Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

Saliva­microbiome­derived signatures: expected to become a potential biomarker for pulmonary nodules (MCEPN-1).

BACKGROUND: Oral microbiota imbalance is associated with the progression of various lung diseases, including lung cancer. Pulmonary nodules (PNs) are often considered a critical stage for the early detection of lung cancer; however, the relationship between oral microbiota and PNs remains unknown. METHODS: We conducted a 'Microbiome with pulmonary nodule series study 1' (MCEPN-1) where we compared PN patients and healthy controls (HCs), aiming to identify differences in oral microbiota characteristics and discover potential microbiota biomarkers for non-invasive, radiation-free PNs diagnosis and warning in the future. We performed 16 S rRNA amplicon sequencing on saliva samples from 173 PN patients and 40 HCs to compare the characteristics and functional changes in oral microbiota between the two groups. The random forest algorithm was used to identify PN salivary microbial markers. Biological functions and potential mechanisms of differential genes in saliva samples were preliminarily explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of Orthologous Groups (COG) analyses. RESULTS: The diversity of salivary microorganisms was higher in the PN group than in the HC group. Significant differences were noted in community composition and abundance of oral microorganisms between the two groups. Neisseria, Prevotella, Haemophilus and Actinomyces, Porphyromonas, Fusobacterium, 7M7x, Granulicatella and Selenomonas were the main differential genera between the PN and HC groups. Fusobacterium, Porphyromonas, Parvimonas, Peptostreptococcus and Haemophilus constituted the optimal marker sets (area under curve, AUC = 0.80), which can distinguish between patients with PNs and HCs. Further, the salivary microbiota composition was significantly correlated with age, sex, and smoking history (P < 0.001), but not with personal history of cancer (P > 0.05). Bioinformatics analysis of differential genes showed that patients with PN showed significant enrichment in protein/molecular functions related to immune deficiency and energy metabolisms, such as the cytoskeleton protein RodZ, nicotinamide adenine dinucleotide phosphate dehydrogenase (NADPH) dehydrogenase, major facilitator superfamily transporters and AraC family transcription regulators. CONCLUSIONS: Our study provides the first evidence that the salivary microbiota can serve as potential biomarkers for identifying PN. We observed a significant association between changes in the oral microbiota and PNs, indicating the potential of salivary microbiota as a new non-invasive biomarker for PNs. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR2200062140; Date of registration: 07/25/2022.

Enhancement of Pulmonary Function and Reduction of Complications Through EIT-Guided Yoga Breathing Exercise After Esophagectomy.

BACKGROUND This study aimed to investigate the impact of EIT-guided yoga breathing training on postoperative pulmonary complications (PPCs) for esophageal cancer patients. MATERIAL AND METHODS Total of 62 patients underwent radical resections of esophageal cancer. Esophageal cancer patients were randomized to the standard care group, or the intervention group receiving an additional complete breathing exercise under the guidance of EIT in AICU. Following extubation after the esophagectomy, pulmonary functions were evaluated by EIT with center of ventilation (CoV), dependent silent spaces (DSS), and non-dependent silent spaces (NSS). RESULTS Sixty-one older esophageal cancer patients (31 in the Control group and 30 in the EIT group) were included in the final analysis. Forty-four patients experienced pulmonary complications after esophagectomy, 27 (87.1%) in the Control group and 17 (36.7%) in the EIT group (RR, 0.42 (95% CI: 0.26, 0.69). The most common pulmonary complication was pleural effusion, with an incidence of 30% in the EIT group and 74.2% in the Control group, with RR of 0.40 (95% CI: 0.23, 0.73). Time for the first pulmonary complication was significantly longer in the EIT group than in the Control group (hazard ratio, HR, 0.43; 95% CI 0.21 to 0.87; P=0.019). Patients in the EIT group had significantly higher scores in CoV, DSS, and NSS than in the Control group. CONCLUSIONS Guided by EIT, the addition of the postoperative breathing exercise to the standardized care during AICU could further improve pulmonary function, and reduce postoperative pulmonary complications after esophagectomy.

Factors influencing self-regulated learning ability among Medical undergraduates in China: a cross-sectional study.

BACKGROUND: Self-regulated learning (SRL) is the core purpose of lifelong learning and the precondition for medical staff to continuously adapt to and excel in their current and future positions. Good SRL abilities positively impact the academic performance and clinical skills of medical students. Despite its importance, the factors influencing SRL among medical students in China remain under-explored. This study investigates these factors among Chinese medical undergraduates. METHODS: This cross-sectional survey was conducted among a convenience sample of undergraduate students at all four medical universities in Guangxi, using a questionnaire developed and tailored by Zude Zhu. Responses from 2,179 Chinese medical undergraduate students were included in the analyses. The data were collected using the College Student SRL Questionnaire which consisted of 69 items rated on a 6-point Likert scale, ranging from 1 (very inconsistent) to 6 (very consistent), and scored by calculating the mean and standard deviation. The data were analyzed using the Statistical Package for Social Sciences, version 22.0 (IBM SPSS Corp). RESULTS: Univariate analysis showed that registered residence, specialty, educational system, parental educational background, parenting style, annual household income, parental occupation, grade point average (GPA), engagement in SRL activities, and participation in SRL training were significantly associated with SRL scores (p < 0.05 for all). The results of the multiple linear regression analysis revealed that educational system ("5 + 3"-year) (p < 0.001; 95% Confidence Interval (CI), 9.842 to 15.686), mother's occupation (staff of government agency/institution) (p < 0.001; 95% CI, - 3.798 to - 2.081), GPA (p < 0.001; 95% CI, - 10.009 to - 5.712), engagement in SRL activities (p = 0.001; 95% CI, - 11.903 to - 3.162), and participation in SRL training (p < 0.001; 95% CI, - 15.966 to - 9.972) were positively related to SRL abilities in medical students. CONCLUSIONS: Further studies are necessary to identify additional external (e.g., academic environment, parents' expectations for their children) and internal factors (e.g., student cadres or not, interest in medicine or not, whether there is a clear career planning) affecting SRL abilities. Initiating relevant training early in the college career could enhance SRL capabilities in medical students.

Malignant melanoma with liver, stomach, and duodenal metastasis.

Malignant melanoma (MM) is a common and highly invasive malignant tumor in clinical practice that is prone to occur in the skin and mucosa and prone to early metastasis. The common sites of metastasis are the liver, lungs, brain, etc. Metastatic gastrointestinal mucosa is relatively rare. Once metastasis occurs, the prognosis of patients is significantly worse. This article reports a case diagnosed as MM with liver, stomach, and duodenal metastasis by ultrasound-guided endoscopic puncture at Fengdu People's Hospital in Chongqing, with gastrointestinal discomfort as the initial symptom and a history of melanoma. Therefore, when a patient has a history of melanoma surgery and presents with digestive symptoms, it is necessary to consider the disease. Regular endoscopic screening should be performed, and early surgical treatment and postoperative chemotherapy combined with targeted therapy may improve patient prognosis and prolong patient survival.

Synthesis, characterization, anticancer efficacy evaluation of ruthenium(II) and iridium(III) polypyridyl complexes toward A549 cells.

A new ligand DFIP (2-(dibenzo[b,d]furan-3-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its two complexes iridium(III) [Ir(ppy)2(DFIP)](PF6) (ppy = 2-phenylpyridine, Ir1) and ruthenium(II) [Ru(bpy)2(DFIP)](PF6)2 (bpy = 2,2'-bipyridine, Ru1) were synthesized and characterized. The anticancer effects of the two complexes on A549, BEL-7402, HepG2, SGC-7901, HCT116 and normal LO2 cells were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 shows high cytotoxic activity on A549, BEL-7402, SGC-7901 and HepG2, Ru1 exhibits moderate anticancer activity toward A549, BEL-7402 and SGC-7901 cells. The IC50 values of Ir1 and Ru1 toward A549 are 7.2 ± 0.1 and 22.6 ± 1.4 µM, respectively. The localization of complexes Ir1 and Ru1 in the mitochondrial, intracellular accumulation of reactive oxygen species (ROS) levels, and the changes of mitochondrial membrane potential (MMP) and cytochrome c (cyto-c) were investigated. Apoptosis and cell cycle were detected by flow cytometry. Immunogenic cell death (ICD) was used to detect the effects of Ir1 and Ru1 on the A549 using a confocal laser scanning microscope. The expression of apoptosis-related proteins was detected by western blotting. Ir1 and Ru1 can increase the intracellular ROS levels and release cyto-c, reduce the MMP, leading to the apoptosis of A549 cells and blocking the A549 cells at the G0/G1 phase. Additionally, the complexes caused a decrease of the expression of polyADP-ribose polymerase (PARP), caspase 3, Bcl-2 (B-cell lymphoma-2), PI3K (phosphoinositide-3 kinase) and upregulated the expression of Bax. All these findings indicated that the complexes exert anticancer efficacy to induce cell death through immunogenic cell death, apoptosis, and autophagy.

ST36 acupoint injection with anisodamine for postoperative nausea and vomiting in female patients after bariatric surgery: a prospective, randomized controlled trial.

BACKGROUND: The use of multimodal pharmacological prophylactic regimes has decreased postoperative nausea and vomiting (PONV) in general but it still occurs in over 60% of female patients after bariatric surgery. This study aimed to evaluate the efficacy of ST36 acupoint injection with anisodamine in prevention of PONV among female patients after bariatric surgery. METHODS: Ninety patients undergoing laparoscopic sleeve gastrectomy were randomly allocated to anisodamine or control group at the ratio of 2:1. Anisodamine or normal saline was injected into Zusanli (ST36) bilaterally after induction of general anesthesia. The incidence and severity of PONV were assessed during the first 3 postoperative days and at 3 months. The quality of early recovery of anesthesia, gastrointestinal function, sleep quality, anxiety, depression, and complications were also evaluated. RESULTS: Baseline and perioperative characteristics were comparable between two groups. In the anisodamine group, 25 patients (42.4%) experienced vomiting within postoperative 24 h compared with 21 (72.4%) in the control group (relative risk 0.59; 95% confidence interval 0.40-0.85). Time to first rescue antiemetic was 6.5 h in anisodamine group, and 1.7 h in the control group (P = 0.011). Less rescue antiemetic was required during the first 24 h in the anisodamine group (P = 0.024). There were no differences in either postoperative nausea or other recovery characteristics. CONCLUSIONS: The addition of ST36 acupoint injection with anisodamine significantly reduced postoperative vomiting without affecting nausea in female patients with obesity undergoing laparoscopic sleeve gastrectomy.

Type I IFNs repolarized a CD169+ macrophage population with anti-tumor potentials in hepatocellular carcinoma.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169+ macrophages exhibited significantly enhanced phagocytotic and CD8+ T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169+ macrophage population and enhancing CD8+ T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization.

Circ_C4orf36 Promotes the Proliferation and Osteogenic Differentiation of BMSCs by Regulating VEGFA.

Fracture healing is a complicated process containing the regulation of cellular process. It has been reported that circRNAs are involved in fracture healing. Our study aims to explore the role and mechanism of circ_C4orf36 in fracture healing. Here, we found that the expressions of Circ_C4orf36 and VEGFA were increased during osteoblast differentiation in MC3T3-E1 cells. Circ_C4orf36 overexpression could accelerate the proliferation and migration, as well as osteoblast differentiation in MC3T3-E1 cells, as well as increased ALP activity and osteogenic markers (Runx2, OCN) via upregulating VEGFA expression. Mechanistically, circ_C4orf36 facilitated the expression of VEGFA by recruiting EIF4A3. Taken together, our results elucidated that circ_C4orf6 promoted the migration, proliferation and osteoblast differentiation in BMSCs by upregulating VEGFA, which indicated that circ_C4orf36 might be a potential target in fracture healing treatment.

The MFF-SIRT1/3 axis, regulated by miR-340-5p, restores mitochondrial homeostasis of hypoxia-induced pulmonary artery smooth muscle cells.

Mitochondrial dynamics and quality control play a central role in the maintenance of the proliferation-apoptosis balance, which is closely related to the progression of pulmonary arterial hypertension (PAH). However, the exact mechanism of this balance remains unknown. Pulmonary artery smooth muscle cells (PASMCs) were cultured in hypoxia condition for constructing a PAH model in vitro. The expression of genes and proteins were determined by qRT-PCR and western bolt assays. Cell proliferation-apoptosis balance were tested by MTT, EdU and TUNEL assays. The mitochondrial functions were assessed by flow cytometry, JC-1, Mito tracker red staining, and corresponding kits. Besides, the molecular interaction was validated by dual-luciferase reporter assay. MFF was overexpressed in hypoxia-treated PAMSCs. Knockdown of MFF significantly repressed the excessive proliferation but enhanced cell apoptosis in hypoxia-treated PAMSCs. Moreover, MFF silencing improved mitochondrial function of hypoxia-treated PAMSCs by increasing ATP production and decreasing ROS release and mitochondrial fission. Mechanistically, MFF was a directly target of miR-340-5p, and could negatively regulate SIRT1/3 expression. Subsequently, functional rescue assays showed that the biological effects of MFF in hypoxia-treated PAMSCs were negatively regulated by miR-340-5p and depended on the regulation on SIRT1/3 pathway. These results provided evidences that miR-340-5p regulated MFF-SIRT1/3 axis to improve mitochondrial homeostasis and proliferation-apoptosis imbalance of hypoxia-treated PAMSCs, which provided a theoretical basis for the prevention and treatment of PAH.

Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice.

BACKGROUND: Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. METHODS: Wild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc. RESULTS: The surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα-/- mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]). CONCLUSIONS: After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

Telemedicine for Preventing and Treating Pressure Injury After Spinal Cord Injury: Systematic Review and Meta-analysis.

BACKGROUND: Pressure injury is a common complication after a spinal cord injury. Long-term multidisciplinary follow-up is difficult after such patients have been discharged. Telemedicine promises to provide convenient and effective support for the prevention and treatment of pressure injury, but previous attempts to demonstrate that have produced inconsistent results. OBJECTIVE: The aim of this study is to evaluate the effectiveness of telemedicine in preventing and treating pressure injury among community-dwelling patients with spinal cord injury, and determine which telemedicine form is more effective. METHODS: This systematic review was performed according to the PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Network Meta-Analysis) standards. Ten databases were searched to identify randomized controlled trials and quasi-experimental studies related to the effectiveness of telemedicine intervention in patients with spinal cord injury. Two researchers worked independently and blindly selected studies, extracted data, and assessed the risk of bias. The results were described as relative risk (RR) and weighted mean difference and 95% CI. RESULTS: The 35 studies comprised 25 randomized controlled trials and 10 quasi-experimental studies involving 3131 patients. The results showed that telemedicine can significantly (P<.05) reduce the incidence of pressure injury (RR 0.24, 95% CI 0.14-0.41; P<.05; I2=0%), promote faster healing (RR 0.73, 95% CI 0.62-0.85; P<.05; I2=0%), and yield lower scores on the pressure ulcer scale of healing (weighted mean difference=-1.98, 95% CI -3.51 to -0.46; P<.05; I2=0%). Cumulative ranking estimates showed that combining telemedicine with conventional intervention (93.5%) was the most effective approach. CONCLUSIONS: Telemedicine is a feasible way to prevent pressure injury among patients with spinal cord injuries. It can decrease the incidence and severity of pressure injury and accelerate patients' healing without imposing economic burden. It is best used in tandem with other, more conventional interventions. Due to the limited quality and quantity of included studies, large-scale and well-designed randomized controlled trials are warranted.

Basaloid squamous cell carcinoma of the hypopharynx: an analysis of 213 cases.

PURPOSE: Basaloid squamous cell carcinoma (BSCC) is a rare aggressive variant of squamous cell carcinoma (SCC) with a poor prognosis. No large series of exclusively hypopharyngeal BSCC patients have been previously reported. Therefore, this retrospective population-based study aims to explain the patient demographics, clinicopathologic characteristics, incidence, and survival outcomes of hypopharyngeal BSCC and how it relates to conventional-type SCC. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results database registry was queried for patients diagnosed with hypopharyngeal BSCC and conventional-type SCC between 2001 and 2016. RESULTS: The incidence of hypopharyngeal BSCC from 2001 to 2016 was 0.0161 per 100,000 individuals. The BSCC group comprised 213 patients, and the SCC group 7958 patients. The majority of BSCCs were considered high grade (Grade III/IV, 89.58%). Most BSCC patients were diagnosed at an advanced stage (American Joint Committee on Cancer [AJCC] stage IV, 65.38%). The 1-, 5-, and 10-year disease-specific survival (DSS) rates for hypopharyngeal BSCC were 84.10%, 57.40%, and 46.20%, respectively. Multivariate analysis, after adjustment for sex, age, race, tumor location, grade, and AJCC stage, showed that patients with BSCC had significantly better DSS than those with conventional-type SCC. Surgery with radiation contributed to a favorable DSS for BSCC patients in comparison with other treatments. CONCLUSION: This analysis of the largest hypopharyngeal BSCC series indicates a better prognosis for this pathologic type compared with conventional-type hypopharyngeal SCC. Multimodality treatment with surgery and radiation may result in a favorable prognosis for hypopharyngeal BSCC patients.

Sevoflurane Induces Neurotoxicity in the Animal Model with Alzheimer's Disease Neuropathology via Modulating Glutamate Transporter and Neuronal Apoptosis.

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer's disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background.

Abnormal phosphorylation of tau protein and neuroinflammation induced by laparotomy in an animal model of postoperative delirium.

Postoperative delirium (POD) is an acute neuropsychological disturbance after surgery, whose prevalence is related with advancing age. Neuroinflammation and abnormal tau phosphorylation that commonly presenting in Alzheimer's disease (AD) may contribute to the progression and duration of POD. To study the acute influence of surgery on cognitive function, wild type male C57BL/6 N mice were randomly divided into three groups: Control (CON), Laparotomy at 4 h and 24 h (LAP-4 h, LAP-24 h), then subjected to laparotomy under sevoflurane anaesthesia. The cognitive performance, peripheral and central inflammatory responses and tau phosphorylation levels were evaluated at 4 h and 24 h postoperatively. When LAP4-hrs displayed anxiety behaviors with high mRNA levels of inflammatory cytokines, such as interleukin-1ß (IL-1ß), IL-6, IL-8, TNF-α and MCP-1 in the liver, and IL-8 in the hippocampus, results at 24 h were different. In the liver, only IL-10 protein was obviously elevated, but in the hippocampus, both pro- and anti-inflammatory cytokines were significantly decreased whilst the elimination of anxiety. The activity of major related kinases and phosphatases was remarkably changed which may contribute to the dephosphorylated tau protein. With tremendous neuropathological changes and significant numbers of activated microglias and astrocytes observed in the sub-regions of hippocampus, the memory impairment existed at both 4 h and 24 h. Since the association of dephosphorylated tau with POD, these findings may supply novel implications for the understanding of tauopathies and as a theoretical basis for preventions from the postoperative cognitive dysfunction (POCD).

Interleukin-22 Plays a Protective Role by Regulating the JAK2-STAT3 Pathway to Improve Inflammation, Oxidative Stress, and Neuronal Apoptosis following Cerebral Ischemia-Reperfusion Injury.

The interleukins (ILs) are a pluripotent cytokine family that have been reported to regulate ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. IL-22 is a member of the IL-10 superfamily and plays important roles in tissue injury and repair. However, the effects of IL-22 on ischemic stroke and cerebral I/R injury remain unclear. In the current study, we provided direct evidence that IL-22 treatment decreased infarct size, neurological deficits, and brain water content in mice subjected to cerebral I/R injury. IL-22 treatment remarkably reduced the expression of inflammatory cytokines, including IL-1ß, monocyte chemotactic protein- (MCP-) 1, and tumor necrosis factor- (TNF-) α, both in serum and the ischemic cerebral cortex. In addition, IL-22 treatment also decreased oxidative stress and neuronal apoptosis in mice after cerebral I/R injury. Moreover, IL-22 treatment significantly increased Janus tyrosine kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 phosphorylation levels in mice and PC12 cells, and STAT3 knockdown abolished the IL-22-mediated neuroprotective function. These findings suggest that IL-22 might be exploited as a potential therapeutic agent for ischemic stroke and cerebral I/R injury.

Specific Biomarkers of Prostate Cancer-Associated Ischemic Stroke: A Case-Control Study.

BACKGROUND Ischemic stroke in cancer patients is associated with poor prognosis. However, the specific biomarkers of cancer-associated ischemic stroke (CaIS) have not been well defined. MATERIAL AND METHODS A retrospective study was conducted on PCaIS patients. Clinical data and laboratory and imaging findings were collected. Multivariable logistic regression analysis was used to analyze the independent risk factors for PCaIS. A multiple model combining the independent risk factors of PCaIS was developed using the receiver operating characteristic (ROC) and area under the ROC curve (AUC). RESULTS A total of 83 PCaIS patients and 83 prostate cancer (PCa) patients were included. PCaIS patients had higher levels of D-dimer, neutrophil-to-lymphocyte ratio (NLR), and total prostate-specific antigen (T-PSA). In the multivariate analysis, D-dimer [OR=1.001, 95% CI: 1.00,1.00, P=0.002], NLR [OR=1.12, 95% CI: 1.04,1.22, P=0.005], and T-PSA [OR=6.275, 95% CI: 2.57,15.31, P<0.001] were independent risk factors of PCaIS. Additionally, the AUC of the multiple model of PCaIS was 0.815 (95% CI, 0.750-0.869), with sensitivity of 81.71% and specificity of 70.21%. CONCLUSIONS Elevated levels of D-dimer and T-PSA and increased NLR are independent risk factors of PCaIS. The multiple model of PCaIS can be a specific biomarker and is a reliable predictor of development of PCaIS.

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

BACKGROUND: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. METHODS: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. RESULTS: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1ß, IL-6, and TNF-α), and hippocampus (IL-1ß and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation.

BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs-exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC)-tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation.

Distinct Prognostic Values of Alcohol Dehydrogenase Family Members for Non-Small Cell Lung Cancer.

BACKGROUND Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The relationships of alcohol dehydrogenase (ADH) enzymes, encoded by the genes ADH1 (1A), ADH1B (ADH2), ADH1C (ADH3), ADH4, ADH5, ADH6, and ADH7, with NSCLC have not been studied. The aim of this study was to explore the associations between NSCLC prognosis and the expression patterns of ADH family members. MATERIAL AND METHODS The online resource Metabolic gEne RApid Visualizer was used to assess the expression patterns of ADH family members in normal and primary lung tumor tissues. The GeneMANIA plugin of Cytoscape software and STRING website were used to evaluate the relationships of the 7 ADH family members at the gene and protein levels. Gene ontology enrichment analysis and KEGG pathway analysis were performed using DAVID. The online website Kaplan-Meier Plotter was used to construct survival curves between NSCLC and ADH isoforms. RESULTS The prognosis of patients with high expression levels of the ADH1B, ADH1C, ADH4, and ADH5 genes was better than those with low expression in adenocarcinoma and all (containing adenocarcinoma and squamous cell cancer) histological types (all P<0.05). Low expression of ADH7 was associated with a better prognosis in patients with both the adenocarcinoma and squamous cell cancer histological types (P=9e-05). Moreover, expression of ADH family members was associated with smoking status, clinical stage, and chemotherapy status. CONCLUSIONS ADH1B, ADH1C, ADH4, ADH5, and ADH7 appear to be useful biomarkers for the prognosis of NSCLC patients.