ProBDNF contributed to patrolling monocyte infiltration and renal damage in systemic lupus erythematosus.

Monocyte aberrations have been increasingly recognized as contributors to renal damage in systemic lupus erythematosus (SLE), however, recognition of the underlying mechanisms and modulating strategies is at an early stage. Our studies have demonstrated that brain-derived neurotrophic factor precursor (proBDNF) drives the progress of SLE by perturbing antibody-secreting B cells, and proBDNF facilitates pro-inflammatory responses in monocytes. By utilizing peripheral blood from patients with SLE, GEO database and spontaneous MRL/lpr lupus mice, we demonstrated in the present study that CX3CR1+ patrolling monocytes (PMo) numbers were decreased in SLE. ProBDNF was specifically expressed in CX3CR1+ PMo and was closely correlated with disease activity and the degree of renal injury in SLE patients. In MRL/lpr mice, elevated proBDNF was found in circulating PMo and the kidney, and blockade of proBDNF restored the balance of circulating and kidney-infiltrating PMo. This blockade also led to the reversal of pro-inflammatory responses in monocytes and a noticeable improvement in renal damage in lupus mice. Overall, the results indicate that the upregulation of proBDNF in PMo plays a crucial role in their infiltration into the kidney, thereby contributing to nephritis in SLE. Targeting of proBDNF offers a potential therapeutic role in modulating monocyte-driven renal damage in SLE.

P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

The regulatory role of ProBDNF in monocyte function: Implications in Stanford type-A aortic dissection disease.

Brain-derived neurotrophic factor precursor (proBDNF) has been reported to strengthen the dysfunction of monocytes/macrophages in animal studies. However, it is still unknown the roles of proBDNF in the dysfunction of monocytes in the inflammatory diseases in humans. In the present study, we showed that proBDNF and pan neurotrophic receptor p75 were significantly upregulated in monocytes from healthy donors (HD) after lipopolysaccharide treatment. Exogenous proBDNF treatment upregulated CD40 and proinflammatory cytokines expression in monocytes including interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. In Stanford type-A acute aortic dissection (AAD) patients, proBDNF was upregulated in CD14+ CD163+ CX3CR1+ M2- but not CD14+ CD68+ CCR2+ M1-like monocytes. In addition, sera from AAD patients activated gene expression of proinflammatory cytokines in cultured PBMCs from HD, which was attenuated by proBDNF monoclonal antibody (Ab-proB) treatment. These findings suggested that upregulation of proBDNF in M2-like monocytes may contribute to the proinflammatory response in the AAD.

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells.

BACKGROUND: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. METHODS: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg-1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. RESULTS: In the septic mice, cognitive function was impaired, the percentage of CD4+ T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the anti-inflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg-1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4+ T cells. Intraperitoneal injection of McAb-proB (100 µg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4+ T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 µg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4+ T cells in cultured splenocytes from septic mice (P = 0.0021). CONCLUSION: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4+ T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/anti-inflammatory homeostasis.

Unveiling the impact of airways: A comparative analysis of oropharyngeal and nasopharyngeal airways in painless fiberoptic bronchoscopy.

Background: This study compared the efficacy of oropharyngeal airways (OA) and nasopharyngeal airways (NA) in maintaining oxygenation during painless fiberoptic bronchoscopy (PFB) in patients sedated with remimazolam besylate. Methods: Two hundred and fifty-two patients were randomized to the OA or NA group. Remimazolam besylate was used for anesthesia induction and maintenance in both groups. We measured and recorded several physiological parameters, including mean arterial pressure, heart rate and oxygen saturation (SpO2), at various time points: before anesthesia (T1), after anesthesia induction (T2), immediately after the bronchoscope reached the trachea (T3), during the procedure (T4), and 5 min after transfer to the post-anesthesia care unit (T5). The incidence and frequency of hypoxemia, minimum SpO2 during the procedure and patient awakening time after flumazenil administration were also recorded. Additionally, the relationship between minimum SpO2 and body mass index (BMI) was investigated. Results: Patients in the NA group experienced a higher incidence of hypoxemia compared to the OA group. Patients in the OA group maintained higher SpO2 levels at T3 and had a higher minimum SpO2 during the procedure than the NA group. Furthermore, a significant negative correlation was observed between minimum SpO2 and BMI. Following flumazenil anesthesia reversal, nearly 97 % of patients awakened within 1 min. Conclusions: This study suggests that OA may provide a better safety profile than NA by preserving respiratory function during PFB.

Platelets reprogram monocyte functions by secreting MMP-9 to benefit postoperative outcomes following acute aortic dissection.

Platelets have a great ability to modulate immune responses. Monocyte-platelet aggregates (MPAs) are associated with the pathogenesis of cardiac disease. Notably, a low preoperative platelet count often indicates poor postoperative recovery following acute aortic dissection (AAD). The functions of platelets and MPAs in AAD, however, remain poorly understood. We found that, despite decreased platelet counts, platelets were also activated in AAD patients, with significant alterations in immune-modulating mediators. Of interest, monocytes in AAD patients had a suppressed immune status, which was correlated with poor outcomes following surgery. Interestingly, platelets preferentially aggregated with monocytes, and the levels of MPAs were related to recovery after surgical repair in AAD patients. Platelets restored suppressed monocyte functions in AAD patients by forming aggregates and partly by secreting matrix metalloproteinase-9 (MMP-9). Thus, the results point to a previously unknown mechanism for platelets involving monocyte reprogramming, which may improve postoperative outcomes following complex cardiovascular surgery.

Brain-Derived Neurotrophic Factor Precursor Contributes to a Proinflammatory Program in Monocytes/Macrophages After Acute Myocardial Infarction.

Background The imbalance of monocyte/macrophage polarization toward the preferential proinflammatory phenotype and a lack of normal inflammation resolution are present in acute myocardial infarction (AMI). Our previous study showed that upregulation of brain-derived neurotrophic factor precursor (proBDNF) in M2-like monocytes may contribute to the proinflammatory response in the Stanford type-A acute aortic dissection. The present study aimed to investigate the role of proBDNF signaling in monocytes/macrophages in the progress of AMI. Methods and Results We observed the upregulation of proBDNF in the proinflammatory monocytes of patients with AMI. The upregulation of proBDNF was also observed in the circulating proinflammatory Ly6Chigh monocytes and cardiac F4/80+CD86+ macrophages 3 days after AMI in a mice model. To neutralize proBDNF, the mice subjected to AMI were injected intraperitoneally with a monoclonal anti-proBDNF antibody. Echocardiography, 2,3,5-triphenyltetrazolium chloride staining, and positron emission tomography/computed tomography results demonstrate that monoclonal anti-proBDNF antibody treatment further impaired cardiac functions, increased infarct size, and exacerbated the proinflammatory state. Moreover, the level of proinflammatory Ly6Chigh in the blood and F4/80+CD86+ in the heart was further increased in monoclonal anti-proBDNF antibody mice. RNA sequencing revealed that matrix metalloprotease-9 protein level was dramatically increased, along with the activated proinflammatory-related cytokines. Matrix metalloprotease-9 inhibitor treatment attenuated the deteriorated effect of monoclonal anti-proBDNF antibody on cardiac function and infarct areas. Conclusions Our study shows that endogenous proBDNF in monocytes/macrophages may exert protective roles in cardiac remodeling after AMI by regulating matrix metalloprotease-9 activity.

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Collembola are among the most abundant and integral group in soil decomposers. They channel C and nutrients from basic food resources to higher trophic levels, and therefore play an irreplaceable role in the underground food web. Collembola community would be altered dramatically by increasing N and P deposition. However, we still know little about how Collembola respond to N and P inputs, which will largely retard our steps to understand the ecological functions of collembolans, material circulation and energy flow of the underground food web, and even C cycling in terrestrial ecosystem. The different classification rules for Collembola functional groups have led to poor comparability of research results in the literature. This review proposed three taxonomic criteria of Collembola and four common research means on trophic relationships, summarized the mechanisms underlying the responses of Collembola to N and P addition alone and coadded. Overall, Collembola generally shows a negative response to N addition namely community density decreases, while a positive response to P addition in most ecosystems. The situation was more complicated under the combined N and P application. In the future, the research of Collembola response to N and P deposition should focus on the scientific taxa of Collembola functional groups, improving the research methods of trophic structure of Collembola, and the mechanism underlying the impacts of N and P interaction on Collembola community.

Up-regulation of proBDNF/p75NTR signaling in antibody-secreting cells drives systemic lupus erythematosus.

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like mice. The increased proBDNF+ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75NTR in CD19+ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.

Early-life sevoflurane exposure impairs fear memory by suppressing extracellular signal-regulated kinase signaling in the bed nucleus of stria terminalis GABAergic neurons.

Sevoflurane exposure in neonates induces long-term impairment of learning and memory; however, its effect on cognition in the later developmental period and the underlying mechanisms remain unclear. In the present study, we showed that multiple sevoflurane exposures impaired fear memory at long retention delays in neonatal (postnatal day 7) and preadolescent mice (postnatal day 22), but not in mice at older ages. After the fear memory test, expression of phosphorylated extracellular signaling-regulated kinase (p-ERK) and c-fos were elevated in the bed nucleus of the stria terminalis (BNST) and central amygdala, but not in the hippocampus or prefrontal cortex. The upregulation of p-ERK was restricted to populations of γ-aminobutyric acid (GABAergic) neurons and was inhibited by multiple sevoflurane exposures. Intra-BNST injection of ERK inhibitor also impaired fear memory at long retention delays. In contrast, intra-BNST injection of ERK agonist attenuated impaired fear memory caused by repeated sevoflurane exposures. Injection of sevoflurane in the BNST but not the caudate putamen impaired the fear memory at long retention delays in preadolescent mice. Finally, chemogenetic activation of BNST GABAergic neurons by designer receptors exclusively activated by designer drug (DREADD) reversed the impaired fear memory at long retention delays by multiple sevoflurane exposures. These findings suggest that multiple sevoflurane exposures impaired fear memory at long retention delays in preadolescent mice by suppressing the ERK signaling in GABAergic neurons in the BNST.

The first copper(I) complex of anthrahydrazone with potential ROS scavenging activity showed significant in vitro anticancer activity by inducing apoptosis and autophagy.

Based on the anticancer pharmacophore of anthrahydrazone and quinoline, a new quinolylanthrahydrazone ligand, 9-AQH (anthracene-9-quinolylhydrazone), was synthesized to further afford four metal complexes, [CoII(9-AQH)(NO3)2(H2O)] (1), [NiII(9-AQH)2(H2O)2]·2NO3 (2), [CuI(9-AQH)2]·NO3 (3), [ZnII(9-AQH)2(NO3)]·NO3 (4), determined by X-ray single crystal diffraction analysis. The reaction of Cu(NO3)2 with 9-AQH formed the stable and repeatable copper(I) complex 3. In vitro screening demonstrated only 3 showed significant and broad-spectrum anticancer activity, indicating that Cu(I) played a key role in exerting the anticancer activity. In solution, Cu(I) was not naturally oxidized to Cu(II) suggested by 1H-NMR (Nuclear Magnetic Resonance) and EPR (Electron Paramagnetic Resonance) analysis. The presence of 3 could also catalyze the H2O2 system to give hydroxyl free radicals, suggested by further EPR and electrophoresis assay. At the cellular level, although no obvious Cu(II) signals were detected and the total ROS (Reactive Oxygen Species) scavenging in the tumor cells treated with 3, the potential redox property between Cu(I)/Cu(II), as a key role, should not be denied for the significant anticancer activity of 3, considering the much complicated circumstance and other reductive substances in cells. The anticancer mechanism of 3 on the most sensitive MGC-803 cells pointed to significant cell apoptosis through mitochondrial pathway, rather than cell cycle arrest. While the autophagy observed in tumor cells treated by 3 suggested its complicated anticancer mechanism, and whether there was an intrinsic correlation still needed to be further investigated.

Early-Life Multiple Sevoflurane Exposures Alleviate Long-term Anxiety-Like Behaviors in Mice via the proBDNF/ERK Pathway.

Early-life multiple anesthetics exposure causes neurotoxicity and hence cognitive dysfunction on developing brain. However, the effects of early-life multiple sevoflurane exposures on emotional changes, especially upon stress, are far beyond understood. In young male C57BL6/J mice, the present study showed that 3% sevoflurane inhalation for 2 h in three consecutive days did not influence anxiety-like behaviors as measured by open field test, light dark transition, and elevated plus maze test. In addition, foot shocks stress induced both the short- and long-term anxiety-like behaviors. However, triple sevoflurane exposures ameliorated the long-term anxiety-like behaviors induced by the foot shocks. In parallel, foot shocks stress upregulated the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and brain-derived neurotrophic factor precursor (proBDNF) in the anterior cingulate cortex (ACC), which were significantly inhibited by triple sevoflurane exposures. Immunofluorescence further indicated that the increased p-ERK was mainly expressed in the proBDNF-positive staining cells. Intra-ACC injection of recombinant proBDNF protein upregulated the p-ERK expression and blocked the anxiolytic effect of sevoflurane exposure on long-term anxiety-like behaviors. Therefore, our study demonstrated that multiple sevoflurane exposures alleviate long-term anxiety-like behaviors upon acute stress in young mice by inhibiting proBDNF-ERK signaling in the ACC.

The copper(II) complexes of new anthrahydrazone ligands: In vitro and in vivo antitumor activity and structure-activity relationship.

Two new copper(II) complexes, 9-PMAH-Cu (1) and 9-FPMAH-Cu (2), of anthrahydrazone were synthesized and structurally characterized, in which 9-FPMAH (9-(4'-trifluoromethyl)-pyrimidine anthrahydrazone) is the 4'-CF3 derivative of 9-PMAH (9-pyrimidine anthrahydrazone). Both complexes 1 and 2 showed similar intercalative binding modes towards DNA and might compete with the typical DNA intercalator, GelRed, in the same binding site. They could also act as topoisomerase (type I) suppressor to effectively inhibit its activity, in which complex 1 was more effective than 2. The in vitro antitumor screening indicated that complex 1 displayed much higher antiproliferative ability than 2 and cisplatin towards all the tested tumor cell lines. On the other hand, complex 1 also showed high cytotoxicity against human normal liver cell line HL-7702, suggesting it is a potential high cytotoxic antitumor candidate. While it was also suggested that the loss of activity of complex 2 might be due to the presence of 4'-CF3 on the pyrimidine ring. Studies on the cellular level showed that complex 1 could arrest the cell cycle of the most sensitive T-24 cells at G2/M phase and induced cell apoptosis. Complex 1 further showed a significant suppression on the tumor growth on the T-24 tumor xenograft mouse model, but not reduced the body weight. Especially, complex 1 could retain its coordination state in H2O even in the presence of HSA. The results suggests that complex 1 is of enough safety to be considered as a promising anticancer candidate by combining the bioactive Cu(II) and the anthrahydrazone pharmacophore.

Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: a randomized controlled preliminary trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a serious complication after surgery, especially in elderly patients. The anesthesia technique is a potentially modifiable risk factor for POCD. This study assessed the effects of dexmedetomidine, propofol or midazolam sedation on POCD in elderly patients who underwent hip or knee replacement under spinal anesthesia. METHODS: The present study was a prospective randomized controlled preliminary trial. From July 2013 and December 2014, a total of 164 patients aged 65 years or older who underwent hip or knee arthroplasty at China-Japan Friendship Hospital and 41 non-surgical controls were included in this study. Patients were randomized in a 1:1:1 ratio to 3 sedative groups. All the patients received combined spinal-epidural anesthesia (CSEA) with midazolam, dexmedetomidine or propofol sedation. The sedative dose was adjusted to achieve light sedation (bispectral index[BIS] score between 70 and 85). All study participants and controls completed a battery of 5 neuropsychological tests before and 7 days after surgery. One year postoperatively, the patients and controls were interviewed over the telephone using the Montreal cognitive assessment 5-minute protocol. RESULTS: In all, 60 of 164 patients (36.6%) were diagnosed with POCD 7 days postoperatively, POCD incidence in propofol group was significantly lower than that in dexmedetomidine and midazolam groups (18.2% vs. 40.0%, 51.9%, χ = 6.342 and 13.603, P = 0.012 and < 0.001). When the patients were re-tested 1 year postoperatively, the incidence of POCD was not significantly different among the 3 groups (14.0%, 10.6% vs. 14.9%, χ = 0.016 and 0.382, P = 0.899 and 0.536). CONCLUSION: Among dexmedetomidine, propofol and midazolam sedation in elderly patients, propofol sedation shows a significant advantage in term of short-term POCD incidence.