CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral Deficits in a Mouse Model of Sepsis-Associated Encephalopathy.

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1ß, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.

Current evidence for J147 as a potential therapeutic agent in nervous system disease: a narrative review.

Curcumin has anti-inflammatory, antioxidant, and anticancer effects and is used to treat diseases such as dermatological diseases, infection, stress, depression, and anxiety. J147, an analogue of curcumin, is designed and synthesized with better stability and bioavailability. Accumulating evidence demonstrates the potential role of J147 in the prevention and treatment of Alzheimer's disease, diabetic neuropathy, ischemic stroke, depression, anxiety, and fatty liver disease. In this narrative review, we summarized the background and biochemical properties of J147 and discussed the role and mechanism of J147 in different diseases. Overall, the mechanical attributes of J147 connote it as a potential target for the prevention and treatment of neurological diseases.

Dual stimulus responsive borosilicate glass (BSG) scaffolds promote diabetic alveolar bone defectsrepair by modulating macrophage phenotype.

The regeneration of alveolar bone is still clinical challenge, particularly accompanied with diabetes, causing metabolic disorder with a protracted low-grade inflammatory phenotype. As a result, the anticipated loading of biomaterials is highly suspicious in spontaneous modulation of cells function, which is mostly disturbed by constant inflammation. In this study, we developed glucose and hydrogen peroxide dual-responsive borosilicate glass (BSG) scaffolds loaded with epigallocatechin gallate (EGCG) to synergistically modulate the abnormal inflammation of diabetic alveolar bone defects. It was found that the release of EGCG by BSG could directly regulate the shift of macrophages from M1 to the M2 phenotype by promoting autophagy and lessening the inhibition of autophagic flux. Moreover, EGCG can also indirectly regulate the polarization phenotype of macrophages by reducing the activation of NF-κb in stem cells and restoring its immunoregulatory capacity. Therefore, the addition of EGCG to BSG scaffold in diabetes allows for a more striking modulation of the macrophage phenotype in a timely manner. The altered macrophage phenotype reduces local inflammation and thus increases the ability to repair diabetic alveolar bone, showing promise for the treatment of alveolar defect in diabetic patients.

Unusual Surface Coagulation Activation Patterns of Crystalline and Amorphous Silicate-Based Biominerals.

Activation of coagulation cascades, especially FX and prothrombin, prevents blood loss and reduces mortality from hemorrhagic shock. Inorganic salts are efficient but cannot stop bleeding completely in hemorrhagic events, and rebleeding carries a significant mortality risk. The coagulation mechanism of biominerals has been oversimplified in the past two decades, limiting the creation of novel hemostats. Herein, at the interface, the affinity of proteins, the protease activity, fibrinolysis, hydration shell, and dynamic microenvironment are monitored at the protein level. Proteomic analysis reveals that fibrinogen and antithrombin III's affinity for kaolin's interface causes a weak thrombus and rebleeding during hemostasis. Inspiringly, amorphous bioactive glass (BG) with a transient-dynamic ion microenvironment breaches the hydration layer barrier and selectively and slightly captures procoagulant components of kiniogen-1, plasma kallikrein, FXII, and FXI proteins on its interface, concurrently generating a continuous biocatalytic interface to rapidly activate both intrinsic and extrinsic coagulation pathways. Thus, prothrombin complexes are successfully hydrolyzed to thrombin without platelet membrane involvement, speeding production of high-strength clots. This study investigates how the interface of inorganic salts assists in coagulation cascades from a more comprehensive micro-perspective that may help elucidate the clinical application issues of kaolin-gauze and pave the way to new materials for managing hemorrhage.

Dietary intake of fructose increases purine de novo synthesis: A crucial mechanism for hyperuricemia.

Background: Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine de novo synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine de novo synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine de novo synthesis in a hepatic cell line and livers of mice. Materials and methods: RNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay. Results: Metabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA. Conclusion: This study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.

The effect of evidence-based cluster nursing intervention on the incidences of delirium and the prognoses of ICU patients.

OBJECTIVE: This study explored the effect of evidence-based cluster nursing intervention on the incidences of delirium and the prognoses of ICU patients. METHODS: 108 ICU patients admitted to our hospital from January 2020 to June 2020 were recruited as the study cohort and randomly divided into a control group and an observation group, with 54 cases in each group. The patients in the control group underwent routine nursing intervention, and the patients in the observation group underwent evidence-based cluster nursing intervention. The incidences of delirium, the durations of the mechanical ventilation, the ICU hospitalization durations, as well as the satisfaction levels in the two groups of patients were compared. RESULT: The incidences of delirium in the observation group were conspicuously lower than they were in the control group (14.81%, 40.74%, X 2 = 9.0462, P = 0.0026). The duration of the delirium in the observation group was conspicuously lower than it was in the control group (2.87 ± 1.28), (5.21 ± 1.33), t = 9.3155, P = 0.0000. The durations of the mechanical ventilation and the ICU hospitalizations in the observation group were conspicuously shorter than they were in the control group. The differences were statistically significant (P < 0.05). The nursing satisfaction levels in the observation group were conspicuously higher than they were in the control group (94.44%, 72.22%, X 2 = 9.6000, P = 0.0019). There was no significant difference in the in-hospital mortality between the two groups (X2 = 2.1862, 0.1393). CONCLUSION: Evidence-based cluster nursing intervention can conspicuously reduce the incidences of delirium, shorten the durations of the mechanical ventilation and the ICU stays, and improve patient prognosis, so it is worthy of clinical application.

Severe pneumonia caused by Parvimonas micra: a case report.

BACKGROUND: Parvimonas micra (P. micra) is a gram-positive anaerobic coccus that is detected widely on the skin, in the oral mucosa and in the gastrointestinal tract. In certain circumstances, P. micra can cause abdominal abscesses, bacteraemia and other infections. To the best of our knowledge, there have been no case reports describing the biological characteristics of P. micra-related pneumonia. These bacteria do not always multiply in an aerobic organ, such as the lung, and they could be easily overlooked because of the clinical mindset. CASE PRESENTATION: A 35-year-old pregnant woman was admitted to the emergency department 4 weeks prior to her due date who was exhibiting 5 points on the Glasgow coma scale. A computed tomography (CT) scan showed a massive haemorrhage in her left basal ganglia. She underwent a caesarean section and brain surgery before being admitted to the ICU. She soon developed severe pneumonia and hypoxemia. Given that multiple sputum cultures were negative, the patient's bronchoalveolar lavage fluid was submitted for next-generation sequencing (NGS) to determine the pathogen responsible for the pneumonia; as a result, P. micra was determined to be the causative pathogen. Accordingly the antibiotic therapy was altered and the pneumonia improved. CONCLUSION: In this case, we demonstrated severe pneumonia caused by the anaerobic organism P. micra, and the patient benefited from receiving the correct antibiotic. NGS was used as a method of quick diagnosis when sputum culture failed to distinguish the pathogen.