Sunflower pollen-derived microcapsules adsorb light and bacteria for enhanced antimicrobial photothermal therapy.

Bacterial infection is one of the most serious clinical complications, with life-threatening outcomes. Nature-inspired biomaterials offer appealing microscale and nanoscale architectures that are often hard to fabricate by traditional technologies. Inspired by the light-harvesting nature, we engineered sulfuric acid-treated sunflower sporopollenin exine-derived microcapsules (HSECs) to capture light and bacteria for antimicrobial photothermal therapy. Sulfuric acid-treated HSECs show a greatly enhanced photothermal performance and a strong bacteria-capturing ability against Gram-positive bacteria. This is attributed to the hierarchical micro/nanostructure and surface chemistry alteration of HSECs. To test the potential for clinical application, an in situ bacteria-capturing, near-infrared (NIR) light-triggered hydrogel made of HSECs and curdlan is applied in photothermal therapy for infected skin wounds. HSECs and curdlan suspension that spread on bacteria-infected skin wounds of mice first capture the local bacteria and then form hydrogels on the wound upon NIR light stimulation. The combination shows a superior antibacterial efficiency of 98.4% compared to NIR therapy alone and achieved a wound healing ratio of 89.4%. The current study suggests that the bacteria-capturing ability and photothermal properties make HSECs an excellent platform for the phototherapy of bacteria-infected diseases. Future work that can fully take advantage of the hierarchical micro/nanostructure of HSECs for multiple biomedical applications is highly promising and desirable.

Tobramycin-mediated self-assembly of DNA nanostructures for targeted treatment of Pseudomonas aeruginosa-infected lung inflammation.

Pseudomonas aeruginosa (PA) is one of the most common multidrug-resistant pathogens found in clinics, often manifesting as biofilms. However, due to the emergence of superbugs in hospitals and the overuse of antibiotics, the prevention and treatment of PA infections have become increasingly challenging. Utilizing DNA nanostructures for packaging and delivering antibiotics presents an intervention strategy with significant potential. Nevertheless, construction of functional DNA nanostructures with multiple functionalities and enhanced stability in physiological settings remains challenging. In this study, the authors propose a magnesium-free assembly method that utilizes tobramycin (Tob) as a mediator to assemble DNA nanostructures, allowing for the functionalization of DNA nanostructures by combining DNA and antibiotics. Additionally, our study incorporates maleimide-modified DNA into the nanostructures to act as a targeting moiety specifically directed towards the pili of PA. The targeting ability of the constructed functional DNA nanostructure significantly improves the local concentration of Tob, thereby reducing the side effects of antibiotics. Our results demonstrate the successful construction of a maleimide-decorated Tob/DNA nanotube (NTTob-Mal) for the treatment of PA-infected lung inflammation. The stability and biocompatibility of NTTob-Mal are confirmed, highlighting its potential for clinical applications. Furthermore, its specificity in recognizing and adhering to PA has been validated. In vitro experiments have shown its efficacy in inhibiting PA biofilm formation, and in a murine model, NTTob-Mal has exhibited significant therapeutic effectiveness against PA-induced pneumonia. In summary, the proposed antibiotic drug-mediated DNA nanostructure assembly approach holds promise as a novel strategy for targeted treatment of PA infections.

Rab26 alleviates sepsis-induced immunosuppression as a master regulator of macrophage ferroptosis and polarization shift.

Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1. During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis. Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS, MDA, and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.

Visible light-driven C/O-g-C3N4 activating peroxydisulfate to effectively inactivate antibiotic resistant bacteria and inhibit the transformation of antibiotic resistance genes: Insights on the mechanism.

Antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) dissemination within water pose a serious threat to public health. Herein, C and O dual-doped g-C3N4 (C/O-g-C3N4) photocatalyst, fabricated via calcination treatment, was utilized to activate peroxydisulfate (PDS) to investigate the disinfection effect on tetracycline-resistant Escherichia coli and the transformation frequency of ARGs. As a result, approximately 7.08 log E. coli were inactivated, and 72.36 % and 53.96 % of antibiotics resistance gene (tetB) and 16 S rRNA were degraded respectively within 80 min. Futhermore, the transformation frequency was reduced to 0.8. Characterization and theoretical results indicated that C and O doping in g-C3N4 might lead to the electronic structure modulation and band gap energy reduction, resulting in the production of more free radicals. The mechanism analysis revealed that C/O-g-C3N4 exhibited a lower adsorption energy and reaction energy barrier for PDS compared to g-C3N4. This was beneficial for the homolysis of O-O bonds, forming SO4•- radicals. The attack of the generated active species led to oxidative stress in cells, resulting in damage to the electron transport chain and inhibition of ATP production. Our findings disclose a valuable insight for inactivating ARB, and provide a prospective strategy for ARGs dissemination in water contamination.

Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria.

Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lungs caused by bacterial or viral infection. Timely phagocytosis and clearance of pathogens by macrophages are important in controlling inflammation and alleviating ARDS. However, the precise mechanism of macrophage phagocytosis remains to be explored. Here, we show that the expression of Rab26 is increased in Escherichia coli- or Pseudomonas aeruginosa-stimulated bone marrow-derived macrophages. Knocking out Rab26 reduced phagocytosis and bacterial clearance by macrophages. Rab26 interacts with mitochondrial fusion protein mitofusin-2 (MFN2) and affects mitochondrial reactive oxygen species generation by regulating MFN2 transport. The levels of MFN2 in mitochondria were reduced in Rab26-deficient bone marrow-derived macrophages, and the levels of mitochondrial reactive oxygen species and ATP were significantly decreased. Knocking down MFN2 using small interfering RNA resulted in decreased phagocytosis and killing ability of macrophages. Rab26 knockout reduced phagocytosis and bacterial clearance by macrophages in vivo, significantly increased inflammatory factors, aggravated lung tissue damage, and increased mortality in mice. Our results demonstrate that Rab26 regulates phagocytosis and clearance of bacteria by mediating the transport of MFN2 to mitochondria in macrophages, thus alleviating ARDS in mice and potentially in humans.

Metagenomic next-generation sequencing for pleural effusions induced by viral pleurisy: A case report.

BACKGROUND: Viral pleurisy is a viral infected disease with exudative pleural effusions. It is one of the causes for pleural effusions. Because of the difficult etiology diagnosis, clinically pleural effusions tend to be misdiagnosed as tuberculous pleurisy or idiopathic pleural effusion. Here, we report a case of pleural effusion secondary to viral pleurisy which is driven by infection with epstein-barr virus. Viral infection was identified by metagenomic next-generation sequencing (mNGS). CASE SUMMARY: A 40-year-old male with a history of dermatomyositis, rheumatoid arthritis, and secondary interstitial pneumonia was administered with long-term oral prednisone. He presented with fever and chest pain after exposure to cold, accompanied by generalized sore and weakness, night sweat, occasional cough, and few sputums. The computed tomography scan showed bilateral pleural effusions and atelectasis of the partial right lower lobe was revealed. The pleural fluids were found to be yellow and slightly turbid after pleural catheterization. Thoracoscopy showed fibrous adhesion and auto-pleurodesis. Combining the results in pleural fluid analysis and mNGS, the patient was diagnosed as viral pleuritis. After receiving Aciclovir, the symptoms and signs of the patient were relieved. CONCLUSION: Viral infection should be considered in cases of idiopathic pleural effusion unexplained by routine examination. mNGS is helpful for diagnosis.

Attenuating endothelial leakiness with self-assembled DNA nanostructures for pulmonary arterial hypertension.

Vascular endothelium dysfunction plays an important role in oncological and pulmonary diseases. Endothelial barrier dysfunction is the initial step of pulmonary vascular remodeling (PVR) and pulmonary arterial hypertension. Upregulation of a pro-autophagy protein Atg101 in the endothelial cells triggered a cascade of intracellular events that leads to endothelial dysfunction through apoptosis. Herein, we proposed a strategy that used endothelial targeting DNA nanostructures to deliver Atg101 siRNA (siAtg101) as a safe, biocompatible "band-aid" to restore pulmonary arterial endothelial barrier integrity within the intricate milieu of pulmonary cells and the pulmonary vasculature. The siAtg101 and aptamer conjugated DNA nanostructures were found to attenuate hypoxia-induced pulmonary endothelial leakiness with surprisingly high selectivity and efficacy. Further in vivo study revealed that functionalized DNA nanostructures likewise attenuated the vascular remodeling in a monocrotaline-induced PVR mouse model. Mechanistically, functionalized DNA nanostructures suppressed PVR by knocking down Atg101, which in turn, downregulated Beclin-1 and subsequently upregulated VE-cadherin to restore endothelial cells' adherin junctions. This work opened a new window for future nanomaterial design that directly addresses the interfacial endothelial cell layer that often stands between the blood and many diseased sites of nanotherapeutic interest.

Framework Nucleic Acids Enabled Pulmonary Artery Endothelial Cell Growth Inhibition by Targeting microRNA-152.

Pulmonary artery vascular endothelial dysfunction plays a pivotal role in the occurrence and progression of pulmonary vascular remodeling (PVR). To address this, aberrantly expressed non-coding microRNAs (miRNAs) are excellent therapeutic targets in human pulmonary artery endothelial cells (HPAECs). Here, we discovered and validated the overexpression of miRNA-152 in HPAECs under hypoxia and its role in endothelial cell dysfunction. We constructed a framework nucleic acid nanostructure that harbors six protruding single-stranded DNA segments that can fully hybridize with miRNA-152 (DNT-152). DNT-152 was efficiently taken up by HPAECs with increasing time and concentration; it markedly induced apoptosis, and inhibited HPAEC growth under hypoxic conditions. Mechanistically, DNT-152 silenced miRNA-152 expression and upregulated its target gene Meox2, which subsequently inhibited the AKT/mTOR signaling pathway. These results indicate that miRNA-152 in HPAECs may be an excellent therapeutic target against PVR, and that framework nucleic acids with carefully designed sequences are promising nanomedicines for noncancerous cells and diseases.

The TLR7/8 agonist R848 optimizes host and tumor immunity to improve therapeutic efficacy in murine lung cancer.

Treatment with the Toll­like receptor 7 (TLR7) agonist, resiquimod (R848), is effective in various types of cancer, such as breast, pancreatic and colorectal cancer. The reported antitumor effect of R848 in lung cancer is considered to be achieved by targeting macrophages. In the present study, it was demonstrated that TLR7 expression on various immune cell types initially rises, then declines in the late stage of lung cancer. Intraperitoneal injection of R848 resulted in a reduction in tumor burden and prolonged survival in both subcutaneous and metastatic lung cancer models in C57BL/6 mice. Initial treatment with R848 at an early stage was found to be the optimal choice. Systemic injection of R848 promoted the activation of innate and adaptive immune responses. Systemic administration of R848 upregulated TLR7 expression in dendritic cells (DCs) and enhanced the activation of DCs and natural killer (NK) cells. Moreover, this treatment also resulted in increased production of T helper cell­associated cytokines in serum, including IFN­Î³, TNF­α and IL­2. In addition, continuous treatment with R848 increased the proportion of DCs, NK and CD8+ T cells, and reduced that of Foxp3+ regulatory T cells in the tumor microenvironment. These findings supported the use of R848 treatment for lung cancer via TLR7 targeting and provided insight into the underlying therapeutic mechanism.

Extracellular HMGB1 Impairs Macrophage-Mediated Efferocytosis by Suppressing the Rab43-Controlled Cell Surface Transport of CD91.

High-mobility group box 1 (HMGB1) protein can impair phagocyte function by suppressing the macrophage-mediated clearance of apoptotic cells (ACs), thereby delaying inflammation resolution in the lungs and allowing the progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the precise mechanism underlying this HMGB1-mediated inhibition of efferocytosis remains unknown. The aim of this study was to determine the effect of HMGB1 on macrophage-mediated efferocytosis. We discovered that HMGB1 prevented efferocytosis by bone marrow-derived macrophages (BMDMs) and suppressed the expression of Ras-related GTP-binding protein 43 (Rab43), a member of the Ras-associated binding (Rab) family. The downregulation of Rab43 expression resulted in impaired clearance of apoptotic thymocytes by BMDMs. Subsequent analysis of HMGB1-treated and Rab43-deficient BMDMs revealed the inhibited transport of cluster of differentiation 91 (CD91), a phagocyte recognition receptor, from the cytoplasm to the cell surface. Notably, Rab43 directly interacted with CD91 to mediate its intercellular trafficking. Furthermore, Rab43 knockout delayed the inflammation resolution and aggravated the lung tissue damage in mice with ALI. Therefore, our results provide evidence that HMGB1 impairs macrophage-mediated efferocytosis and delays inflammation resolution by suppressing the Rab43-regulated anterograde transport of CD91, suggesting that the restoration of Rab43 levels is a promising strategy for attenuating ALI and ARDS in humans.

Protein-mediated DNA self-assembly by controlling the surface charge in a molecular crowding environment.

Designing and building artificial nanodevices and nanoarchitectures in living systems are extremely intriguing subjects in nanotechnology and synthetic biology. Taking advantage of cellular machinery and endogenous biomacromolecules, such as proteins, is key to achieving the precise and sophisticated manipulation of nanoarchitectures. In this study, we proposed a protein-mediated DNA self-assembly strategy in a molecular crowding environment. By carefully controlling the surface charge of basic nuclear proteins in a crowding environment that mimicked the intracellular environment, we demonstrated that highly positively charged protamine can assemble individual DNA strands into defined structures similar to a catalytic process manner. Successful self-assembly required an optimized protamine surface charge and a crowding environment; otherwise, this self-assembly was impossible. Polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), and dynamic light scattering (DLS) results showed that tile-based DNA tubular structures, tetrahedra, and two dimensional DNA origami structures were successfully assembled. We inferred that the assembly process occurred between the arginine-rich domain of protamine and DNA strands that repeatedly interacted with each other in the viscous system. The current study provides a potential strategy to construct nanodevices in living systems and presents an alternative protein-DNA interaction for the potential fabrication of protein-DNA hybrid nanomaterials.

Extracellular CIRP-Impaired Rab26 Restrains EPOR-Mediated Macrophage Polarization in Acute Lung Injury.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a condition with an imbalanced inflammatory response and delayed resolution of inflammation. Macrophage polarization plays an important role in inflammation and resolution. However, the mechanism of macrophage polarization in ALI/ARDS is not fully understood. We found that mice with lipopolysaccharide administration developed lung injury with the accumulation of extracellular cold-inducible RNA-binding protein (eCIRP) in the lungs. eCIRP, as a damage-associated molecular pattern (DAMP), inhibited M2 macrophage polarization, thereby tipping the balance toward inflammation rather than resolution. Anti-CIRP antibodies reversed such phenotypes. The levels of macrophage erythropoietin (EPO) receptor (EPOR) were reduced after eCIRP treatment. Myeloid-specific EPOR-deficient mice displayed restrained M2 macrophage polarization and impaired inflammation resolution. Mechanistically, eCIRP impaired Rab26, a member of Ras superfamilies of small G proteins, and reduced the transportation of surface EPOR, which resulted in macrophage polarization toward the M1 phenotype. Moreover, EPO treatment hardly promotes M2 polarization in Rab26 knockout (KO) macrophages through EPOR. Collectively, macrophage EPOR signaling is impaired by eCIRP through Rab26 during ALI/ARDS, leading to the restrained M2 macrophage polarization and delayed inflammation resolution. These findings identify a mechanism of persistent inflammation and a potential therapy during ALI/ARDS.

Hyperglycemia and Correlated High Levels of Inflammation Have a Positive Relationship with the Severity of Coronavirus Disease 2019.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a considerable global public health threat. This study sought to investigate whether blood glucose (BG) levels or comorbid diabetes are associated with inflammatory status and disease severity in patients with COVID-19. METHODS: In this retrospective cohort study, the clinical and biochemical characteristics of COVID-19 patients with or without diabetes were compared. The relationship among severity of COVID-19, inflammatory status, and diabetes or hyperglycemia was analyzed. The severity of COVID-19 in all patients was determined according to the diagnostic and treatment guidelines issued by the Chinese National Health Committee (7th edition). RESULTS: Four hundred and sixty-one patients were enrolled in our study, and 71.58% of patients with diabetes and 13.03% of patients without diabetes had hyperglycemia. Compared with patients without diabetes (n = 366), patients with diabetes (n = 95) had a higher leucocyte count, neutrophil count, neutrophil to lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR). There was no association between severity of COVID-19 and known diabetes adjusted for age, sex, body mass index (BMI), known hypertension, and coronary heart disease. The leucocyte count, NLR, and C-reactive protein (CRP) level increased with increasing BG level. Hyperglycemia was an independent predictor of critical (OR 4.00, 95% CI 1.72-9.30) or severe (OR 3.55, 95% CI 1.47-8.58) COVID-19, and of increased inflammatory levels (high leucocyte count (OR 4.26, 95% CI 1.65-10.97), NLR (OR 2.76, 95% CI 1.24-6.10), and CRP level (OR 2.49, 95% CI 1.19-5.23)), after adjustment for age, sex, BMI, severity of illness, and known diabetes. CONCLUSION: Hyperglycemia was positively correlated with higher inflammation levels and more severe illness, and it is a risk factor for the increased severity of COVID-19. The initial measurement of plasma glucose levels after hospitalization may help identify a subset of patients who are predisposed to a worse clinical course.

Functionalizing DNA nanostructures with natural cationic amino acids.

Complexing self-assembled DNA nanostructures with various functional guest species is the key to unlocking new and exciting biomedical applications. Cationic guest species not only induce magnesium-free DNA to self-assemble into defined structures but also endow the final complex nanomaterials with new properties. Herein, we propose a novel strategy that employs naturally occurring cationic amino acids to induce DNA self-assembly into defined nanostructures. Natural l-arginine and l-lysine can readily induce the assembly of tile-based DNA nanotubes and DNA origami sheets in a magnesium-free manner. The self-assembly processes are demonstrated to be pH- and concentration-dependent and are achieved at constant temperatures. Moreover, the assembled DNA/amino acid complex nanomaterials are stable at a physiological temperature of 37 °C. Substituting l-arginine with its D form enhances its serum stability. Further preliminary examination of this complex nanomaterial platform for biomedical applications indicates that DNA/amino acids exhibit distinct cellular uptake behaviors compared with their magnesium-assembled counterparts. The nanomaterial mainly clusters around the cell membrane and might be utilized to manipulate molecular events on the membrane. Our study suggests that the properties of DNA nanostructures can be tuned by complexing them with customized guest molecules for a designed application. The strategy proposed herein might be promising to advance the biomedical applications of DNA nanostructures.

Current situation of asthma-COPD overlap in Chinese patients older than 40 years with airflow limitation: a multicenter, cross-sectional, non-interventional study.

BACKGROUND AND AIMS: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is poorly recognized in China. Our study determined the distribution of ACO and its clinical characteristics among patients (aged ⩾40 years) with airflow limitation at Chinese tertiary hospitals. METHODS: This cross-sectional, non-interventional study (NCT02600221), conducted between December 2015 and October 2016 in 20 Tier-3 Chinese hospitals, included patients aged ⩾40 years with post-bronchodilator (BD) FEV1/FVC <0.7. The primary variable was distribution of ACO in adults with post-BD forced expiratory volume /forced vital capacity (FEV1/FVC) <0.7 based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2015 and 2017 reports. Other variables included determination of characteristics of ACO and its clinical recognition rate. RESULTS: In 2003 patients (mean age 62.30 ± 9.86 years), distribution of ACO, COPD and asthma were 37.40%, 48.50% and 14.10%, respectively. Proportions of patients with A, B, C and D grouping were 11.70%, 31.00%, 6.90% and 50.30% as per GOLD 2017, whereas they were 15.10%, 51.10%, 3.60% and 30.20% as per GOLD 2015. Similar clinical symptoms were reported in all three groups. A higher percentage of ACO patients presented with dyspnea, wheezing and chest tightness. Compared with the COPD group, a greater proportion of ACO patients reported wheezing (74.6% and 65.40%), while a lower proportion in the ACO group reported cough (79.40% versus 82.70%) and expectoration (76.50% versus 81.60%). Blood eosinophil count ⩾0.3 × 109/L was observed in 34.6% of ACO patients. The clinical recognition rate of ACO was 31.4%. CONCLUSION: Despite ACO affecting two-fifths of the study population, the initial diagnosis rate was low at 6% in China, thus warranting concerted efforts to improve ACO diagnosis. CLINICALTRIALS.GOV: [ClinicalTrials.gov identifier: NCT02600221] registered 22 October 2015, https://clinicaltrials.gov/ct2/show/NCT02600221The reviews of this paper are available via the supplemental material section.

Assembling Defined DNA Nanostructure with Nitrogen-Enriched Carbon Dots for Theranostic Cancer Applications.

DNA nanostructures as scaffolds for drug delivery, biosensing, and bioimaging are hindered by its vulnerability in physiological settings, less favorable of incorporating arbitrary guest molecules and other desirable functionalities. Noncanonical self-assembly of DNA nanostructures with small molecules in an alternative system is an attractive strategy to expand their applications in multidisciplinary fields and is rarely explored. This work reports a nitrogen-enriched carbon dots (NCDs)-mediated DNA nanostructure self-assembly strategy. Given the excellent photoluminescence and photodynamic properties of NCDs, the obtained DNA/NCDs nanocomplex holds great potential for bioimaging and anticancer therapy. NCDs can mediate DNA nanoprism (NPNCD ) self-assembly isothermally at a large temperature and pH range in a magnesium-free manner. To explore the suitability of NPNCD in potential biomedical applications, the cytotoxicity and cellular uptake efficiency of NPNCD are evaluated. NPNCD with KRAS siRNA (NPNCD K) is further conjugated for KRAS-mutated nonsmall cell lung cancer therapy. The NPNCD K shows excellent gene knockdown efficiency and anticancer effect in vitro. The current study suggests that conjugating NCDs with programmable DNA nanostructures is a powerful strategy to endow DNA nanostructures with new functionalities, and NPNCD may be a potential theranostic platform with further fine-tuned properties of CDs such as near-red fluorescence or photothermal activities.

Efficacy of Shenqi Pollen Capsules for High-Altitude Deacclimatization Syndrome via Suppression of the Reoxygenation Injury and Inflammatory Response.

High-altitude deacclimatization syndrome (HADAS) is involved in hypoxia-reoxygenation injury and inflammatory response, induced a series of symptoms, and has emerged as a severe public health issue. Here, we investigated the mechanism as well as potential means to prevent HADAS using Shenqi pollen capsules (SPCs) in subjects with HADAS in a multicenter, double-blinded, randomized, placebo-controlled study. All subjects were at the same high altitude (3650 m) for 4-8 months before returning to lower altitudes. Subjects (n = 288) in 20 clusters were diagnosed with mild or moderate HADAS on the third day of the study. We randomly allocated 20 clusters of subjects (1 : 1) to receive SPCs or a placebo for 7 weeks, and they were then followed up to the 14th week. The primary endpoints were subjects' HADAS scores recorded during the 14 weeks of follow-up. Compared with the placebo, SPC treatment significantly decreased the subjects' HADAS scores and reduced the incidence of symptom persistence. SPC therapy also reduced the serum levels of CK, CK-MB, LDH, IL-17A, TNF-α, and miR-155 and elevated IL-10 and miR-21 levels. We thus demonstrate that SPCs effectively ameliorated HADAS symptoms in these subjects via suppression of the hypoxia-reoxygenation injury and inflammatory response.

Mutated p53 Promotes the Symmetric Self-Renewal of Cisplatin-Resistant Lung Cancer Stem-Like Cells and Inhibits the Recruitment of Macrophages.

It has been proposed that mutant p53 is correlated with the recurrence of lung cancer. Recently, a small population of cells with asymmetric or symmetric self-renewal potential has been identified in lung cancer, which was termed as cancer stem-like cells (CSCs) and was speculated to be the reason for cancer recurrence after chemotherapy. In this study, we used lung cancer cell lines with different TP53 backgrounds to elucidate the potential role of mutant p53 in regulating lung CSC self-renewal and on lung cancer recurrence. Cisplatin-resistant lung cancer cells with different TP53 backgrounds were generated in vitro by exposing A549, H460, and H661 lung cancer cell lines repeatedly to cisplatin. CD44+/CD90+ stem-like cells were identified in above cisplatin-resistant lung cancers (termed as cisplatin-resistant lung cancer stem-like cells, (Cr-LCSCs)) and stained with PKH26 dye which was used to define the self-renewal pattern. The proportion of symmetric divisions was significantly higher in Cr-LCSCs with mutant (mt) p53 compared with Cr-LCSCs with wild-type (wt) p53, and forced expression of mt p53 promoted the symmetric division of Cr-LCSCs. Furthermore, fewer macrophages accumulated in subcutaneously implanted xenografts consisting of mt p53 Cr-LCSCs compared with wt p53 Cr-LCSCs. These results indicated that mt p53 might accelerate the recurrence of lung cancer by regulating the self-renewal kinetics of Cr-LCSCs as well as the recruitment of macrophages.

PK/PD modeling of Ceftiofur Sodium against Haemophilus parasuis infection in pigs.

BACKGROUND: Ceftiofur Sodium is widely used in China. Our aim was to determine Ceftiofur Sodium activity and optimize dosing regimens against the pathogen Haemophilus parasuis using an in vitro and ex vivo pharmacokinetics/pharmacodynamics modeling approach. By adopting these strategies, we wanted to extend the effective life of Ceftiofur Sodium in reduce drug-resistance in pigs. RESULTS: We established an H. parasuis infection model in pigs, and assessed the pharmacokinetics of Ceftiofur Sodium in both healthy and infected animals. After Ceftiofur Sodium (10 mg/kg, i.m.) administration to healthy and H. parasuis-infected pigs, plasma based desfuroylceftiofur (a metabolite of Ceftiofur Sodium) was measured by High Performance Liquid Chromatography. The pharmacokinetics of Ceftiofur Sodium (desfuroylceftiofur) was consistent with a two-compartment open model, with first-order absorption. We observed no significant differences (P > 0.05) in pharmacokinetic parameters between healthy and infected pigs. Pharmacodynamics data showed that Ceftiofur Sodium was highly inhibitory against H. parasuis, with MIC, MBC, and MPC values of 0.003125, 0.0125 and 0.032 µg/mL, respectively. Desfuroylceftiofur in plasma also had strong bactericidal activity. Almost all H. parasuis cultured in plasma medium of Ceftiofur Sodium-inoculated healthy pigs, at each time point, were killed within 24 h. A weaker antibacterial activity was measured in infected-pig plasma medium at 18, 24, 36, and 48 h, after Ceftiofur Sodium inoculation. Pharmacokinetic parameters were combined with ex vivo pharmacodynamic parameters, and the bacteriostatic effect (36.006 h), bactericidal effect (71.637 h) and clearance (90.619 h) within 24 h, were determined using the Hill equation. Dose-calculation equations revealed the optimal dose of Ceftiofur Sodium to be 0.599-1.507 mg/kg. CONCLUSIONS: There were no significant differences in Ceftiofur Sodium pharmacokinetic parameters between healthy and infected pigs, although pharmacokinetics/pharmacodynamics fitting curves showed obviously differences. The optimal dose of Ceftiofur Sodium was lower than recommended (3 mg/kg), which may provide improved treatments for Glässers disease, with lower drug-resistance possibility.