduced in SCD patients, and lipid synthesis proteins were reduced in pAD patients. Meanwhile, elevated plasma LPS and CRP were observed in SCD patients, and higher plasma occludin in aMCI patients. The IM was correlated with plasma claudin-1, LPS, inflammatory factors, neuropsychological assessment, and clinical characteristics.ConclusionThe intestines of SCD and aMCI patients preoperatively exhibited IM dysbiosis and barrier dysfunction, and elevated plasma LPS and CRP were observed in SCD patients.

Background: Postoperative cognitive dysfunction (POCD) is associated with neuroinflammation by triggering the systemic inflammatory responses. Related studies have demonstrated that ulinastatin, which is a urinary trypsin inhibitor, inhibited the release of inflammatory mediators and improved postoperative cognitive function in elderly patients undergoing major surgery. However, there are controversial results put forwarded by some studies. This systemic review aimed to evaluate the effect of ulinastatin on POCD in elderly patients undergoing surgery.Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, and Ovid to find relevant randomized controlled trials (RCTs) of ulinastatin on POCD in elderly patients undergoing surgery. The primary outcomes included the incidence of POCD and the Mini-Mental State Examination (MMSE) scores. The secondary outcome was the levels of inflammatory cytokines such as tumor necrosis factor (TNF)-α, S100β, C-reactive protein (CRP), interleukin (IL)-6, and IL-10. RevMan 5.3 was used to conduct the meta-analysis.Results: Ten RCTs were included finally. Compared with controls, ulinastatin significantly reduced the incidence of POCD [risk ratio (RR) = 0.29, 95% CI 0.21–0.41, test of RR = 1: Z = 7.05, p < 0.00001]. In addition, patients in the ulinastatin group have lower levels of TNF-α, S100β, CRP, and IL-6 and higher level of IL-10 in serum following surgery.Conclusion: These findings suggested that ulinastatin can be used as an anti-inflammatory drug for POCD prevention in elderly patients undergoing surgery.Systematic Review Registration Number: CRD42019137449.

Objective: This study aimed to investigate the brain functional alterations with resting-state functional magnetic resonance imaging (rs-fMRI) in older patients with knee osteoarthritis (KOA) before and after total knee arthroplasty (TKA) and to assess the causal relationship of the brain function and neuropsychological changes. Methods: We performed rs-fMRI to investigate brain function of 23 patients aged ≥65 with KOA and 23 healthy matched controls. Of the KOA patients, 15 completed postoperative rs-fMRI examinations. Analyzes of the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) were used to estimate differences in brain functional parameters between KOA patients, postoperative patients, and the controls. The relationship between changes of pre- and post-surgical status in ALFF and neuropsychological test results was analyzed. Results: Compared with the controls, all patients with KOA exhibited decreased ALFF in the default mode network (bilateral angular gyrus, precuneus gyrus, medial superior frontal gyrus) and increased ALFF in the bilateral amygdala and cerebellum posterior lobe before surgery ( P < 0.001). Altered ALFF persisted in the same brain regions 1 week postoperatively. The decreased ALFF in the left precuneus gyrus and middle temporal gyrus was found after surgery when compared with preoperative data ( P < 0.01). Preoperatively, the KOA patients exhibited increased FC between the left precuneus gyrus and the right supplementary motor area compared to the controls ( P < 0.001), but this connectivity became no significant difference after TKA. The left Cerebelum_9 was found to have decreased FC with the right precuneus gyrus postoperatively ( P < 0.001) although this was not significantly different before surgery. The significantly altered ALFF values were not correlated with changes in cognitive assessment scores. Conclusion: In older patients with end-stage KOA, functional alterations in important brain regions were detected with the persistence and further changes observed at an early stage after knee replacement. Our data further our understanding of brain functional abnormalities and cognitive impairment in older patients following knee replacement, which may provide therapeutic targets for preventive/treatment strategy to be developed. Trial registration: Clinical Trial Registration: http://www.chictr.org.cn/index.aspx , ChiCTR1800016437; Registered June 1, 2018.

Objective: To investigate gut microbiota and intestinal barrier function changes after orthopedic surgery in elderly patients with either normal cognition (NC) or a prodromal Alzheimer disease phenotype (pAD) comprising either subjective cognitive decline (SCD) or amnestic mild cognitive impairment (aMCI). Background: Homeostatic disturbances induced by surgical trauma and/or stress can potentially alter the gut microbiota and intestinal barrier function in elderly patients before and after orthopedic surgery. Methods: In this prospective cohort study, 135 patients were subject to preoperative neuropsychological assessment and then classified into: NC (n=40), SCD (n=58), or aMCI (n=37). Their gut microbiota, bacterial endotoxin (lipopolysaccharide), tight junction (TJ) protein, and inflammatory cytokines in blood were measured before surgery and on postsurgical day 1, 3, and 7 (or before discharge). Results: The short-chain fatty acid (SCFA)-producing bacteria were lower while the gram-negative bacteria, lipopolysaccharide and TJ were higher preoperatively in both the SCD and aMCI (pAD) groups compared with the NC group. After surgery, a decrease in SCFA-producing bacteria, and an increase in both gram-negative bacteria and plasma claudin were significant in the pAD groups relative to the NC group. SCFA-producing bacteria were negatively correlated with TJ and cytokines in pAD patients on postsurgical day 7. Furthermore, surgery-induced perioperative metabolic stress and inflammatory responses were associated with gut microbiota alterations. Conclusions: Surgery exacerbates both preexisting microbiota dysbiosis and intestinal barrier dysfunction in pAD patients, all of which may be associated with systemic inflammation and, in turn, may lead to further cognitive deterioration.

The adjustment of cellular redox homeostasis is essential in when responding to environmental perturbations, and the mechanism by which cells distinguish between normal and oxidized states through sensors is also important. In this study, we found that acyl-protein thioesterase 1 (APT1) is a redox sensor. Under normal physiological conditions, APT1 exists as a monomer through S-glutathionylation at C20, C22 and C37, which inhibits its enzymatic activity. Under oxidative conditions, APT1 senses the oxidative signal and is tetramerized, which makes it functional. Tetrameric APT1 depalmitoylates S-acetylated NAC (NACsa), and NACsa relocates to the nucleus, increases the cellular glutathione/oxidized glutathione (GSH/GSSG) ratio through the upregulation of glyoxalase I expression, and resists oxidative stress. When oxidative stress is alleviated, APT1 is found in monomeric form. Here, we describe a mechanism through which APT1 mediates a fine-tuned and balanced intracellular redox system in plant defence responses to biotic and abiotic stresses and provide insights into the design of stress-resistant crops.

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