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Acute type A aortic dissection (ATAAD) is a lethal pathological process within the aorta with high mortality and morbidity. T lymphocytes are perturbed and implicated in the clinical outcome of ATAAD, but the exact characteristics of T cell phenotype and its underlying mechanisms in ATAAD remain poorly understood. Here we report that CD4 + T cells from ATAAD patients presented with a hypofunctional phenotype that was correlated with poor outcomes. Whole transcriptome profiles showed that ferroptosis and lipid binding pathways were enriched in CD4 + T cells. Inhibiting ferroptosis or reducing intrinsic reactive oxygen species limited CD4 + T cell dysfunction. Mechanistically, CD36 was elevated in CD4 + T cells, whose blockade effectively alleviated palmitic acid-induced ferroptosis and CD4 + T cell hypofunction. Therefore, targeting the CD36-ferroptosis pathway to restore the functions of CD4 + T cells is a promising therapeutic strategy to improve clinical outcomes in ATAAD patients., (© 2024. The Author(s).)

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI., Competing Interests: Declaration of Competing Interest We state explicitly that no potential competing interests exist., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study investigated the concentrations of atmospheric pollutants in the urban area of Suzhou from May to June, 2017-2021. The variation characteristics and annual changes of ozone (O 3 ), nitrogen oxide (NO x ), total oxidant (O x ), carbon monoxide (CO), and volatile organic compounds (VOCs) were analyzed. The O 3 formation mechanism and its annual changes were studied using an Observation-Based Model (OBM), and VOCs source apportionments and their trends were discussed. The results indicated that ① The volume fractions of O x and the concentrations of NO x and CO have decreased in the urban area of Suzhou in recent years, while the volume fractions of VOCs have increased, and sufficient photochemical conditions for O 3 formation still existed during polluted days. ② The O 3 -NO x -VOCs sensitivity in Suzhou was in the VOCs-limited regime. The long-term reduction ratio between VOCs and NO x should not be less than 5:1, and aromatics and alkenes were the critical VOCs for mitigating O 3 pollution. ③ The results of VOCs source apportionment revealed that industrial emissions, gasoline vehicle exhaust, and diesel engine exhaust were the major sources of VOC emissions in Suzhou. Industrial emissions and solvent usage declined from 2017 to 2021; however, gasoline vehicle exhaust and gasoline evaporation, which possess higher O 3 formation potential(OFP), increased significantly. ④ The OFP source apportionments results indicated that controlling VOC emissions from solvent usage and gasoline vehicle exhaust is crucial for O 3 pollution control in Suzhou.

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., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Carotid intima-media thickness (CIMT) is a noninvasive marker of atherosclerosis, a typical pathologic process underlying cardiovascular diseases (CVDs). It is essential to explore the relationships between weight loss and the reduction of CIMT., Study Design: This was an updated systematic review and meta-analysis., Methods: A systematic literature search was conducted to collect relevant clinical trials. The pooled results of meta-analyses were assessed by weighted mean difference (WMD) and the corresponding 95 % confidence interval (95% CI)., Results: Thirty-three articles involving 2273 participants were collected in this meta-analysis. Among all participants with obesity, the pooled mean of weight loss was -23.26 kg (95% CI: -27.71 to -18.81), and the pooled mean change of CIMT was -0.06 mm (95% CI: -0.08 to -0.04). Compared with Non-surgical interventions, Surgical ones could lead to much higher weight loss (P between groups < 0.001). A more significant CIMT reduction was identified among Surgical intervention patients than among Non-surgical intervention participants (P between groups < 0.001)., Conclusions: Effective interventions, especially Surgical interventions, could reduce the weight of patients with obesity, followed by the decline of CIMT, which might further disturb atherosclerosis progression and lower CVD risk., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Tumor cells and macrophages communicate through the secretion of various cytokines to jointly promote the malignant development of cancers. We synthesized and characterized an oxoaporphine Pr(III) complex (PrL 3 (NO 3 ) 3 ) and found that it inhibits hepatocellular carcinoma (HCC) progression and metastasis by disrupting HCC cell-macrophage crosstalk. PrL 3 (NO 3 ) 3 treatment upregulated CD86, TNF-α, and IL-1β and downregulated CD163, CD206, CCL2, and VEGFA in macrophages. Our mRNA-Seq results demonstrated that PrL 3 (NO 3 ) 3 inhibited macrophage M2-like polarization by inhibiting the AMPK pathway and activating the NF-κB pathway by upregulating RelA/p65 Ser536 phosphorylation. This kind of macrophage polarization significantly inhibited HCC cell proliferation, migration, and invasion. In addition, PrL 3 (NO 3 ) 3 inhibited the migration, invasion, and chemotaxis of HCC cells by downregulating the expression of EMT-related markers and CCL2. hTFtarget database analysis revealed that PrL 3 (NO 3 ) 3 inhibited NF-κB nuclear translocation by upregulating RelA/p65 Ser536 phosphorylation in HCC cells, thereby downregulating the expression of Snail and CCL2. HCC tissue microarray analysis revealed that downregulation of RelA/p65 Ser536 phosphorylation is a driving event in HCC malignant progression. In conclusion, PrL 3 (NO 3 ) 3 effectively inhibits HCC cell-macrophage crosstalk by upregulating RelA/p65 Ser536 phosphorylation. This is the first report of a lanthanide complex exerting regulatory effects on both tumors and tumor-associated macrophages, providing a new strategy for the development of effective antitumor drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Atypical femoral fractures (AFFs) are associated with delayed union and higher reoperation rates. Axial dynamization of intramedullary nails is hypothesized to reduce time-to-union (TTU) and fixation failure as compared to static locking., Methods: Consecutive acutely displaced AFFs fixed with long intramedullary nails across five centres between 2006 and 2021 with a minimum postoperative follow-up of three months were retrospectively reviewed. The primary outcome was TTU, compared between AFFs treated with dynamically or statically locked intramedullary nails. Fracture union was defined as a modified Radiographic Union Score for Tibial fractures score of 13 or greater. Secondary outcomes involved revision surgery and treatment failure, defined as non-union beyond 18 months or revision internal fixation for mechanical reasons., Results: A total of 236 AFFs (127 dynamically locked and 109 statically locked) were analysed with good interobserver reliability of fracture union assessment (intraclass correlation coefficient = 0.89; 95% CI = 0.82-0.98). AFFs treated with dynamized nails had significantly shorter median TTU (10.1 months; 95% CI = 9.24-10.96 vs 13.0 months; 95% CI = 10.60-15.40) (log-rank test, p = 0.019). Multivariate Cox regression revealed that dynamic locking was independently associated with greater likelihood of fracture union within 24 months (p = 0.009). Reoperations were less frequent in the dynamic locking group (18.9% vs 28.4%), although the difference was not statistically significant (p = 0.084). Static locking was an independent risk factor for reoperation (p = 0.049), as were varus reduction and lack of teriparatide use within three months of surgery. Static locking also demonstrated a higher frequency of treatment failure (39.4% vs 22.8%, p = 0.006) and was an independent predictor of treatment failure in logistic regression (p = 0.018). Other factors associated with treatment failure included varus reduction and open reduction., Conclusions: Dynamic locking of intramedullary nails in AFFs is associated with faster time to union, lower rate of non-union, and fewer treatment failures., Competing Interests: Declaration of Competing Interest Christian Fang is a shareholder of Lifespans Ltd and is also a speaker for Depuy Synthes. He has received research support from AO Foundation and Agnovos LLC. Frankie Leung is a shareholder of Lifespans Ltd and is also a speaker for Depuy Synthes, he has received research support from AO Trauma. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

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 Ly6C high 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 Ly6C high 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.

Three copper(II) complexes C1-C3 were synthesized and fully characterized as chemodynamic therapy (CDT) anticancer agents. C1-C3 showed greater cytotoxicity than their ligands toward SK-OV-3 and T24 cells. Particularly, C2 showed high cytotoxicity toward T24 cells and low cytotoxicity toward normal human HL-7702 and WI-38 cells. Mechanistic studies demonstrated that C2 oxidized GSH to GSSG and produced ˙OH, which induced mitochondrial dysfunction and ER stress, finally leading to apoptosis of T24 cells. In addition, C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.

Objective: To assess the efficacy of induction chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of FLT3-ITD(+) acute myeloid leukemia (AML) with normal karyotype. Methods: The clinical data of FLT3-ITD(+) AML patients with normal karyotype in the First Affiliated Hospital of Nanjing Medical University from Jan 2018 to March 2021 were retrospectively analyzed. Results: The study included 49 patients with FLT3-ITD(+)AML, 31 males, and 18 females, with a median age of 46 (16-59) years old. All patients received induction chemotherapy, and 24 patients received sequential allo-HSCT (transplantation group) . The median follow-up time was 465 days, the one-year overall survival (OS) from diagnosis was (70.0 ± 7.4) %, and one-year disease-free survival (DFS) was (70.3±7.4) %. The one-year OS was significantly different between the transplantation group and the non-transplantation group [ (85.2 ± 7.9) % vs (52.6 ± 12.3) %, P =0.049]. but one-year DFS [ (84.7 ± 8.1) % vs (55.2 ± 11.9) %, P =0.061] was not. No significance was found in one-year OS between patients with low-frequency and high-frequency FLT3-ITD(+) ( P >0.05) . There were 12 patients with high-frequency FLT3-ITD(+) in the transplantation and the non-transplantation groups, respectively. The one-year OS [ (68.8 ± 15.7) % in the transplantation group vs (26.2 ± 15.3) % in the non-transplantation group, P =0.027] and one-year DFS [ (45.5 ± 21.3) % in the transplantation group vs (27.8±15.8) % in the non-transplantation group, P =0.032] were significantly different between the two groups. Conclusion: Induction chemotherapy followed by allo-HSCT can enhance the prognosis of FLT3-ITD(+) patients, particularly those with FLT3-ITD high-frequency mutation.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the most invasive cancer types globally, and distant metastasis (DM) is associated with a poor prognosis. The objective of this study was designed to construct a novel nomogram and risk classification system to predict overall survival (OS) in HNSCC patients presenting with DM at initial diagnosis., Methods: HNSCC patients with initially diagnosed DM between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Firstly, all patients were randomly assigned to a training cohort and validation cohort (8:2), respectively. The Cox proportional hazards regression model was used to analyze the prognostic factors associated with OS. Then, the nomogram based on the prognostic factors and the predictive ability of the nomogram were assessed by the calibration curves, receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Finally, a risk classification system was established according to the nomogram scores., Results: A total of 1240 patients initially diagnosed with HNSCC with DM were included, and the 6-, 12- and 18-month OS of HNSCC with DM were 62.7%, 40.8% and 30%, respectively. The independent prognostic factors for HNSCC patients with DM included age, marital status, primary site, T stage, N stage, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery, radiotherapy and chemotherapy. Based on the independent prognostic factors, a nomogram was constructed to predict OS in HNSCC patients with DM. The C-index values of the nomogram were 0.713 in the training cohort and 0.674 in the validation cohort, respectively. The calibration curves and DCA also indicated the good predictability of the nomogram. Finally, a risk classification system was built and it revealed a statistically significant difference among the three groups of patients according to the nomogram scores., Conclusions: Factors associated with the overall survival of HNSCC patients with DM were found. According to the identified factors, we generated a nomogram and risk classification system to predict the OS of patients with initially diagnosed HNSCC with DM. The prognostic nomogram and risk classification system can help to assess survival time and provide guidance when making treatment decisions for HNSCC patients with DM., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ferroptosis plays a key role in aggravating the progression of spinal cord injury (SCI), but the specific mechanism remains unknown. In this study, we constructed a rat model of T10 SCI using a modified Allen method. We identified 48, 44, and 27 ferroptosis genes that were differentially expressed at 1, 3, and 7 days after SCI induction. Compared with the sham group and other SCI subgroups, the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower. These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression. Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI: STAT3, JUN, TLR4, ATF3, HMOX1, MAPK1, MAPK9, PTGS2, VEGFA, and RELA. Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3, JUN, TLR4, ATF3, HMOX1, PTGS2, and RELA mRNA levels were up-regulated and VEGFA, MAPK1 and MAPK9 mRNA levels were down-regulated. Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI. We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs, 10 miRNAs, and 12 genes. Our results help further the understanding of the mechanism underlying ferroptosis in SCI., Competing Interests: None

Objectives: The overexpansion of CD3 + B220 + cells is the hallmark and main pathological mechanism of clinical manifestations of spontaneously developed MRL/lpr mice, which are primarily used as a mouse model of SLE. Our recent report demonstrated that blocking brain-derived neurotrophic factor precursor (proBDNF) suppressed the antibody-secreting cell differentiation and proliferation and inhibited the progression of SLE; however, the effect of proBDNF blockade on these CD3 + B220 + cells in MRL/lpr mice is unclear., Methods: To explore the effect of proBDNF on CD3 + B220 + cells, MRL/lpr mice at 12 weeks old were intraperitoneally injected with monoclonal anti-proBDNF antibody (McAb-proB) or control IgG continuously for 8 weeks. The manifestations in mice were observed, and peripheral blood and splenocytes were collected and analysed via flow cytometry at 20 weeks old. In addition, splenic CD3 + B220 + cells were subjected to RNA sequencing (RNA-seq) analysis to identify transcriptomic alterations., Results: CD3 + B220 + cells in peripheral blood (p=0.0101) and spleen (p<0.0001) were expanded in MRL/lpr mice. Meanwhile, inhibition of proBDNF signalling reduced the percentage of CD3 + B220 + cells in peripheral blood (p=0.0036) and spleen (p=0.0280), alleviated lymphadenopathy, reduced urine protein level (p<0.0001) and increased the body weight (p=0.0493). RNA-seq revealed 501 upregulated and 206 downregulated genes in splenic CD3 + B220 + cells in McAb-proB-treated MRL/lpr mice compared with IgG-treated mice. The differentially expressed genes were found to be involved in apoptosis, tumour necrosis factor signalling, and T cell differentiation and proliferation., Conclusion: Systemic blockade of proBDNF inhibited the overexpansion of CD3 + B220 + cells and altered their signals related to cell cycle, cell apoptosis and the immune response, which may contribute to the attenuation of disease symptoms in murine lupus., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Differences inmethane (CH 4 ) production potential in paddy soils under different rice-based cropping systems and especially in the methanogenic pathways (mainly acetate fermentation and CO 2 /H 2 reduction) remain unclear. Anaerobic incubations of soil with or without fluoromethane (CH 3 F) inhibitor (2% and 0%) were conducted. With the soils from three typical paddy ecosystems (rice-wheat rotation, RW; rice-fallow, RF; double-rice, DR) in China, the cumulative concentration of CH 4 production, CH 4 production potential, dissolved organic carbon (DOC) content, and acetic acid content were determined. Meanwhile, the relative contribution of acetate-dependent methanogenesis ( f ac ) was quantified using the stable carbon isotope method. The results showed that the CH 4 production potential was 7.18 μg·(g·d) -1 in RF, which was significantly lower than that in RW[10.33 μg·(g·d) -1 ]and DR[13.42 μg·(g·d) -1 ] ( P <0.05). Correlation analysis showed that CH 4 production potential was significantly negatively correlated with soil cation exchange capacity and pH ( P <0.01); the addition of CH 3 F significantly inhibited CH 4 production ( P <0.05). The content of DOC and acetic acid in DR were 255 mg·kg -1 and 7.34 mg·kg -1 , respectively, which were 17%-51% and 22%-23% higher than those in RW and RF, respectively. The δ 13 CH 4 and δ 13 CO 2 values were affected greatly by different rice-based cropping systems, and the highest δ 13 CH 4 value was -43.89‰ in RF, which was more positive than that of RW and DR by 11.06‰ and 8.33‰, respectively ( P <0.05). By contrast, the lowest value of δ 13 CO 2 was observed in RF, which was more negative than that of RW (7.63‰) and DR (5.14‰) ( P <0.05). The α (CO 2 /CH 4 ) values of RW and RF were 1.057 and 1.058, respectively, which were significantly lower than 1.062 in DR ( P <0.05). The f ac values of RF ranged from 84% to 98%, being 34%-38% and 20%-23% higher than those of RW and DR, respectively ( P <0.05).

Objective: The investigation and research on the application status of Hepatic Venous Pressure Gradient (HVPG) is very important to understand the real situation and future development of this technology in China. Methods: This study comprehensively investigated the basic situation of HVPG technology in China, including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications and existing problems. Results: According to the survey, there were 70 hospitals in China carrying out HVPG technology in 2021, distributed in 28 provinces (autonomous regions and municipalities directly under the central Government). A total of 4 398 cases of HVPG were performed in all the surveyed hospitals in 2021, of which 2 291 cases (52.1%) were tested by HVPG alone. The average cost of HVPG detection was (5 617.2±2 079.4) yuan. 96.3% of the teams completed HVPG detection with balloon method, and most of the teams used thrombectomy balloon catheter (80.3%). Conclusion: Through this investigation, the status of domestic clinical application of HVPG has been clarified, and it has been confirmed that many domestic medical institutions have mastered this technology, but it still needs to continue to promote and popularize HVPG technology in the future.

Zebrafish are an effective vertebrate model to study the mechanisms underlying recovery after spinal cord injury. The subacute phase after spinal cord injury is critical to the recovery of neurological function, which involves tissue bridging and axon regeneration. In this study, we found that zebrafish spontaneously recovered 44% of their swimming ability within the subacute phase (2 weeks) after spinal cord injury. During this period, we identified 7762 differentially expressed genes in spinal cord tissue: 2950 were up-regulated and 4812 were down-regulated. These differentially expressed genes were primarily concentrated in the biological processes of the respiratory chain, axon regeneration, and cell-component morphogenesis. The genes were also mostly involved in the regulation of metabolic pathways, the cell cycle, and gene-regulation pathways. We verified the gene expression of two differentially expressed genes, clasp2 up-regulation and h1m down-regulation, in zebrafish spinal cord tissue in vitro. Pathway enrichment analysis revealed that up-regulated clasp2 functions similarly to microtubule-associated protein, which is responsible for axon extension regulated by microtubules. Down-regulated h1m controls endogenous stem cell differentiation after spinal cord injury. This study provides new candidate genes, clasp2 and h1m, as potential therapeutic intervention targets for spinal cord injury repair by neuroregeneration. All experimental procedures and protocols were approved by the Animal Ethics Committee of Tianjin Institute of Medical & Pharmaceutical Sciences (approval No. IMPS-EAEP-Q-2019-02) on September 24, 2019., Competing Interests: None

In this project, a commercial polytetrafluoroethylene (PTFE) membrane was coated with a thin layer of polyether block amide (PEBAX) via vacuum filtration to improve hydrophilicity and to study the bubble formation. Two parameters, namely PEBAX concentration (of 0-1.5 wt%) and air flow rate (of 0.1-50 mL/s), were varied and their effects on the bubble size formation were investigated. The results show that the PEBAX coating reduced the minimum membrane pore size from 0.46 μm without coating (hereafter called PEBAX0) to 0.25 μm for the membrane coated with 1.5wt% of PEBAX (hereafter called PEBAX1.5). The presence of polar functional groups (N-H and C=O) in PEBAX greatly improved the membrane hydrophilicity from 118° for PEBAX0 to 43.66° for PEBAX1.5. At an air flow rate of 43 mL/s, the equivalent bubble diameter size decreased from 2.71 ± 0.14 cm for PEBAX0 to 1.51 ± 0.02 cm for PEBAX1.5. At the same air flow rate, the frequency of bubble formation increased six times while the effective gas-liquid contact area increased from 47.96 cm 2 /s to 85.6 cm 2 /s. The improved growth of C. vulgaris from 0.6 g/L to 1.3 g/L for PEBAX1.5 also shows the potential of the PEBAX surface coating porous membrane as an air sparger.

The main purpose of our study was to evaluate the efficacy and safety of eltrombopag plus cyclosporine A (CsA) in transfusion-dependent non-severe aplastic anemia(TD-NSAA). The clinical characteristics of 13 TD-NSAA patients who received initial treatment of eltrombopag plus CsA from 2019 to 2021 were retrospectively analyzed. The 3-month overall hematological response (OR) rate was 12/13. Until the end of follow-up, 12 patients responded, among whom 2 patients reached complete response (CR) and 9 patients reached partial response (PR) and 1 with HR. Paroxysmal nocturnal hemoglobinuria (PNH) developed in one patient at 6 months after treatment. Five of thirteen patients reported mild adverse reactions, which were all manageable. Compared with historical data, the combination of eltrombopag with CsA is an effective regimen in patients with TD-NSAA.

Twelve new complexes Cu(L 1 ) 2 - Cu(L 12 ) 2 were designed and synthesized to improve their chemotherapeutic properties. They showed considerable antiproliferative activity against T24 cancer cells but lower cytotoxicity to human normal cells HL-7702 and WI-38. A mechanism study indicated that Cu(L 4 ) 2 and Cu(L 10 ) 2 were reduced to Fenton-like Cu + by glutathione depletion, and the resulting Cu + catalyzed the generation of highly toxic hydroxyl radicals from excess H 2 O 2 . Simultaneously, Cu(L 4 ) 2 and Cu(L 10 ) 2 could decrease the catalase activity to restrain H 2 O 2 transfer to H 2 O for enhanced chemodynamic therapy (CDT). These induced mitochondrial dysfunctions and endoplasmic reticulum stress to induce T24 cell apoptosis. In addition, Cu(L 4 ) 2 and Cu(L 10 ) 2 inhibited autophagy flux to promote cell apoptosis. Cu(L 4 ) 2 and Cu(L 10 ) 2 demonstrated strong tumor inhibition ability in the T24 xenograft model. Moreover, Cu(L 10 ) 2 showed higher antitumor activity and a better safety profile than the CDT agent Cu1 . Cu(L 10 ) 2 exhibited excellent pharmacokinetic properties. Collectively, Cu(L 4 ) 2 and Cu(L 10 ) 2 could be developed as potential CDT candidates for cancer treatment.

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(L n )(H 2 O)Cl 3 ] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca 2+ ), and reduced mitochondrial membrane potential (Δ Ψ ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c , Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.

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 (p75 NTR ) are highly expressed in CD19 + CD27 hi CD38 hi ASCs in patients with SLE and in CD19 + CD44 hi CD138 + 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 p75 NTR 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 p75 NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75 NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.

Three Cu(II) complexes of quinoline derivatives as cancer chemodynamic therapy agents were synthesized and characterized. These complexes were heavily taken up by cells and reacted with cellular glutathione (GSH) to reduce Cu 2+ to Fenton-like Cu + , which catalyzed endogenous H 2 O 2 to produce the highly toxic hydroxyl radicals (•OH) to kill cancer cells. Cu1 and Cu2 initiated CAT activity declines, mitochondrial membrane potential and ATP concentration decrease, mitochondrial Ca 2+ overload and ER stress response, leading to cell cycle arrest in sub-G1 and cancer cell caspase-dependent apoptosis. On account of the high GSH and H 2 O 2 specific properties of the tumor microenvironment, Cu1 and Cu2 exhibited higher in vitro anticancer activity and lower toxicity to normal cells. Cu1 and Cu2 efficiently inhibited tumor growth in the SK-OV-3 xenograft mouse model without obvious systemic toxicity., Competing Interests: Declaration of competing interest All authors declare no conflict of interest for this work., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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.

Objective: To investigate the effects of thoracoscopy-guided thoracic paravertebral block for analgesia after single-port video-assisted pulmonary lobectomy. Methods: From December 2019 to April 2020, 60 patients receiving single-port video-assisted pulmonary lobectomy at Ningbo Medical Center Lihuili Hospital were selected. The patients were randomly and equally divided into control group and paravertebral block group using a random number table. Patients of paravertebral block group were injected into the thoracic 4-5 intercostal, paravertebral 1 cm using 0.375% ropivacaine (20 ml) with thoracoscopy-guided at the end of surgery, while patients of control group were given patient controlled intravenous analgesia (PCIA). Postoperative visual analogue scale (VAS) and Ramsay sedation scale were recorded at 6, 12, 24, 36, 48 h after the surgery. The incidence of postoperative adverse reactions, additional dose and times of pethidine, the time to resume eating, the rate of postoperative active cough, the first time to get out of bed after surgery and postoperative hospital stay of two groups' patients were recorded. t test and chisquare test were used for statistical analysis. Results: The VAS score of paravertebral block group were lower than those of control group at all time points (all P< 0.05). The Ramsay sedation scale of paravertebral block group were higher than those of control group at all time points (all P< 0.05). The additional dose and times of pethidine of paravertebral block group were (8.2±2.3) mg and (0.2±0.1) time, which were lower than (87.8±15.3) mg and (1.8±0.3) time of control group, the differences were statistically significant ( t= 28.91, 34.37, all P< 0.05). Incidence of nausea, vomiting and pruritus of paravertebral block group were 10.0%, 6.7% and 0, which were lower than 40.0%, 30.0% and 13.3% of control group, the differences were statistically significant (χ(2)=7.20, 5.45, 4.29, all P< 0.05). The rate of postoperative active cough of paravertebral block group was 33.3%, which was higher than 10.0% of control group, the difference was statistically significant (χ(2)=4.81, P< 0.05). The time to resume eating, the first time to get out of bed after surgery and postoperative hospital stay were (6.5±0.4) h, (20.9±3.1) h and (4.6±1.0) d, which were lower than (8.5±0.7) h, (28.6±4.8) h and (6.1±1.3) d of control group, the differences were statistically significant ( t= 13.47, 7.39, 4.19, all P< 0.05). Conclusion: Thoracic paravertebral block under thoracoscopy-guided can effectively reduce the postoperative pain of single-port thoracoscopic lobectomy, with fewer adverse reactions, and is beneficial to postoperative recovery.

This study aims to investigate the value of the combined detection of carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE) and the level of Interleukin-18 (IL-18) in the serum in the diagnosis of lung cancer. The correlation between these parameters and the expression levels of B-cell lymphoma-2 (Bcl-2) protein were also studied. Eighty patients with lung cancer were included in the lung cancer group. These patients underwent surgery in the Department of Oncology of Huai'an Second People's Hospital between February 2016 and February 2018. During the same period, another 80 patients with benign lung lesions were registered in the benign lesion group and 80 healthy people were enrolled in the control group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of CEA, NSE and IL-18. The diagnostic critical value of these factors was used as positive indicator. When CEA, NSE and IL-18 levels were positive at the same time, the combined detection was considered to be positive. WB was used to detect Bcl-2 expression level. We also analyzed the possible correlation between CEA, NSE, IL-18 levels and the Bcl-2 expression levels. The CEA, NSE and IL-18 expression levels in the serum of the lung cancer group were significantly higher than those in the benign lesion and the control groups (p<0.05). The area under ROC curve for CEA, NSE and IL-18 respectively was 0.770 (0.697-0.843), 0.829 (0.767-0.890), 0.721 (0.642-0.800) (p<0.001). IL-18 level was negatively correlated with the level of Bcl-2 mRNA in the tissue (r=-0.380, p<0.001). In conclusion, CEA, NSE and IL-18 have a good auxiliary diagnostic value in patients with lung cancer. The combined detection could improve the sensitivity and specificity of lung can¬cer diagnosis. There was a negative correlation between IL-18 and Bcl-2 levels which suggested a potential inhibitory role of IL-18 on the lung cancer cells apoptosis pathway., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury. However, it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death. By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin, it was found that these cell types respond differentially to the duration and concentration of erastin treatment. Therefore, we studied the mechanisms of ferroptosis using primary cortical neurons from E16 mouse embryos. After treatment with 50 μM erastin for 48 hours, reactive oxygen species levels increased, and the expression of the cystine/glutamate antiporter system light chain and glutathione peroxidase 4 decreased. Pretreatment with deferoxamine for 12 hours inhibited these changes, reduced cell death, and ameliorated cellular morphology. Pretreatment with the apoptosis inhibitor Z-DEVD-FMK or the necroptosis inhibitor necrostain-1 for 12 hours did not protect against erastin-induced ferroptosis. Only deferoxamine protected the primary cortical neurons from ferroptosis induced by erastin, confirming the specificity of the in vitro ferroptosis model. This study was approved by the Animal Ethics Committee at the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences, China (approval No. DWLL-20180913) on September 13, 2018., Competing Interests: None

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.

Objective: We aimed to establish the reference range of thromboelastograph (TEG) maximum amplitude (MA) in patients taking antiplatelet drugs., Methods: Between August 2015 and July 2018, a total of 4614 patients administrating with antiplatelet drugs (clopidogrel and aspirin) were retrospectively analyzed in this study. For MA A parameter, we used the 10th and 90th percentiles to establish a reference range. The Spearman correlation was used for the correlation analysis among the inhibition rate of adenosine diphosphate (ADP%) and MA ADP , inhibition rate of arachidonic acid (AA%) and MA AA . Then, through receiver operating characteristic (ROC) curve analysis of the best cutoff point, the reference ranges of MA ADP and MA AA could be deduced. Consistency evaluation was performed by statistical analysis of ADP% and MA ADP , AA% and MA AA pairing for 4459 patients., Results: The reference range of MA A was 8.1-25.8 mm. The reference range of MA ADP was 19.8-43.2 mm, and the corresponding sensitivity of two endpoints was 0.796, 0.856 and specificity were 0.897, 0.904, respectively. The reference range of MA AA was 18.9-37.7 mm, and the corresponding sensitivity of two endpoints was 0.819, 0.829 and specificity were 0.922, 0.896, respectively. The inconsistency rate of ADP% and MA ADP , and AA% and MA AA was 20.1% (898 cases) and 16.6% (738 cases), respectively., Conclusions: The reference range of MA ADP and MA AA established by us were better in sensitivity and specificity. MA ADP and MA AA were more accurate than conventional inhibition rate analysis in guidance of antiplatelet therapy, especially in patients with excessive low MA or high MA A ., (© 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.)

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)-1β, 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., (© 2019 Federation of American Societies for Experimental Biology.)

Seven Cu(II) complexes with 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline derivatives as ligands: [Cu 2 (L 1 ) 2 Cl 4 ] (1), [Cu(L 2 )Cl 2 ] (2), [Cu(L 1 )(NO 3 ) 2 ] (3), [Cu(L 2 )(NO 3 ) 2 ] (4), [Cu(L 3 )Cl 2 ] (5), [Cu(L 3 )Br 2 ] (6) and [Cu(L 3 )(NO 3 ) 2 ] (7){L 1 =9-nitro-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline, L 2 =4-nitro-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline, L 3 =9-bromo-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline}, were synthesized and characterized. Their in vitro anticancer activities against T-24, MGC-80-3, HeLa, Hep-G2, A549 and SK-OV-3 were evaluated. Compared with their corresponding ligands, most of these complexes exhibited enhanced anticancer activities in contrast to their corresponding ligands and copper salt. Among them, complexes 1 and 3 displayed selective cytotoxicity to HeLa cells comparing with normal liver cell HL-7702, with IC 50 values of 5.03 ± 1.20 μM and 10.05 ± 0.52 μM, respectively. Complexes 1 and 3 inhibited telomerase activity by interacting with c-myc promoter elements, and therefore exerted their antitumor activity. Furthermore, complexes 1 and 3 could trigger cell apoptosis via disruption of mitochondrial pathway through notably increased reactive oxygen species (ROS) levels, loss of mitochondrial membrane potential (Δψ m ), increase of the cytochrome c and apaf-1, decrease of bcl-2, and activation of caspases 3/9. Complexes 1 and 3 exhibited enhanced cytotoxicity, presenting synergetic effect after the ligands coordinated to copper(II) center., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Herein, a dual-response fluorescent sensor, L, based on pyrazolopyrimidine was designed and developed for the simultaneous detection of Ni 2+ and Cu 2+ ions in the presence of other metal ions; the structural characterization of L was carried out by FTIR spectroscopy, NMR spectroscopy, HRMS and X-ray diffraction analysis. The sensor L effectively displayed fluorescence quenching towards the Ni 2+ and Cu 2+ ions with high sensitivity without interference from other metal ions. The results reveal that L binds to Ni 2+ and Cu 2+ in a 2 : 1 pattern, which matches well with the result of the Job's plot. The association constants of L with Ni 2+ and Cu 2+ were 3.2 × 10 4 M -1 and 7.57 × 10 4 M -1 , respectively. The detection limits (DLs) are down to 8.9 nM for Ni 2+ and 8.7 nM for Cu 2+ . The fluorescence imaging of L in T-24 cells was investigated because of the low cytotoxicity of L, indicating that L could be used to detect Ni 2+ and Cu 2+ in living cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

(3β,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX-001), a structural analogue of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effects of JLX001 on ischemic stroke (IS) and research its induction of autophagy function via 5'-AMP-activated protein kinase (AMPK)-Human Serine/threonine-protein kinase (ULK1) signaling pathway activation. The therapeutic effects of JLX001 were evaluated by infarct sizes, brain edema, neurological scores and proportion of apoptotic neurons in Sprague-Dawley (SD) rats with middle cerebral artery occlusion/reperfusion (MCAO/R). The number of autophagosomes was obtained by transmission electron microscopy. The expression of LC3-II was measured by immunofluorescence. p-AMPK and activated ULK1 were detected by western blots. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, neurological scores and proportion of apoptotic neurons in MCAO/R rats. The number of autophagosomes was increased, accompanying with the increased expressions of LC3-II, p-AMPK and ULK1. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms may relate to inducing autophagy via AMPK-ULK1 signaling pathway activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)