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The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO2, PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates.

Hua Bai,1 Na He,2 Yan Zhang,3 Aqsa Ahmad,3 Xing-Xing Yang,3 Yan Ma,3 Li-Jun Liang1 1Department of Pediatrics, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2PKUFH-NINGXIA Women Children’s Hospital, Yinchuan, 750001, People’s Republic of China; 3The First Clinical Medical College of Ningxia Medical University General Hospital, Yinchuan, 750004, People’s Republic of ChinaCorrespondence: Li-Jun Liang, Department of Pediatrics, General Hospital of Ningxia Medical University, 804 Shengli South Street, Yinchuan, Ningxia, 750004, People’s Republic of China, Tel +86 137 0959 6527, Email lianglijunlj@126.comObjective: In this study, we aimed to evaluate the current status of the quality of life (QOL) of pediatric patients and plasma glucose concentration regulation in children with type 1 diabetes (T1DM) in the Ningxia Hui autonomous region.Methods: The study involved children with T1DM admitted to the General Hospital of Ningxia Medical University between October 2011 and October 2021. The children and their parents completed general information and quality of life (QOL) questionnaires. The regulation of plasma glucose concentration was assessed based on HbA1c levels, and plasma glucose and QOL-influencing components were investigated.Results: Among the 136 pediatric patients diagnosed with T1DM, the mean glycated hemoglobin (HbA1c) level was recorded at 8.7% (7.2%, 10.5%). A breakdown of the patient cohort revealed that 44 patients (32.4%) demonstrated good regulation of plasma glucose, 33 patients (24.3%) exhibited acceptable glycemic control, and 59 patients (43.3%) displayed poor regulation of plasma glucose. The control of plasma glucose in pediatric patients diagnosed with T1DM was affected by the duration of the disease, the patient’s age, the frequency of daily plasma glucose measurements, the use of CGM, diabetic ketoacidosis (DKA), and the education level of the mother. The control of plasma glucose, dietary management, DKA, the ability to learn, and health education are interfering factors of quality of life in children diagnosed with T1DM. Effective control of plasma glucose may ensure the QOL in children with T1DM, and DKA was the risk factor for QOL.Conclusion: In Ningxia, the regulation of plasma glucose in pediatric and adolescent patients with T1DM remains suboptimal, leading to poor QOL. There is a pressing need to enhance glucose regulation and QOL through comprehensive strategies, which include reinforced dietary management, rigorous monitoring of plasma glucose levels, and heightened health education levels.Keywords: current status of regulation of plasma glucose concentration, influencing factors, QOL, type 1 diabetes

Jiakang Chen,1,* Kasim Allel,2– 4,* Chuyue Zhuo,1,* Wenwei Luo,5 Nanhao He,1 Xu Yang,1 Yingyi Guo,1 Jiong Wang,1 Likang Yao,1 Jiahui Li,1 Yexin Lin,1 Ruiyang Tu,6 Laith Yakob,2,3 Chao Zhuo1 1State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Disease Control, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; 3Antimicrobial Resistance Centre, London School of Hygiene & Tropical Medicine, London, UK; 4Institute for Global Health, University College London, London, UK; 5Department of Clinical Laboratory, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 6Department of Science and Technology Studies, University College London, London, UK*These authors contributed equally to this workCorrespondence: Chao Zhuo, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong, People’s Republic of China, Email chaosheep@gzhmu.edu.cnIntroduction: Although Extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) significantly contribute to bloodstream infections, their economic repercussions remain largely unquantified.Data Source and Methods: We performed a retrospective analysis of inpatients diagnosed with Escherichia coli or Klebsiella pneumoniae bacteremia in a tertiary hospital from January 2020 to December 2022 in Guangzhou, China. We employed the chi-square test to examine ESBL risk factors and utilized propensity score matching (PSM) to negate baseline confounding factors, assessing economic burden through disability-adjusted life years (DALYs), hospital costs and productivity losses. We employed mediation analysis to eliminate confounding factors and better identify ESBL sources of burden related.Results: We found 166 ESBL-EC/KP BSI patients (52.2% of the total examined 318 patients). Post-PSM analysis revealed that ESBL-producing EC/KP will reduce the effectiveness of empirical medication by 19.8%, extend the total length of hospitalization by an average of 3 days, and increase the patient’s financial burden by US$2047. No significant disparity was found in overall mortality and mean DALYs between the groups. Mediation analysis showed that the link between ESBL and hospital costs is predominantly, if not entirely, influenced by the appropriateness of empirical antibiotic treatment and length of hospital stay.Conclusion: Patients with BSI due to ESBL-producing ESBL-EK incur higher costs compared to those with non-ESBL-EK BSI. This cost disparity is rooted in varying rates of effective empirical antimicrobial therapy and differences in hospital stay durations. A nuanced approach, incorporating a thorough understanding of regional epidemiological trends and judicious antibiotic use, is crucial for mitigating the financial impact on patients.Keywords: Escherichia coli, Klebsiella pneumoniae, bacteremia, ESBL, risk factors, medical costs

Mingtang Zeng,1 Yao Wang,1 Maozhu Liu,1 Yuxun Wei,2 Jie Wen,3 Yuchen Zhang,1 Tao Chen,4 Nianyu He,1 Ping Fan,1 Xinhua Dai5 1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Pharmacy, Zhongjiang County People’s Hospital, Deyang, 618000, People’s Republic of China; 3Department of Pharmacy, Shehong Municipal Hospital of Traditional Chinese Medicine, Shehong, 629600, People’s Republic of China; 4Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 5Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xinhua Dai, Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email dxh9123@163.com Ping Fan, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email m13980602288@163.comAbstract: Carbon dots (CDs), a crucial component of nanomaterials, are zero-dimensional nanomaterials with carbon as the backbone structure and smaller than 10 nm. Due to their beneficial characteristics, they are widely used in biomedical fields such as biosensors, drug delivery, bio-imaging, and interactions with DNA. Interestingly, a novel type of carbon dot, generated by using herbal medicines as synthetic raw materials, has emerged as the most recent incomer in the family of CDs with the extensive growth in the number of materials selected for carbon dots synthesis. Herbal medicine-derived carbon dots (HM-CDs) have been employed in the biomedical industry, and are rapidly emerging as “modern nanomaterials” due to their unique structures and exceptional capabilities. Emerging trends suggest that their specific properties can be used in bleeding disorders, gastrointestinal disorders, inflammation-related diseases, and other common intractable diseases including cancer, menopausal syndrome, central nervous system disorders, and pain of various forms and causes. In addition, HM-CDs have been found to have organ-protective and antioxidant properties, as evidenced by extensive studies. This research provides a more comprehensive understanding of the biomedical applications of HM-CDs for the aforementioned disorders and investigates the intrinsic pharmacological activities and mechanisms of these HM-CDs to further advance their clinical applications. Keywords: herbal medicine, carbon dots, disease treatment, nanomaterials, potential mechanism

Zeng M, Wang Y, Liu M, et al. Int J Nanomedicine. 2023;18:6503–6525. The authors have advised that Figure 2 on page 6510 was published in error. The correct Figure 2 is as follows. Figure 2 HM-CDs significantly improved blood-brain barrier (BBB) permeability. HM-CD-1 has an ultra-tiny size and abundance surface functional groups. The covalent binding of HM-CD-2 to the drug facilitates passive transport of the drug. HM-CD-3 has a strong affinity for the BBB endothelial cell membrane. The authors apologize for this error.

Adenine nucleotide translocator (ANT) is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner membrane. It plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the cytoplasm. The isoform ANT1 predominately expresses in cardiac and skeletal muscles. Mutations or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular diseases. We aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-deficient mice. Hearts and quadriceps resected from age-matched wild type (WT) and ANT1-deficient mice were snap-frozen in liquid nitrogen. The Chance redox scanner was utilized to perform 3D optical redox imaging. Each sample underwent scanning across 3–5 sections. Global averaging analysis showed no significant differences in the redox indices (NADH, flavin adenine dinucleotide containing-flavoproteins Fp, and the redox ratio Fp/(NADH+Fp) between WT and ANT1-deficient groups. However, quadriceps had higher Fp than hearts in both groups ([Formula: see text] and 0.01, respectively). Furthermore, the quadriceps were also more oxidized (a higher redox ratio) than hearts in WT group ([Formula: see text]). NADH levels were similar in all cases. Our data suggest that under non-stressful physical condition, the ANT1-deficient muscle cells were in the same mitochondrial state as WT ones and that the significant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-deficient ones. Redox imaging of muscles under physical stress can be conducted in future.

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD.

To develop imaging biomarkers for tumors aggressiveness, our previous optical redox imaging (ORI) studies of the reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp, containing flavin adenine dinucleotide, i.e., FAD) in tumor xenografts of human melanoma associated the high optical redox ratio (ORR = Fp/(Fp + NADH)) and its heterogeneity to the high invasive/metastatic potential, without having reported quantitative results for NADH and Fp. Here, we implemented a calibration procedure to facilitate imaging the nominal concentrations of tissue NADH and Fp in the mouse xenografts of two human melanoma lines, an indolent less metastatic A375P and a more metastatic C8161. Images of the redox indices (NADH, Fp, ORR) revealed the existence of more oxidized areas (OAs) and more reduced areas (RAs) within individual tumors. ORR was found to be higher and NADH lower in C8161 compared to that of A375P xenografts, both globally for the whole tumors and locally in OAs. The ORR in the OA can differentiate xenografts with a higher statistical significance than the global averaged ORR. H&E staining of the tumors indicated that the redox differences we identified were more likely due to intrinsically different cell metabolism, rather than variations in cell density.

Ling Li,1,2,* Yaoyao Du,1,* Yang Wang,3 Ning He,2 Bing Wang,1,4 Tong Zhang1 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People’s Republic of China; 3Metabo-Profile Biotechnology (Shanghai) Co. Ltd, Shanghai, People’s Republic of China; 4Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing Wang; Tong Zhang, Email bwang@simm.ac.cn; zhangtdmj@hotmail.comBackground: Gastric ulcer (GU) is the most common multifactor gastrointestinal disorder affecting millions of people worldwide. There is evidence that gut microbiota is closely related to the development of GU. Atractylone (ATR) has been reported to possess potential biological activities, but research on ATR alleviating GU injury is unprecedented.Methods: Helicobacter pylori (H. pylori)-induced GU model in zebrafish and ethanol-induced acute GU model in rat were established to evaluate the anti-inflammatory and ulcer inhibitory effects of ATR. Then, 16S rRNA sequencing and metabolomics analysis were performed to investigate the effect of ATR on the microbiota and metabolites in rat feces and their correlation.Results: Therapeutically, ATR inhibited H. pylori-induced gastric mucosal injury in zebrafish. In the ulceration model of rat, ATR mitigated the gastric lesions damage caused by ethanol, decreased the ulcer area, and reduced the production of inflammatory factors. Additionally, ATR alleviated the gastric oxidative stress injury by increasing the activity of superoxide dismutase (SOD) and decreasing the level of malondialdehyde (MDA). Furthermore, ATR played a positive role in relieving ulcer through reshaping gut microbiota composition including Parabacteroides and Bacteroides and regulating the levels of metabolites including amino acids, short-chain fatty acids (SCFAs), and bile acids.Conclusion: Our work sheded light on the mechanism of ATR treating GU from the perspective of the gut microbiota and explored the correlation between gut microbiota, metabolites, and host phenotype.Keywords: atractylone, gastric ulcer, inflammation, oxidative stress, gut microbiota, metabolomics

Huabin Wang,1,2,* Junbin Huang,1,2,* Wenfang Yi,1,2,* Jiahong Li,3 Nannan He,4 Liangliang Kang,4 Zhijie He,5 Chun Chen1,2 1Division of Hematology/Oncology, Department of Pediatrics, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China; 2Department of Pediatric Intensive Care Unit, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China; 3Department of Neonatal Intensive Care Unit, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China; 4Department of Pediatric Intensive Care Unit, Shenzhen Children’s Hospital, Shenzhen, 518000, People’s Republic of China; 5Department of Intensive Care Unit, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhijie He; Chun Chen, Email hezhijie@mail.sysu.edu.cn; chenchun69@126.comObjective: The pathogenesis of sepsis is still unclear due to its complexity, especially in children. This study aimed to analyse the immune microenvironment and regulatory networks related to sepsis in children at the molecular level and to identify key immune-related genes to provide a new basis for the early diagnosis of sepsis.Methods: The GSE145227 and GSE26440 datasets were downloaded from the Gene Expression Omnibus. The analyses included differentially expressed genes (DEGs), functional enrichment, immune cell infiltration, the competing endogenous RNA (ceRNA) interaction network, weighted gene coexpression network analysis (WGCNA), protein–protein interaction (PPI) network, key gene screening, correlation of sepsis molecular subtypes/immune infiltration with key gene expression, the diagnostic capabilities of key genes, and networks describing the interaction of key genes with transcription factors and small-molecule compounds. Finally, real-time quantitative PCR (RT–qPCR) was performed to verify the expression of key genes.Results: A total of 236 immune-related DEGs, most of which were enriched in immune-related biological functions, were found. Further analysis of immune cell infiltration showed that M0 macrophages and neutrophils infiltrated more in the sepsis group, while fewer activated memory CD4+ T cells, resting memory CD4+ T cells, and CD8+ T cells did. The interaction network of ceRNA was successfully constructed. Six key genes (FYN, FBL, ATM, WDR75, FOXO1 and ITK) were identified by WGCNA and PPI analysis. We found strong associations between key genes and constructed septic molecular subtypes or immune cell infiltration. Receiver operating characteristic analysis showed that the area under the curve values of the key genes for diagnosis were all greater than 0.84. Subsequently, we successfully constructed an interaction network of key genes and transcription factors/small-molecule compounds. Finally, the key genes in the samples were verified by RT–qPCR.Conclusion: Our results offer new insights into the pathogenesis of sepsis in children and provide new potential diagnostic biomarkers for the disease.Keywords: sepsis in children, key immune-related genes, transcriptomic analysis, Gene Expression Omnibus, diagnostic biomarkers

Na He,1,2 Fei Dong,3 Wei Liu,1 Suodi Zhai1 1Department of Pharmacy, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing, People’s Republic of China; 3Department of Hematology, Peking University Third Hospital, Beijing, People’s Republic of ChinaCorrespondence: Suodi Zhai; Wei LiuDepartment of Pharmacy, Peking University Third Hospital, 49 Huayuan North Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86 10-82266686; +86 10-82265740Email zhaisuodi@163.com; andthen0023@163.comObjective: To provide a comprehensive review of vancomycin dosing in patients with hematologic malignancies or neutropenia.Methods: PubMed, Embase and the Cochrane Library were searched through April 2, 2020. Original studies relevant to vancomycin dosing regimen in adults with hematologic malignancies or neutropenia were included. No restriction was applied in study design and language. A descriptive analysis was performed.Results: Twenty-three studies were included eventually, of which eighteen were case series studies, four were cohort studies and another one was a randomized controlled trial. Five case series studies made a clinical audit of conventional vancomycin dosing in patients with malignancies or neutropenia, showing that the proportion of patients with sub-therapeutic trough levels remained high, ranging from 32% to 88%. Seven case series studies and four cohort studies demonstrated that vancomycin clearance (CLva) tended to be higher in patients with hematologic malignancies or neutropenia, whereas volume of distribution (V) seemed to be comparable to the control group. Five studies proposed individualized initial dosing regimen per the pharmacokinetic changes; however, no prospective validation has been conducted in clinical setting. Additionally, four case series studies suggested that the correlation between vancomycin clearance and estimated creatinine clearance was relatively poor, bringing a great challenge to proper dosing strategy. A randomized controlled trial stated that therapeutic drug monitoring (TDM) of vancomycin could decrease the incidence of nephrotoxicity in immunocompromised febrile patients with hematologic malignancies.Conclusion: The available evidence indicates that conventional vancomycin dosing leads to suboptimal concentration in patients with hematologic malignancy or neutropenia. TDM accompanied by pharmacokinetic interpretation can decrease the risk of nephrotoxicity. The individualization of the initial dosing regimen and mechanisms of augmented clearance require further research.Keywords: vancomycin, hematologic malignancy, neutropenia, pharmacokinetics, evidence-based practice

Breast cancer is the most diagnosed cancer type in women, with it being the second most deadly cancer in terms of total yearly mortality. Due to the prevalence of this disease, better methods are needed for both detection and treatment. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent biomarkers that lend insight into cell and tissue metabolism. As such, we developed an endoscopic device to measure these metabolites in tissue to differentiate between malignant tumors and normal tissue. We performed initial validations in liquid phantoms as well as compared to a previously validated redox imaging system. We also imaged ex vivo tissue samples after modulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and a combination of rotenone and antimycin A. We then imaged the rim and the core of MDA-MB-231 breast cancer tumors, with our results showing that the core of a cancerous lesion has a significantly higher optical redox ratio ([FAD]/([FAD] + [NADH])) than the rim, which agrees with previously published results. The mouse muscle tissues exhibited a significantly lower FAD, higher NADH, and lower redox ratio compared to the tumor core or rim. We also used the endoscope to measure NADH and FAD after photodynamic therapy treatment, a light-activated treatment methodology. Our results found that the NADH signal increases in the malignancy rim and core, while the core of cancers demonstrated a significant increase in the FAD signal.

A substantial decline in nicotinamide adenine dinucleotide (NAD) has been reported in brain tissue homogenates or neurons isolated from Alzheimer’s disease (AD) models. NAD, together with flavin adenine dinucleotide (FAD), critically supports energy metabolism and maintains mitochondrial redox homeostasis. Optical redox imaging (ORI) of the intrinsic fluorescence of reduced NAD (NADH) and oxidized FAD yields cellular redox and metabolic information and provides biomarkers for a variety of pathological conditions. However, its utility in AD has not been characterized at the tissue level. We performed ex vivo ORI of freshly dissected hippocampi from a well-characterized AD mouse model with five familial Alzheimer’s disease mutations (5XFAD) and wild type (WT) control littermates at various ages. We found (1) a significant increase in the redox ratio with age in the hippocampi of both the WT control and the 5XFAD model, with a more prominent redox shift in the AD hippocampi; (2) a higher NADH in the 5XFAD versus WT hippocampi at the pre-symptomatic age of 2 months; and (3) a negative correlation between NADH and Aβ42 level, a positive correlation between Fp and Aβ42 level, and a positive correlation between redox ratio and Aβ42 level in the AD hippocampi. These findings suggest that the ORI can be further optimized to conveniently study the metabolism of freshly dissected brain tissues in animal models and identify early AD biomarkers.

Nong He, Fu-Shan Xue, Cheng-Wen Li Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Fu-Shan Xue, Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, People’s Republic of China, Tel +86 13911177655, Fax +86 10-63138362, Email xuefushan@aliyun.com; fushanxue@outlook.com View the original paper by Prof. Dr. Kang and colleagues

Employing the optical redox imaging technique, we previously identified a significant redox shift of nicotinamide adenine dinucleotide (NAD and the reduced form NADH) in freshly isolated alveolar macrophages (AM) from ozone-exposed mice. The goal here was twofold: (a) to determine the NAD(H) redox shift in cryopreserved AM isolated from ozone-exposed mice and (b) to investigate whether there is a difference in the redox status between cryopreserved and freshly isolated AM. We found: (i) AM from ozone-exposed mice were in a more oxidized redox state compared to that from filtered air (FA)-exposed mice, consistent with the results obtained from freshly isolated mouse AM; (ii) under FA exposure, there was no significant NAD(H) redox difference between fresh AM that had been placed on ice for 2.5 h and cryopreserved AM; however, under ozone exposure, fresh AM were more oxidized than cryopreserved AM; (iii) via the use of nutrient starvation and replenishment and H2O2-induced oxidative stress of an AM cell line, we showed that this redox difference between cryopreserved and freshly isolated AM is likely the result of the double “hit”, i.e., the ozone-induced oxidative stress plus nutrient starvation that prevented freshly isolated AM from a full recovery after being on ice for a prolonged time period. The cryopreservation technique we developed eliminates/minimizes the effects of oxidative stress and nutrient starvation on cells. This method can be adopted to preserve lung macrophages from animal models or clinical patients for further investigations.

We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.

Ning He,1–3 Xiaohong Chen,2 Luo Zhang,2 Xuejun Chen,2 Zhigang Huang,2 Qi Zhong,2 Hongzhi Ma,2 Ling Feng,2 Lizhen Hou,2 Jugao Fang1,2,4 1Department of Otolaryngology – Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, 2Key Laboratory of Otorhinolaryngology, Head and Neck Surgery, Ministry of Education, Beijing Institute of Otorhinolaryngology, Beijing, 3Department of Otolaryngology & Head and Neck Oncology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, 4Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Beijing, People’s Republic of China Purpose: The role of minimally invasive endoscopic resection (MIER) in the treatment of sinonasal malignancy is controversial. Herein, we performed a retrospective review of a large case series of sinonasal malignancy patients treated with MIER aimed at evaluating the outcomes and identifying the risk factors for recurrence.Methods: Patients with sinonasal malignancy who underwent MIER from March 2000 to May 2015 were enrolled, and their clinical data were collected. The clinical outcomes were evaluated by determining the 5-year overall survival (OS) and disease-free survival (DFS). The predictive factors for survival and potential independent risk factors for recurrence were explored.Results: A total of 120 patients were enrolled, including 62 males and 58 females. The mean follow-up period was 51.4 (95% confidence interval: 44.0–59.1) months. The most frequent histological type was mucosal malignant melanoma. The positive margin rate was 19.2% (23/120). Seventy-one patients had the safety anatomic plane (SAP). Age ≥50 years, nodal metastasis, and not having the SAP were found to be predictive factors for survival, and absence of SAP was found to be an independent risk factor for recurrence.Conclusion: Our study indicated that MIER is an effective and safe surgical procedure in appropriately selected patients. Tumor resection with a safety anatomic boundary is likely to lead to improved survival and decreased recurrence. However, a larger sample and long-term prospective observation are still required to establish the role of MIER in treatment of sinonasal malignancy. Keywords: minimally invasive endoscopic resection, sinonasal skull base, malignancy, outcome, recurrence

Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8+-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.

Co-enzyme nicotinamide adenine dinucleotide (NAD(H)) redox plays a key role in macrophage function. Surfactant protein (SP-) A modulates the functions of alveolar macrophages (AM) and ozone (O3) exposure in the presence or absence of SP-A and reduces mouse survival in a sex-dependent manner. It is unclear whether and how NAD(H) redox status plays a role in the innate immune response in a sex-dependent manner. We investigated the NAD(H) redox status of AM from SP-A2 and SP-A knockout (KO) mice in response to O3 or filtered air (control) exposure using optical redox imaging technique. We found: (i) In SP-A2 mice, the redox alteration of AM in response to O3 showed sex-dependence with AM from males being significantly more oxidized and having a higher level of mitochondrial reactive oxygen species than females; (ii) AM from KO mice were more oxidized after O3 exposure and showed no sex differences; (iii) AM from female KO mice were more oxidized than female SP-A2 mice; and (iv) Two distinct subpopulations characterized by size and redox status were observed in a mouse AM sample. In conclusions, the NAD(H) redox balance in AM responds to O3 in a sex-dependent manner and the innate immune molecule, SP-A2, contributes to this observed sex-specific redox response.

In our work, interface synthesis method was put forward to prepare FePO4 with different morphologies, and the effect of morphology on the preparation and electrochemical performance of LiFePO4/C was investigated. The results showed that the morphology of FePO4 was amorphous and monoclinic at the treatment temperatures of 30 °C and 80 °C, respectively. LiFePO4/C prepared from two crystal precursors were both hemispherical hollow with an olivine crystal structure. LiFePO4/C produced from the monoclinic structured precursor exhibited smaller- sized morphology and better electrochemical performance, and its discharge capacities were 155.9 mA h g−1 and 141.8 mA h g−1 at the rates of 0.1 C and 1 C, respectively. After 150 cycles, its capacity retention was about 97.8 % and 95.1 % at 0.1 C and 1 C, respectively

The heart requires continuous ATP availability that is generated in the mitochondria. Although studies using the cell culture and perfused organ models have been carried out to investigate the biochemistry in the mitochondria in response to a change in substrate supply, mitochondrial bioenergetics of heart under normal feed or fasting conditions has not been studied at the tissue level with a sub-millimeter spatial resolution either in vivo or ex vivo. Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+ couple acting as a central electron carrier. We employed the Chance redox scanner — the low-temperature fluorescence scanner to image the three-dimensional (3D) spatial distribution of the mitochondrial redox states in heart tissues of rats under normal feeding or an overnight starvation for 14.5 h. Multiple consecutive sections of each heart were imaged to map three redox indices, i.e., NADH, oxidized flavoproteins (Fp, including flavin adenine dinucleotide (FAD)) and the redox ratio NADH/Fp. The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices. The quantitative analysis showed that in the fasted hearts the standard deviation of both NADH and Fp, i.e., SD_NADH and SD_Fp, significantly decreased with a p value of 0.032 and 0.045, respectively, indicating that the hearts become relatively more homogeneous after fasting. The fasted hearts contained 28.6% less NADH (p = 0.038). No significant change in Fp was found (p = 0.4). The NADH/Fp ratio decreased with a marginal p value (0.076). The decreased NADH in the fasted hearts is consistent with the cardiac cells' reliance of fatty acids consumption for energy metabolism when glucose becomes scarce. The experimental observation of NADH decrease induced by dietary restriction in the heart at tissue level has not been reported to our best knowledge. The Chance redox scanner demonstrated the feasibility of 3D imaging of the mitochondrial redox state in the heart and provides a useful tool to study heart metabolism and function under normal, dietary-change and pathological conditions at tissue level.

NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes as well as in the regulation of embryonic development and aging. To fluorimetrically assess the mitochondrial redox state, Dr. Chance and co-workers measured the fluorescence of NADH and oxidized flavoproteins (Fp) including flavin–adenine–dinucleotide (FAD) and demonstrated their ratio (i.e. the redox ratio) is a sensitive indicator of the mitochondrial redox states. The Chance redox scanner was built to simultaneously measure NADH and Fp in tissue at submillimeter scale in 3D using the freeze-trap protocol. This paper summarizes our recent research experience, development and new applications of the redox scanning technique in collaboration with Dr. Chance beginning in 2005. Dr. Chance initiated or actively involved in many of the projects during the last several years of his life. We advanced the redox scanning technique by measuring the nominal concentrations (in reference to the frozen solution standards) of the endogenous fluorescent analytes, i.e., [NADH] and [Fp] to quantify the redox ratios in various biological tissues. The advancement has enabled us to identify an array of the redox indices as quantitative imaging biomarkers (including [NADH], [Fp], [Fp]/([NADH]+[Fp]), [NADH]/[Fp], and their standard deviations) for studying some important biological questions on cancer and normal tissue metabolism. We found that the redox indices were associated or changed with (1) tumorigenesis (cancer versus non-cancer of human breast tissue biopsies); (2) tumor metastatic potential; (3) tumor glucose uptake; (4) tumor p53 status; (5) PI3K pathway activation in pre-malignant tissue; (6) therapeutic effects on tumors; (7) embryonic stem cell differentiation; (8) the heart under fasting. Together, our work demonstrated that the tissue redox indices obtained from the redox scanning technique may provide useful information about tissue metabolism and physiology status in normal and diseased tissues. The Chance redox scanner and other redox imaging techniques may have wide-ranging potential applications in many fields, such as cancer, diabetes, developmental process, mitochondrial diseases, neurodegenerative diseases, and aging.

The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported. Nor has how p53 regulates mitochondrial respiration been measured at (deep) tissue level, presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth. Our prior work demonstrated that the mitochondrial redox state and its intratumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models, with the more metastatic tumors exhibiting localized regions of more oxidized redox state. Using the Chance redox scanner with an in-plane spatial resolution of 200 μm, we imaged the mitochondrial redox state of the wild-type p53 colon tumors (HCT116 p53 wt) and the p53-deleted colon tumors (HCT116 p53-/-) by collecting the fluorescence signals of nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins [Fp, including flavin adenine dinucleotide (FAD)] from the mouse xenografts snap-frozen at low temperature. Our results show that: (1) both tumor lines have significant degree of intratumor heterogeneity of the redox state, typically exhibiting a distinct bi-modal distribution that either correlates with the spatial core–rim pattern or the "hot/cold" oxidation-reduction patches; (2) the p53-/- group is significantly more heterogeneous in the mitochondrial redox state and has a more oxidized tumor core compared to the p53 wt group when the tumor sizes of the two groups are matched; (3) the tumor size dependence of the redox indices (such as Fp and Fp redox ratio) is significant in the p53-/- group with the larger ones being more oxidized and more heterogeneous in their redox state, particularly more oxidized in the tumor central regions; (4) the H&E staining images of tumor sections grossly correlate with the redox images. The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattern of the mitochondrial redox state in colon cancer and the first to indicate that at tissue level the mitochondrial redox state is p53 dependent. The findings should assist in our understanding on colon cancer pathology and developing new imaging biomarkers for clinical applications.

We report herein the preparation, characterization, and catalytic performance of a series of heterogeneous catalysts featuring highly dispersed zinc sites on zeolitic SSZ-13 and ZSM-5 frameworks. The materials are evaluated in the CO2-assisted oxidative ethane dehydrogenation, a very important reaction for the synthesis of platform chemicals. In particular, we find that Zn2.92/SSZ-13 exhibits high reactivity in the conversion of C2H6 and CO2 and high ethene selectivity. In line with the experimental results, we show that the selective character of the catalyst is due to the characteristic compositional structure of the support and its topology that can effectively confine CO2 molecules. An in-depth molecular analysis via operando studies and DFT calculations shows that the rate-limiting step of the reaction with CO2 is the second C-H bond dissociation to give C2H4. The addition of CO2 effectively reduces the energy barrier of this step, favoring desorption of C2H4 while limiting byproduct formation. Overall, this work demonstrates the breakthrough potential of catalysts made of highly dispersed zinc species on zeolites in relevant transformations.

BACKGROUND: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. METHODS: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. RESULTS: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). CONCLUSIONS: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Despite important progress in understanding the influence of deforestation on the bacterial α diversity and community structure at local scales, little is known about deforestation impacts in terms of spatial turnover and soil bacterial community network interactions, especially at regional or global scales. To address this research gap, we examined the bacterial spatial turnover rate and the species networks in paired primary and secondary forest soils along a 3700-km north-south transect in eastern China using high-throughput 16S rRNA gene sequencing. The spatial turnover rate of bacterial communities was higher in primary forests than in secondary, suggesting deforestation increased biotic homogenization at a large geographic scale. Multiple regression on matrices analysis revealed that both geographic distance and soil properties (especially soil pH and organic matter availability) strongly affected bacterial spatial turnover. Through the phylogenetic molecular ecological network approach, we demonstrate that the bacterial network of primary forests was more intricate than in secondary forests. This suggests that microbial species have greater niche-sharing and more interactions in primary forests as compared to secondary forests. On the other hand, the bacterial network in secondary forests was more modular, and the taxa tended to co-occur, with positive correlations accounting for 82% of all potential interactions. In conclusion, our findings demonstrate that anthropogenic deforestation has clear effects on bacterial spatial turnover and network interactions, with potential for serious consequences such as microbial diversity loss in primary forests.

Bacteria are one of the most abundant and diverse groups of micro-organisms and mediate many critical terrestrial ecosystem processes. Despite the crucial ecological role of bacteria, our understanding of their large-scale biogeography patterns across forests, and the processes that determine these patterns lags significantly behind that of macroorganisms. Here, we evaluated the geographic distributions of bacterial diversity and their driving factors across nine latitudinal forests along a 3,700-km north–south transect in eastern China, using high-throughput 16S rRNA gene sequencing. Four of 32 phyla detected were dominant: Acidobacteria, Actinobacteria, Alphaproteobacteria and Chloroflexi (relative abundance > 5%). Significant increases in bacterial richness and phylogenetic diversity were observed for temperate forests compared with subtropical or tropical forests. The soil organic matter (SOM) mineralisation rate (SOMmin, an index of SOM availability) explained the largest significant variations in bacterial richness. Variation partition analysis revealed that the bacterial community structure was closely correlated with environmental variables and geographic distance, which together explained 80.5% of community variation. Among all environmental factors, climatic features (MAT and MAP) were the best predictors of the bacterial community structure, whereas soil pH and SOMmin emerged as the most important edaphic drivers of the bacterial community structure. Plant functional traits (community weighted means of litter N content) and diversity resulted in weak but significant correlations with the bacterial community structure. Our findings provide new evidence of bacterial biogeography patterns from tropical to cold temperate forests. Additionally, the results indicated a close linkage among soil bacterial diversity, climate and SOM decomposition, which is critical for predicting continental-scale responses under future climate change scenarios and promoting sustainable forest ecosystem services. A plain language summary is available for this article.

This study investigates the characteristics of submerged vortices in an intake sump through a combination of numerical simulations, experimental validations, and advanced modeling techniques. The aim of this study is to gain insights into the complex flow patterns and vortex structures within the sump, focusing on their behavior under varying flow rates. The Shear Stress Transfer (SST) k-ω model is utilized to capture turbulence, and the Volume of Fluid (VOF) method is employed to visualize the water-air interface. Model tests are conducted to validate the simulations. The findings suggest that under low flow conditions, the flow beneath the bell mouth becomes highly turbulent, leading to the formation of a complex vortex system with three distinct high-pressure zones. With increasing flow rates, the shape and strength of these high-pressure zones fluctuate, and a quadrupole vortex structure emerges at the sump bottom. This quadrupole vortex plays a pivotal role in the transformation of a floor-attached vortex upward, culminating in a dual vortex column structure. This structure, in turn, generates additional low-amplitude pressure pulsations. Wall-attached vortices are also observed on both sides of the inlet pipe, a result of flow stratification due to velocity disparities. The insights gained from this study contribute to a deeper understanding of intake sump dynamics and offer valuable guidance for designing and optimizing fluid systems to mitigate potential turbulence-related issues. [ABSTRACT FROM AUTHOR]

Simple Summary: Use of cancer biomarkers for tumor aggressiveness is an unmet clinical need. Differentiation of high-risk versus low-risk tumors may guide physicians to select appropriate treatment strategies tailored to the risk level of individual patients. This study aimed to evaluate the value of an optical redox imaging technique for differentiating a human melanoma mouse xenograft model with a high risk of metastasis from a low-risk mouse model. Several imaging indices were found to be significantly different between the two models. The high-risk model was found to be in a more oxidized status and to have a higher intratumor redox heterogeneity. These findings may inform further research development of the optical redox imaging approach into translatable cancer biomarkers in the future. To develop imaging biomarkers for tumors aggressiveness, our previous optical redox imaging (ORI) studies of the reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp, containing flavin adenine dinucleotide, i.e., FAD) in tumor xenografts of human melanoma associated the high optical redox ratio (ORR = Fp/(Fp + NADH)) and its heterogeneity to the high invasive/metastatic potential, without having reported quantitative results for NADH and Fp. Here, we implemented a calibration procedure to facilitate imaging the nominal concentrations of tissue NADH and Fp in the mouse xenografts of two human melanoma lines, an indolent less metastatic A375P and a more metastatic C8161. Images of the redox indices (NADH, Fp, ORR) revealed the existence of more oxidized areas (OAs) and more reduced areas (RAs) within individual tumors. ORR was found to be higher and NADH lower in C8161 compared to that of A375P xenografts, both globally for the whole tumors and locally in OAs. The ORR in the OA can differentiate xenografts with a higher statistical significance than the global averaged ORR. H&E staining of the tumors indicated that the redox differences we identified were more likely due to intrinsically different cell metabolism, rather than variations in cell density. [ABSTRACT FROM AUTHOR]

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD. [ABSTRACT FROM AUTHOR]