Association of different doses of antenatal corticosteroids exposure with early major outcomes and early weight loss percentage in extremely preterm infants or extremely low birthweight infants: a multicentre cohort study.

OBJECTIVES: To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage (EWLP) in hospital among extremely preterm infants (EPI) or extremely low birthweight infants (ELBWI). METHODS: A multicentre, retrospective cohort study of EPI or ELBWI born between 2017 and 2018 was conducted. Infants were classified into no ANS, partial ANS and complete ANS exposure group; three subgroups were generated by gestational age and birth weight. Multiple logistic regression and multiple linear regression were performed. RESULTS: There were 725 infants included from 32 centres. Among no ANS, partial ANS and complete ANS exposure, there were significant differences in the proportions of bronchopulmonary dysplasia (BPD) (24.5%, 25.4% and 16.1%), necrotising enterocolitis (NEC) (6.7%, 2.0% and 2.0%) and death (29.6%, 18.5% and 13.5%), and insignificant differences in the proportions of intraventricular haemorrhage (IVH) (12.5%, 13.2% and 12.2%), and extrauterine growth restriction (EUGR) (50.0%, 56.6% and 59.5%). In the logistic regression, compared with no ANS exposure, complete ANS reduced the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91), NEC (OR 0.21, 95% CI 0.08 to 0.57) and death (OR 0.36, 95% CI 0.23 to 0.56), and partial ANS reduced the risk of NEC (OR 0.23, 95% CI 0.07 to 0.72) and death (OR 0.54, 95% CI 0.34 to 0.87). Compared with partial ANS exposure, complete ANS decreased the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91). There were insignificant associations between ANS exposure and IVH, EUGR. In the multiple linear regression, partial and complete ANS exposure increased EWLP only in the ≥28 weeks (w) and <1000 g subgroup (p<0.05). CONCLUSIONS: Different doses of ANS (dexamethasone) exposure were protectively associated with BPD, NEC, death in hospital, but not EUGR at discharge among EPI or ELBWI. Beneficial dose-dependent associations between ANS (dexamethasone) exposure and BPD existed. ANS exposure increased EWLP only in the ≥28 w and<1000 g subgroup. ANS administration, especially complete ANS, is encouraged before preterm birth. TRIAL REGISTRATION NUMBER: NCT06082414.

Extracellular vesicles derived from M2-like macrophages alleviate acute lung injury in a miR-709-mediated manner.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterised by an uncontrolled inflammatory response, and current treatment strategies have limited efficacy. Although the protective effect of M2-like macrophages (M2φ) and their extracellular vesicles (EVs) has been well-documented in other inflammatory diseases, the role of M2φ-derived EVs (M2φ-EVs) in the pathogenesis of ALI/ARDS remains poorly understood. The present study utilised a mouse model of lipopolysaccharide-induced ALI to first demonstrate a decrease in endogenous M2-like alveolar macrophage-derived EVs. And then, intratracheal instillation of exogenous M2φ-EVs from the mouse alveolar macrophage cell line (MH-S) primarily led to a take up by alveolar macrophages, resulting in reduced lung inflammation and injury. Mechanistically, the M2φ-EVs effectively suppressed the pyroptosis of alveolar macrophages and inhibited the release of excessive cytokines such as IL-6, TNF-α and IL-1ß both in vivo and in vitro, which were closely related to NF-κB/NLRP3 signalling pathway inhibition. Of note, the protective effect of M2φ-EVs was partly mediated by miR-709, as evidenced by the inhibition of miR-709 expression in M2φ-EVs mitigated their protective effect against lipopolysaccharide-induced ALI in mice. In addition, we found that the expression of miR-709 in EVs derived from bronchoalveolar lavage fluid was correlated negatively with disease severity in ARDS patients, indicating its potential as a marker for ARDS severity. Altogether, our study revealed that M2φ-EVs played a protective role in the pathogenesis of ALI/ARDS, partly mediated by miR-709, offering a potential strategy for assessing disease severity and treating ALI/ARDS.

Efficacy of remimazolam tosilate versus propofol for total intravenous anaesthesia in urological surgery: A randomised clinical trial.

BACKGROUND: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that acts on the gamma-aminobutyric acid type A receptor (GABAAR). OBJECTIVE: To compare the efficacies of remimazolam (RMZ), and propofol (PROP) combined with remifentanil and cisatracurium for total intravenous anaesthesia (TIVA) in patients undergoing urological surgery. DESIGN: A prospective, single-blind, randomised, noninferiority clinical trial. SETTING: Single centre from 1 January 2022 to 30 March 2022. PATIENTS: A total of 146 adult patients undergoing elective urological surgery. INTERVENTION: Patients were randomly allocated in a 1 : 1 ratio to the PROP or RMZ groups. In the PROP group, anaesthesia was induced with propofol at 100 mg min -1 to reach a bispectral index score (BIS) of 40 to 60. After loss of consciousness (LOC), intravenous fentanyl 3 µg kg -1 was administered, followed by cisatracurium 0.3 mg kg -1 . Patients were intubated 3 min after cisatracurium administration. Anaesthesia was maintained with the combination of propofol (plasma concentration: 2.5 to 4 µg ml -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). In the RMZ group, anaesthesia was induced with remimazolam tosilate starting at 10 mg kg -1  h -1 to reach a BIS of 40 to 60 and maintained between 0.2 and 2 mg kg -1  h -1 . After LOC, fentanyl and cisatracurium were administered and intubation was performed as in the PROP group. Anaesthesia was maintained with a combination of remimazolam (0.2 to 2 mg kg -1  h -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). MAIN OUTCOME MEASURES: The primary outcome was the TIVA success rate. The predefined noninferiority margin considered an absolute difference of 6% in the primary outcome between the groups. The secondary outcomes were vital signs, anaesthesia and surgery characteristics, and adverse events. RESULTS: All patients completed the trial. The success rates of TIVA with remimazolam and propofol were 100 and 98.6%, respectively. The incidence of hypotension during anaesthesia was lower in the RMZ group (26%) than in the PROP group (46.6%) ( P  = 0.016). The median [IQR] total consumption of ephedrine during anaesthesia was higher in the PROP group 10 [0 to 12.5] mg than in the RMZ group 0 [0 to 10] mg ( P  = 0.0002). The incidence of injection pain was significantly higher in the PROP group (76.7%) than in the RMZ group (0; P  < 0.001). No significant differences in the controllability of the anaesthesia depth, anaesthesia and surgery characteristics, or vital signs were observed between the groups. CONCLUSION: Remimazolam demonstrated noninferior efficacy to propofol combined with remifentanil and cisatracurium for TIVA in patients undergoing urological surgery. TRIAL REGISTRATION: Chictr.org.cn, identifier: ChiCTR2100050923. CLINICAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100050923, Principal investigator: Xuehai Guan, Date of registration: 8 November 2021, https://www.chictr.org.cn/showproj.html?proj=133466 ).

KDM6A/UTX promotes spermatogenic gene expression across generations and is not required for male fertility†.

Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild-type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias toward downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.

The mechanism of ferroptosis and its related diseases.

Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation of lipid peroxides, provides a novel avenue for delving into the intersection of cellular metabolism, oxidative stress, and disease pathology. We have witnessed a mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological and pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, and traumatic tissue injuries. By unraveling the intricate underpinnings of the molecular machinery, pivotal contributors, intricate signaling conduits, and regulatory networks governing ferroptosis, researchers aim to bridge the gap between the intricacies of this unique mode of cellular death and its multifaceted implications for health and disease. In light of the rapidly advancing landscape of ferroptosis research, we present a comprehensive review aiming at the extensive implications of ferroptosis in the origins and progress of human diseases. This review concludes with a careful analysis of potential treatment approaches carefully designed to either inhibit or promote ferroptosis. Additionally, we have succinctly summarized the potential therapeutic targets and compounds that hold promise in targeting ferroptosis within various diseases. This pivotal facet underscores the burgeoning possibilities for manipulating ferroptosis as a therapeutic strategy. In summary, this review enriched the insights of both investigators and practitioners, while fostering an elevated comprehension of ferroptosis and its latent translational utilities. By revealing the basic processes and investigating treatment possibilities, this review provides a crucial resource for scientists and medical practitioners, aiding in a deep understanding of ferroptosis and its effects in various disease situations.

The difference in mean arterial pressure induced by remimazolam compared to etomidate in the presence of fentanyl at tracheal intubation: A randomized controlled trial.

Background: Combined use of hypnotic and opioids during anesthesia inductions decreases blood pressure. Post-induction hypotension (PIHO) is the most common side effect of anesthesia induction. We aimed to compare the difference in mean arterial pressure (MAP) induced by remimazolam with that induced by etomidate in the presence of fentanyl at tracheal intubation. Methods: We assessed 138 adult patients with American Society of Anesthesiologists physical status I-II who underwent elective urological surgery. Patients were randomly allocated to receive either remimazolam or etomidate as alterative hypnotic in the presence of fentanyl during anesthesia induction. Comparable BIS values were achieved in both groups. The primary outcome was the difference in the MAP at tracheal intubation. The secondary outcomes included the characteristics of anesthesia, surgery, and adverse effects. Results: The MAP was higher in the etomidate group than in the remimazolam group at tracheal intubation (108 [22] mmHg vs. 83 [16] mmHg; mean difference, -26; 95% confidence interval [CI], -33 to -19; p < 0.0001). Heart rate was significantly higher in the etomidate group than in the remimazolam group at tracheal intubation. The patients' condition warranted the administration of ephedrine more frequently in the remimazolam group (22%) than in the etomidate group (5%) (p = 0.0042) during anesthesia induction. The remimazolam group had a lower incidence of hypertension (0% vs. 9%, p = 0.0133), myoclonus (0% vs. 47%, p < 0.001), and tachycardia (16% vs. 35%, p = 0.0148), and a higher incidence of PIHO (42% vs. 5%, p = 0.001) than the etomidate group during anesthesia induction. Conclusion: Remimazolam was associated with lower MAP and lower heart rate compared to etomidate in the presence of fentanyl at tracheal intubation. Patients in the remimazolam group had a higher incidence of PIHO, and their condition warranted the administration of ephedrine more frequently than in the etomidate group during anesthesia induction.

Effect of melatonin on oxidative stress indicators in animal models of fibrosis: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Imbalance of oxidative stress has been detected in a range of fibrotic diseases. Melatonin as an indoleamine hormone plays an important role in regulating the circadian rhythm of human, while in recent years, its antioxidant effect has also attracted increasing attention. This study aimed to perform a systematic review and meta-analysis to comprehensively evaluate the antioxidant effect of melatonin in animal models of fibrosis. METHODS: The PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database (VIP), and SinoMed databases were searched from inception to March 1st, 2022 to retrieve eligible studies that evaluated the effect of melatonin supplementation on the levels of malondialdehyde (MDA), lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT) in animal models of fibrosis. RESULTS: A total of 64 studies were included in this meta-analysis. The results showed that melatonin supplementation significantly reduced the levels of oxidative indicators including MDA (P < 0.00001), LPO (P < 0.00001) and NO (P < 0.0001), and elevated the levels of antioxidant indicators including GSH (P < 0.00001), GPx (P < 0.00001) and SOD (P < 0.00001) in fibrotic diseases. CONCLUSIONS: Our research findings showed that melatonin supplementation could significantly reduce the levels of oxidative indicators including MDA, LPO and NO and elevate the levels of antioxidant indicators including GSH, GPx and SOD so as to correct oxidative stress in animal models of fibrosis. However, no significant changes were observed in CAT level. More clinical studies are needed to further confirm the beneficial role of melatonin in fibrotic diseases.

Cyclin D1 mediates pain behaviour in a rat model of breast cancer-induced bone pain by a mechanism involving regulation of the proliferation of spinal microglia.

AIMS: The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold. METHODS: Female Sprague Dawley (SD) rats were used to establish a rat model of BCP, and the messenger RNA (mRNA) and protein expression of ionized calcium binding adaptor molecule 1 (IBA1) and cyclin D1 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot, respectively. The proliferation of spinal microglia was detected by immunohistochemistry. The pain behaviour test was assessed by quantification of spontaneous flinches, limb use, and guarding during forced ambulation, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. RESULTS: IBA1 and cyclin D1 in the ipsilateral spinal horn increased in a time-dependent fashion. Spinal microglia proliferated in BCP rats. The microglia inhibitor minocycline attenuated the pain behaviour in BCP rats. The cyclin-dependent kinase inhibitor flavopiridol inhibited the proliferation of spinal microglia, and was associated with an improvement in pain behaviour in BCP rats. CONCLUSION: Our results revealed that the inhibition of spinal microglial proliferation was associated with a decrease in pain behaviour in a rat model of BCP. Cyclin D1 acts as a key regulator of the proliferation of spinal microglia in a rat model of BCP. Disruption of cyclin D1, the restriction-point control of cell cycle, inhibited the proliferation of microglia and attenuated the pain behaviours in BCP rats. Cyclin D1 and the proliferation of spinal microglia may be potential targets for the clinical treatment of BCP.Cite this article: Bone Joint Res 2022;11(11):803-813.

Esketamine prevents propofol-induced injection pain: Randomized controlled trial.

Background: Propofol is widely used during anesthesia. However, propofol-induced injection pain (PIP) is considered an unpleasant perioperative outcome. This study aimed to investigate the efficacy of a mixture of esketamine and propofol in preventing propofol injection pain in patients undergoing general anesthesia. Methods: This was a prospective, double-blind, multicenter, and randomized controlled trial. We included 252 adult patients with the American Society of Anesthesiologists physical status I to II who underwent surgery under general anesthesia. Patients were randomly allocated in a 1:1:1:1 ratio to four groups (n = 63 per group). Group NS received a mixture of 1% propofol (20 ml) and 0.9% normal saline (1 ml), group ESK-4 received a mixture of 1% propofol (20 ml) and esketamine 4 mg (diluted with 0.9% normal saline, 1 ml), group ESK-12 received a mixture of 1% propofol (20 ml) and esketamine 12 mg (diluted with 0.9% normal saline, 1 ml), and group ESK-20 received a mixture of 1% propofol (20 ml) and esketamine 20 mg (diluted with 0.9% normal saline, 1 ml) as sedative drugs during anesthesia. The primary outcome was the incidence and distribution of different degrees of PIP. The secondary outcomes were vital signs, characteristics of surgery and anesthesia, and adverse events. Results: The incidence of PIP in group ESK-20 (33.3%) was significantly lower than that in groups NS, ESK-4, and ESK-12 (63.3%, 62.2%, and 49.1%, respectively; p < 0.01). The incidence of moderate PIP in group NS (33.3%) and group ESK-4 (22.6%) was higher than that in groups ESK-12 (7.5%) and ESK-20 (6.7%). The incidence of severe PIP in group NS (6.7%) and group ESK-4 (9.4%) was higher than that in groups ESK-12 (1.9%) and ESK-20 (0%). There were no differences in the vital signs, characteristics of surgery and anesthesia, or adverse events between the groups. Conclusion: Our results indicated that the esketamine-propofol admixture reduced the incidence of PIP in patients undergoing general anesthesia without severe side effects.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Screening of atrial fibrillation diagnostic markers based on a GEO database chip and bioinformatics analysis.

Background: Study have shown that atrial fibrillation (AF) is a disease with genetic risk, and its pathogenesis is still unclear. This study sought to screen the gene microarray data of AF patients and to perform a bioinformatics analysis to identify AF signature diagnostic genes. Methods: The AF gene sets from the Gene Expression Omnibus (GEO) database were screened, and the differentially expressed genes (DEGs) were identified after the normalization of the data set by R software. We conducted a gene set enrichment analysis, a protein-protein interaction (PPI) network analysis, a gene-gene interaction (GGI) network analysis, and an immuno-infiltration analysis. The core genes were identified from the DEGs, and base on receiver operating characteristic, the top 5 core genes in the 2 data sets were selected as diagnostic factors and a nomogram was constructed. The miRNA of the core genes were predicted and an immune cell correlation analysis was performed. Results: A total of 20 DEGs were identified. The functions of these DEGs were mainly related to muscle contraction, autophagosome, and bone morphogenetic protein (BMP) binding, and focused on the calcium signaling pathway, ferroptosis, the extracellular matrix-receptor interaction, and other pathways. A total of 5 core genes [i.e., GPR22 (G protein-coupled receptor 22), COG5 (component of oligomeric golgi complex 5), GALNT16 (polypeptide N-acetylgalactosaminyltransferase 16), OTOGL (otogelin-like), and MCOLN3 (mucolipin 3)] were identified, and a linear model for risk prediction was constructed, which has good prediction ability. Plasma cells and Macrophages M2 were significantly increased in AF, while T cells follicular helper and Dendritic cells activated were significantly decreased. Conclusions: In our study, we identified 5 potential diagnostic key genes (i.e., GPR22, COG5, GALNT16, OTOGL, and MCOLN3). Our findings may provide a theoretical basis for susceptibility analyses and target drug development in AF.

Efficacy of Pre-Treatment with Remimazolam on Prevention of Propofol-Induced Injection Pain in Patients Undergoing Abortion or Curettage: A Prospective, Double-Blinded, Randomized and Placebo-Controlled Clinical Trial.

BACKGROUND: Propofol-induced injection pain (PIP) is a well-known problem in general anesthesia. We hypothesized that pre-treatment with remimazolam prevents PIP in patients undergoing abortion or curettage. MATERIALS AND METHODS: In this prospective, single-center, double-blinded, randomized, placebo-controlled clinical trial, adult patients aged 18 to 60 undergoing abortion or curettage were randomly assigned to three groups. Group Lido received system lidocaine (a bolus of 0.5 mg kg-1, iv). Group Remi received remimazolam (a bolus of 0.1 mg kg-1, iv). Group NS received identical volumes of 0.9% normal saline. Sixty seconds after the injection of lidocaine, remimazolam or saline, patients were injected with propofol at a rate of 12 mL/min until the loss of consciousness. The primary outcome was the incidence of PIP at the time of induction using 4-point scale. Secondary outcomes included propofol-induced injection pain, vital signs, the characteristics of anesthesia and surgery, and adverse events. RESULTS: The incidence of patients with PIP was higher in group NS than that in group Lido and group Remi (75.7, 44.3, and 42.9%, respectively, p < 0.001). The percentages of patients with moderate PIP were higher in group NS than that in group Lido and group Remi (20.0, 2.9, and 1.4%, respectively, p < 0.001). Moreover, the consumption of propofol and the incidence of adverse event (hypoxemia and chin lifting) in group Remi were lower than that in group NS and Lido, and less patients got physical movement and cough in group Remi. The recovery time in group NS was longer than that in group Lido and Remi. CONCLUSION: Our findings indicate that pre-treatment with remimazolam reduced the incidence and intensity of PIP in abortion or curettage patients, equivalent to that of lidocaine without severe adverse effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR2100041805).

Chemical Constituents of the Marine Fungus Penicillium sp. MCCC 3A00228.

One new (d-arabinitol-anofinicate, 1) and fourteen known (2-15) compounds were isolated from the marine Penicillium sp. MCCC 3A00228. The structure of the new compound was established mainly by extensive spectroscopic analyses. Compound 1 exhibited weak transcriptional effect on Nur77. While compound 13 showed moderate in vitro anti-proliferative effect against QGY7701, H1299, and HCT116 tumor cells with IC50 values of 21.2 µM, 18.2 µM, and 17.6 µM, respectively.

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production.

Neddylation, a posttranslational modification in which NEDD8 is covalently attached to target proteins, has emerged as an endogenous regulator of innate immunity. However, the role of neddylation in methicillin-resistant Staphylococcus aureus (MRSA) infection remains unknown. In this study, we found that neddylation was activated after MRSA infection in vivo and in vitro. Inhibition of neddylation with MLN4924 promoted injury of liver and kidneys in C57BL/6 mice with MRSA bloodstream infection and increased mortality. Blockade of neddylation, either pharmacologically (MLN4924, DI591) or through the use of Uba3 small interfering RNA, inhibited Cullin3 neddylation and promoted Nrf2 accumulation, thus reducing reactive oxygen species (ROS) induction and bacterial killing ability in mouse peritoneal macrophages. In summary, our findings suggest that activation of neddylation in macrophages plays a critical protective role against MRSA infection by increasing ROS production, partially by signaling through the NEDD8-Cullin3-Nrf2-ROS axis. Furthermore, our results may provide a new non-antibiotic treatment strategy for MRSA infection through targeting of neddylation.

PP7080 expedites the proliferation and migration of lung adenocarcinoma cells via sponging miR-670-3p and regulating UHRF1BP1.

BACKGROUND: An increasing body of evidence has revealed that long non-coding RNAs play a significant part in a variety of human cancers, including lung adenocarcinoma (LUAD). METHODS: The expression of PP7080, miR-670-3p and UHRF1BP1 in LUAD cells and tissues was detected using a quantitative real-time polymerase chain reaction. The role of PP7080 in LUAD cells was validated by CCK-8, flow cytometry, colony formation, transwell and wound healing assays. The binding capacity between PP7080/UHRF1BP1 and miR-670-3p was confirmed by luciferase reporter assays. Moreover, the interactional mechanism among PP7080, miR-670-3p and UHRF1BP1 was determined by means of RNA immunoprecipitation and western blot assays. RESULTS: The expression level of PP7080 is up-regulated in LUAD cells and tissues compared to their matched controls. Down-regulation of PP7080 restrained the proliferative and migratory abilities of LUAD cells, but induced cell apoptosis. PP7080 up-regulation led to the opposite results. Moreover, the binding ability between miR-670-3p and PP7080/UHRF1BP1 in LUAD cells was confirmed. A rescue assay revealed that PP7080 contributes to LUAD development by modulating the miR-670-3p/UHRF1BP1 signaling pathway. CONCLUSIONS: PP7080 expedites the proliferation and migration of LUAD cell via sponging miR-670-3p and modulating UHRF1BP1.

Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC-EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC-EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC-EVs in a C1q-dependent manner. RBC-EVs loaded with antisense oligonucleotides of microRNA-155 showed macrophage-dependent protective effects against acute liver failure (ALF) in a mouse model. These RBC-EVs were also effective in treatment of ALF. Furthermore, compared to routine doses of doxorubicin and sorafenib (SRF), RBC-EVs loaded with doxorubicin or SRF showed enhanced therapeutic effects on a murine model of orthotopic liver cancer through a mechanism dependent on macrophages. Importantly, drug-loaded RBC-EVs showed no systemic toxicity at therapeutically effective doses, whereas routine doses of doxorubicin and SRF showed obvious toxicity. Thus, drug-loaded RBC-EVs hold high potential for clinical applications in the treatment of liver disease therapy.

SSR2 overexpression associates with tumorigenesis and metastasis of Hepatocellular Carcinoma through modulating EMT.

Background: Hepatocellular carcinoma (HCC) is a common malignancy around the world. The molecular mechanisms underlying HCC tumorigenesis and metastasis are far from clear. Numerous studies have pointed out that signal sequence receptor (SSR) is an endoplasmic reticulum-related protein involved in protein folding and processing of eukaryotic cells. SSR2 is a subunit of SSR protein, but the role of SSR2 in hepatocellular carcinoma is largely unknown and warrants further study. Materials and Methods: Several public databases were data mined to analyze the expression of four subunits of SSR between tumor and its peritumor counterparts. Also, the expression of SSR2 in our own collected tissues from HCC patients were analyzed by IHC and quantitative PCR. Survival analyses were conducted to delineate the prognostic value of SSR2. Clinical data were obtained followed by analysis based on SSR2 expression. Afterwards, cell proliferation, migration and invasion were detected by IncuCyte and trans-well assays, respectively. RNA interference was carried out by transfecting specific siRNA targeting SSR2 into cells using lipo2000. Western blot was applied to validate the knockdown effect and regulation on EMT-related proteins. Results: We examined the expression of SSR and its correlation with recurrence and survival of patients. We discovered that SSR2 overexpression was negatively associated with survival of HCC patients from TCGA databases and the mutation of SSR2 was most among the four subunits of SSR protein. Additionally, in this study, we collected tumor and adjacent tissues from 125 cases of HCC patients. Through constructing tissue microarray, we have identified that SSR2 was highly expressed in HCC tumor tissues compared with adjacent normal tissues of hepatocellular carcinoma patients by immunohistochemistry assays. Furthermore, Kaplan-Meier survival analysis from our collected tissues revealed that the overexpression of SSR2 was inversely correlated with disease free survival and overall survival of HCC patients. We elucidated that SSR2 promotes proliferation, migration and invasion of HCC cells. SSR2 knockdown suppressed epithelial mesenchymal transition (EMT) of HCC cells. Conclusions: These results collectively show that SSR2 is overexpressed in HCC tumor tissues, and it is an important factor in predicting survival of HCC patients. Additionally, it is involved in metastasis of HCC. These findings may help to exploit SSR2 as a novel factor in predicting prognosis and metastasis of HCC.

Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment.

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.

Antiproliferative chromone derivatives induce K562 cell death through endogenous and exogenous pathways.

A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.