Heat-Resistant Inbred Lines Coordinate the Heat Response Gene Expression Remarkably in Maize (Zea mays L.).

High temperatures are increasingly becoming a prominent environmental factor accelerating the adverse influence on the growth and development of maize (Zea mays L.). Therefore, it is critical to identify the key genes and pathways related to heat stress (HS) tolerance in maize. Great challenges have been faced in dissecting genetic mechanisms and uncovering master genes for HS tolerance. Here, Z58D showed more thermotolerance than AF171 at the seedling stage with a lower wilted leaf rate and H2O2 accumulation under HS conditions. Transcriptomic analysis identified 3006 differentially expressed genes (DEGs) in AF171 and 4273 DEGs in Z58D under HS treatments, respectively. Subsequently, GO enrichment analysis showed that commonly upregulated genes in AF171 and Z58D were significantly enriched in the following biological processes, including protein folding, response to heat, response to temperature stimulus and response to hydrogen peroxide. Moreover, the comparison between the two inbred lines under HS showed that response to heat and response to temperature stimulus were significantly over-represented for the 1234 upregulated genes in Z58D. Furthermore, more commonly upregulated genes exhibited higher expression levels in Z58D than AF171. In addition, maize inbred CIMBL55 was verified to be more tolerant than B73, and more commonly upregulated genes also showed higher expression levels in CIMBL55 than B73 under HS. These consistent results indicate that heat-resistant inbred lines may coordinate the remarkable expression of genes in order to recover from HS. Additionally, 35 DEGs were conserved among five inbred lines via comparative transcriptomic analysis. Most of them were more pronounced in Z58D than AF171 at the expression levels. These candidate genes may confer thermotolerance in maize.

The First Generation of Asian American Pediatric Surgical Trainees in North America.

INTRODUCTION: Pediatric surgical trainees come from diverse races and ethnicities. However, Asian-Americans (AAs) including West, South, and East Asians may represent a unique group of individuals. We sought to identify any unique challenges and experiences. METHODS: Pediatric surgical trainees were identified from, "The Genealogy of North American Pediatric Surgery: From Ladd to Now" and "Celebrating 50 Years: Canadian Association of Paediatric Surgeons/Association Canadienne de Chirurgie Pediatrique". A database was compiled, and AAs identified who completed their pediatric surgical training on or before 1980. Personal interviews and online sources provided further information. RESULTS: Of 635 pediatric surgical trainees in North America (NA) there were 49 AA trainees (7.7%). There was insufficient information for seven, thus leaving 42 (41 male, one female) for review. The region of Asia of origin included 16 East, 16 West, and 10 South. Thirty-seven (88.0%) had moved to NA for training. The most frequent training programs included seven from Toronto and four each at Buffalo, Detroit, Pittsburgh, and Chicago (Children's Memorial). Thirty-five (83%) trainees spent most of their careers in NA while 7 (17%) practiced in their home country. CONCLUSIONS: The first AA pediatric surgical trainees voiced few examples of discrimination but indicated needs to adjust to the NA culture and often confusion over non-Western names. Mentorship was valued and gratitude expressed over the opportunity offered to train in NA. While some had intended to return to their home countries, plans changed due to meeting spouses or political turmoil. Many of those reviewed sought each other out at national meetings.

Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy.

Inflammation is a fundamental defensive response to harmful stimuli, but the overactivation of inflammatory responses is associated with most human diseases. Reactive oxygen species (ROS) are a class of chemicals that are generated after the incomplete reduction of molecular oxygen. At moderate levels, ROS function as critical signaling molecules in the modulation of various physiological functions, including inflammatory responses. However, at excessive levels, ROS exert toxic effects and directly oxidize biological macromolecules, such as proteins, nucleic acids and lipids, further exacerbating the development of inflammatory responses and causing various inflammatory diseases. Therefore, designing and manufacturing biomaterials that scavenge ROS has emerged an important approach for restoring ROS homeostasis, limiting inflammatory responses and protecting the host against damage. This review systematically outlines the dynamic balance of ROS production and clearance under physiological conditions. We focus on the mechanisms by which ROS regulate cell signaling proteins and how these cell signaling proteins further affect inflammation. Furthermore, we discuss the use of potential and currently available-biomaterials that scavenge ROS, including agents that were engineered to reduce ROS levels by blocking ROS generation, directly chemically reacting with ROS, or catalytically accelerating ROS clearance, in the treatment of inflammatory diseases. Finally, we evaluate the challenges and prospects for the controlled production and material design of ROS scavenging biomaterials.

ASPP2 binds to hepatitis C virus NS5A protein via an SH3 domain/PxxP motif-mediated interaction and potentiates infection.

Hepatitis C virus (HCV) infects millions of people worldwide and is a leading cause of liver disease. Despite recent advances in antiviral therapies, viral resistance can limit drug efficacy and understanding the mechanisms that confer viral escape is important. We employ an unbiased interactome analysis to discover host binding partners of the HCV non-structural protein 5A (NS5A), a key player in viral replication and assembly. We identify ASPP2, apoptosis-stimulating protein of p53, as a new host co-factor that binds NS5A via its SH3 domain. Importantly, silencing ASPP2 reduces viral replication and spread. Our study uncovers a previously unknown role for ASPP2 to potentiate HCV RNA replication.

Bioimaging of glutathione variation for early diagnosis of hepatocellular carcinoma using a liver-targeting ratiometric near-infrared fluorescent probe.

Reliable biomarkers are crucial for early diagnosis of diseases and precise therapy. Biological thiols (represented by glutathione, GSH) play vital roles in the antioxidant defense system for maintaining intracellular redox homeostasis in organisms. However, the aberrant variation in the cellular concentration of GSH correlates with diverse diseases including cancer. Here, a ratiometric near-infrared fluorescent probe CyO-Disu is constructed for the specific sensing of GSH variation in live cells and mice models of hepatic carcinoma (HCC). CyO-Disu features three key elements, a response moiety of bis(2-hydroxyethyl) disulfide, a near-infrared fluorescence signal transducer of heptamethine ketone cyanine, and a targeting moiety of D-galactose. By virtue of its liver-targeting capability, CyO-Disu was utilized for evaluating GSH fluctuations in primary and metastatic hepatoma living cells. To evaluate the efficacy of CyO-Disuin vivo, orthotopic HCC and pulmonary metastatic hepatoma mice models were employed for GSH imaging using two-dimensional and three-dimensional fluorescence molecular tomographic imaging systems. The bioimaging results offered direct evidence that GSH displayed varied concentrations during the progression of HCC. Therefore, the as-synthesized probe CyO-Disu could serve as a potential powerful tool for the early diagnosis and precise treatment of HCC using GSH as a reliable biomarker.

Impact of institutional prophylaxis guidelines on rates of pediatric venous thromboembolism following trauma-A multicenter study from the pediatric trauma society research committee.

BACKGROUND: A paucity of data exists with regard to the incidence, management, and outcomes of venous thromboembolism (VTE) in injured children. We sought to determine the impact of institutional chemoprophylaxis guidelines on VTE rates in a pediatric trauma population. METHODS: A retrospective review of injured children (≤15 years) admitted between 2009 and 2018 at 10 pediatric trauma centers was performed. Data were gathered from institutional trauma registries and dedicated chart review. The institutions were surveyed as to whether they had chemoprophylaxis guidelines in place for high-risk pediatric trauma patients, and outcomes were compared based on the presence of guidelines using χ 2 analysis ( p < 0.05). RESULTS: There were 45,202 patients evaluated during the study period. Three institutions (28,359 patients, 63%) had established chemoprophylaxis policies during the study period ("Guidelines"); the other seven centers (16,843 patients, 37%) had no such guidelines ("Standard"). There were significantly lower rates of VTE in the Guidelines group, but these patients also had significantly fewer risk factors. Among critically injured children with similar clinical presentations, there was no difference in VTE rate. Specifically within the Guidelines group, 30 children developed VTE. The majority (17/30) were actually not indicated for chemoprophylaxis based on institutional guidelines. Still, despite protocols only one VTE patient in the guidelines group who was indicated for intervention ended up receiving chemoprophylaxis prior to diagnosis. No consistent ultrasound screening protocol was in place at any institution during the study. CONCLUSION: The presence of an institutional policy to guide chemoprophylaxis for injured children is associated with a decreased overall frequency of VTE, but this disappears when controlling for patient factors. However, the overall efficacy is impacted by a combination of deficits in guideline compliance and structure. Further prospective data are needed to help determine the ideal role for chemoprophylaxis and protocols in pediatric trauma. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Metabolic reprogramming in cancer: Mechanisms and therapeutics.

Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.

Postoperative Respiratory Complications in SARS-CoV-2 Positive Pediatric Patients Across 20 United States Hospitals: A Cohort Study.

INTRODUCTION: Data examining rates of postoperative complications among SARS-CoV-2 positive children are limited. The purpose of this study was to evaluate the impact of symptomatic and asymptomatic SARS-CoV-2 positive status on postoperative respiratory outcomes for children. METHODS: This retrospective cohort study included SARS-CoV-2 positive pediatric patients across 20 hospitals who underwent general anesthesia from March to October 2020. The primary outcome was frequency of postoperative respiratory complications, including: high-flow nasal cannula/non invasive ventilation, reintubation, pneumonia, Extracorporeal Membrane Oxygenation (ECMO), and 30-day respiratory-related readmissions or emergency department (ED) visits. Univariate analyses were used to evaluate associations between patient and procedure characteristics and stratified analyses by symptoms were performed examining incidence of complications. RESULTS: Of 266 SARS-CoV-2 positive patients, 163 (61.7%) were male, and the median age was 10 years (interquartile range 4-14). The majority of procedures were emergent or urgent (n = 214, 80.5%). The most common procedures were appendectomies (n = 78, 29.3%) and fracture repairs (n = 40,15.0%). 13 patients (4.9%) had preoperative symptoms including cough or dyspnea. 26 patients (9.8%) had postoperative respiratory complications, including 15 requiring high-flow oxygen, 8 with pneumonia, 4 requiring non invasive ventilation, 3 respiratory ED visits, and 2 respiratory readmissions. Respiratory complications were more common among symptomatic patients than asymptomatic patients (30.8% vs. 8.7%, p = 0.01). Higher ASA class and comorbidities were also associated with postoperative respiratory complications. CONCLUSIONS: Postoperative respiratory complications are less common in asymptomatic versus symptomatic SARS-COV-2 positive children. Relaxation of COVID-19-related restrictions for time-sensitive, non urgent procedures in selected asymptomatic patients may be reasonably considered. Additionally, further research is needed to evaluate the costs and benefits of routine testing for asymptomatic patients. LEVEL OF EVIDENCE: Iii, Respiratory complications.

Fluorescent imaging to provide visualized evidences for mercury induced hypoxia stress.

As one typical toxic and dangerous heavy metal, mercury brings incalculable hazards to the environment and human, the mechanism at the molecular level is unclear. There is no visualized evidence to support directly that mercury ions (Hg2+) exposure may induce secondary stress, which is associated with the risk of hypoxia microenvironment in biological systems. Hypoxia occurs in many physiological and pathophysiological processes in the living system, accompanying overexpression of various biomarkers, such as nitroreductase (NTR). Hence, we had successfully developed two NTR-selective fluorescent probes with excellent performance for evaluating the hypoxia degree in vivo and in vitro. We visualized and qualitatively monitored the fluctuations of the endogenous NTR levels in living cells and zebrafish. The imaging results exhibited that different doses of Hg2+ exposure elevated the NTR levels and the same trend in changes of NTR as extrinsic hypoxia exposure, suggesting that Hg2+ exposure induced microenvironmental changes resulting in the hypoxia stress. This is the first time to provide visual evidence to support that Hg2+ stress may involve in the intracellular hypoxia microenvironment through monitoring the dynamic of NTR levels in the living systems. Our results may provide a novel insight into the molecular mechanisms of typical heavy metal element induced toxicity.

Congenital Diaphragmatic Hernia: Considerations for the Adult General Surgeon.

The contemporary pillars of congenital diaphragmatic hernia (CDH) management include prenatal diagnosis for multidisciplinary care coordination and counseling, medical optimization after birth, and elective (not emergent) operative repair after stabilization, allowing for improvement in pulmonary hypertension and maturation of lungs. Lung hypoplasia and pulmonary hypertension in infants with CDH represent a medical emergency, not one that necessitates immediate surgery. Many infants surviving CDH repair have significant morbidities that may persist into adulthood. Rare cases of previously occult CDH may present acutely in the older child or adult with nonspecific gastrointestinal or pulmonary symptoms.

The combined toxic effects of polyvinyl chloride microplastics and di(2-ethylhexyl) phthalate on the juvenile zebrafish (Danio rerio).

Microplastics (MPs) have the characteristics of large specific surface area, high hydrophobicity and surface charge, so they are easy to combine with other pollutants and cause toxic effects on aquatic organisms. Here, we prepared a polyvinyl chloride-microplastics (PVC-MPs) fragmentation model to simulate the real microplastic state, and characterized its composition, morphology, particle size and zeta potential. On this basis, we used single and compound exposure of PVC and di(2-ethylhexyl) phthalate (DEHP) to explore their effects on hatchability and mortality of zebrafish (Danio rerio) embryos and toxicity to oxidative stress and cardiac development in zebrafish larvae. Herein, PVC-MPs slowed down the hatching rate of zebrafish embryos and induced the death of zebrafish, while DEHP could slow down the induced of death, it had no effect on hatching rate. The PVC-MPs/DEHP single pollution could induce the reactive oxygen species (ROS) and activated the antioxidant defense signaling pathway, while the compound group showed the level of feedback autoregulation of NF-E2-related factor 2 (Nrf2) signaling pathway. The single pollution also could inhibit the expression of genes related to cardiac development, while the combined pollution showed an antagonistic effect. This study provided a theoretical basis for the ecotoxicology and biomonitoring of MPs in the natural state.

CRISIS ventilator: A 3D printed option for ventilator surge in mass respiratory pandemics.

BACKGROUND: The COVID-19 pandemic revealed flaws in the stockpiling and distribution of ventilators. In this study, we assessed the durability, sterilizability, and performance of a 3D-printed ventilator. METHODS: SLS-printed devices were dropped from 1.83 m and autoclaved before evaluation on a COVID-19 simulated patient. The respiratory performance of an extrusion-printed device was studied using a variable compliance model. Ranges of sustainable respiratory rates were evaluated as a function of tidal volume. RESULTS: Autoclaving and dropping the device did not negatively impact minute ventilation or PIP for sustained ventilation. Equivalence was significant across all measures except for comparing the autoclaved and dropped with p = 0.06. Extrusion produced ventilators achieved minute ventilation ranging from 4.1 to 12.2 L/min for all simulated compliances; there was an inverse correlation between tidal volume and respiratory rate. CONCLUSION: The CRISIS ventilator is a durable, sterilizable, and reusable 3D-printed ventilator using off-the-shelf materials which could be employed variety of adult lung diseases. Further in-vivo testing is needed.

The distinct toxicity effects between commercial and realistic polystyrene microplastics on microbiome and histopathology of gut in zebrafish.

As a ubiquitous emerging pollutant, microplastics (MPs) have attracted widespread attention. At this stage, researchers mainly employed commercial MPs (CMPs) as the model particles to explore the toxic effects of MPs. But whether CMPs can reflect the effects of realistic MPs (RMPs) still remains unknown. Herein, the effects of commercial and realistic polystyrene MPs on gut microbiota of zebrafish were compared. Considering MPs co-exist with antibiotics in real environment, we further distinguished the effects of CMPs and RMPs when they co-existed with enrofloxacin (ENR). The results revealed that while both CMPs and RMPs significantly shifted the gut microbiota, CMPs exhibited stronger toxic effects and more severe damage to gut. Furthermore, ENR exhibited a distinct effect with both CMPs and RMPs on gut microbiota, while the addition of CMPs and RMPs significantly alleviated the toxicity of ENR. In addition, analysis via Kyoto Encyclopedia of Genes and Genomes pathway database revealed that seven major level 1 pathways associated with metabolism, information processing and diseases in the microbial community were affected. Taken together, this work is the first to report that CMPs could not represent RMPs in terms of toxicity and other behaviors, reminding people the limits of using CMPs in ecotoxicology studies.

Fluorescent probes for biomolecule detection under environmental stress.

The use of fluorescent probes in visible detection has been developed over the last several decades. Biomolecules are essential in the biological processes of organisms, and their distribution and concentration are largely influenced by environmental factors. Significant advances have occurred in the applications of fluorescent probes for the detection of the dynamic localization and quantity of biomolecules during various environmental stress-induced physiological and pathological processes. Herein, we summarize representative examples of small molecule-based fluorescent probes that provide bimolecular information when the organism is under environmental stress. The discussion includes strategies for the design of smart small-molecule fluorescent probes, in addition to their applications in biomolecule imaging under environmental stresses, such as hypoxia, ischemia-reperfusion, hyperthermia/hypothermia, organic/inorganic chemical exposure, oxidative/reductive stress, high glucose stimulation, and drug treatment-induced toxicity. We believe that comprehensive insight into the beneficial applications of fluorescent probes in biomolecule detection under environmental stress should enable the further development and effective application of fluorescent probes in the biochemical and biomedical fields.

Visualizing and evaluating mitochondrial cysteine via near-infrared fluorescence imaging in cells, tissues and in vivo under hypoxia/reperfusion stress.

Increasingly grim environmental pollutions are closely related with the occurrence and development of diseases. However, it's obscure how environmental stress disturbs the normal physiological process, and then how endogenous reactive species mend the cases. Hypoxia/reperfusion (H/R), a common and intractable injury in aquaculture and clinic, can induce oxidative stress and ultimately cause irreversible injury to organism. Cysteine (Cys) plays essential roles in maintaining transduction of numerous reactive species and redox homeostasis in subcellular structures, cells and organisms. A great deal of fluorescence research about Cys are focusing on development of selective probes but with poor exploration of the biofunction under environmental stress. Therefore, it is of great significance to examine the bio-effects of Cys against H/R stress. In the present work, we design a fluorescent probe BCy-AC for in situ detecting Cys, the unique Enol-Keto tautomerization of fluorophore BCy-Keto propels the reaction process which will improve the sensitivity and potential application performance of the probe. BCy-AC is conveniently applied to visualize Cys in HT-22 cells, zebrafish and mice tissues. Moreover, imaging results obtained from H/R models reveal that endogenous Cys changes with hypoxia and reperfusion time and Cys pretreatment effectively defend H/R injury in cells and in vivo.

A high-selectivity fluorescent probe for hypoxia imaging in cells and a tumor-bearing mouse model.

Nitroreductase (NTR) with a high expression level in tumors has been considered as a biomarker of highly aggressive hypoxia tumors. Thus, it is important to develop powerful tools for tumor hypoxia detection. Here, we developed a two-photon fluorescent probe hTP-NNO2 for NTR detection. The probe with one-step synthesis exhibited high yield. hTP-NNO2 showed high selectivity and sensitivity for NTR and the detection limit was as low as 43 ng mL-1. hTP-NNO2 also showed low cytotoxicity and high stability, indicating that hTP-NNO2 is suitable for NTR detection in real-time and in situ under physiological conditions. hTP-NNO2 was used for NTR imaging in hypoxia cells and the fluorescence intensity of hTP-NNO2 increased with decreasing oxygen concentration. Benefiting from the advantages of two-photon fluorescent probes, we performed NTR detection in deep brain tissue with an imaging depth of up to 100 µm. hTP-NNO2 was further successfully applied for NTR detection in zebrafish and tumors. These results indicated that we developed a promising fluorescence imaging tool for NTR detection in vitro and in vivo.

Evaluating the Protective Effects of Mitochondrial Glutathione on Cerebral Ischemia/Reperfusion Injury via Near-Infrared Fluorescence Imaging.

Cerebral ischemia/reperfusion (I/R) is common and intractable in the clinic, associated with the outburst of reactive oxygen species (ROS) in mitochondria. Although numerous research studies have been conducted to prove the protective-effect roles of glutathione (GSH) in this event, the changes in GSH concentrations in living cells remain largely unexplained, and there is scarce evidence by fluorescence imaging for its roles. Herein we have designed and synthesized two distinctive "off-on" near-infrared (NIR) fluorescent probes BCy-SeSe and BCy-SS based on a new fluorophore BCy-Keto for specific response to mitochondrial GSH changes during the cerebral I/R process. Both of them exhibit powerful targeting capability in mitochondria and excellent photophysical properties toward endogenous GSH with high selectivity and sensitivity. In contrast to BCy-SS, BCy-SeSe was screened for biological application on account of its faster response rate. We have utilized BCy-SeSe to real-time image GSH during the cerebral I/R process in living cells and the mice focal cerebral ischemia model (middle cerebral artery occlusion, MCAO), and these intensive studies revealed that low GSH levels were associated with aggravation of apoptosis and cerebral infarction. Pretreatment with GSH synthase inhibitor aggravates damage while GSH-ester alleviates damage, confirming that GSH is effective on the cerebrum for protection from I/R. All the results demonstrated that the probes were powerful tools for investigating mitochondrial GSH during the I/R process in living cells and in vivo.

Evaluation Selenocysteine Protective Effect in Carbon Disulfide Induced Hepatitis with a Mitochondrial Targeting Ratiometric Near-Infrared Fluorescent Probe.

As important active sites of oxidoreductase in mitochondria, selenocysteine (Sec) takes the responsibility for cytoprotective effect and intracellular redox homeostasis. Carbon disulfide (CS2) is a common solvent in industry, which can inhibit the activities of oxidoreductase and induce oxidative stress. It is necessary to investigate the cytoprotective effect of Sec against CS2 exposure. After integrated, the response moiety 2,4-dinitrobenzenesulfonamide and mitochondrial targeting moiety into the near-infrared heptamethine cyanine fluorophore, we develop a mitochondrial targeting near-infrared ratiometric fluorescent probe Mito- diNO2 for the selective and sensitive analysis of Sec concentration fluctuations in living cells and in mice models under the stimulation of CS2. The probe can effectively accumulate in mitochondria and selectively detect the endogenous Sec concentrations in BRL 3A, RH-35, HL-7702, HepG2, and SMMC-7721 cell lines. The results indicate that CS2 exposure can lead to a decrease of Sec level and result in mitochondrial related acute inflammation. The exogenous supplement of Sec can protect cells from oxidative damage and reduce the symptoms of inflammation. We also establish CS2 induced acute and chronic hepatitis mice models to examine the tissue toxicity of CS2 and cytoprotection of Sec in liver. The organism can increase the concentration of Sec to deal with the damage caused by CS2 in acute hepatitis mice model. Also the exogenous supplement of Sec for the two mice models can effectively defend the CS2 induced liver damage. The real-time imaging of Sec concentrations in liver can be used to assess the degrees of liver injury during CS2 poisoning. The above applications make our probe a potential candidate for the clinical accurate diagnosis and treatment of CS2 poisoning.

Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy.

The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics. Methods: We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC. The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor-targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib via a cleavable disulfide linker. Furthermore, the integration of the near-infrared azo-BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine in vivo. Results: PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug. PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells. We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy. The in vivo results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects. Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens. The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h. Conclusion: Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models. The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC.

A near-infrared fluorescent probe for sensitive detection and imaging of sulfane sulfur in living cells and in vivo.

Sulfane sulfur refers to ionized sulfur that is reversibly attached to other sulfur atoms in the form of 6-valence electrons (S0). Sulfane sulfur possesses stronger nucleophilicity and reducibility than hydrogen sulfide in a series of physiological reactions, which probably makes sulfane sulfur the actual signal molecule in cells. Herein, we designed and synthesized a near-infrared (NIR) fluorescent probe BD-diSH for sensitive detection and imaging of sulfane sulfur in living cells and in vivo. The probe BD-diSH is composed of two moieties: the fluorophore azo-BODIPY and the sulfane sulfur recognition unit, viz., 2-mercapto benzoate. BD-diSH displayed high sensitivity and selectivity towards sulfane sulfur. The mercapto group (-SH) of 2-mercapto benzoic acid can nucleophilically capture the sulfur atom of thiosulfoxide tautomers in sulfane sulfur to form -SSH. The group -SSH will immediately induce intramolecular cyclization reaction and release the azo-BODIPY fluorophore to emit NIR fluorescence. The probe BD-diSH was successfully applied to detect and image sulfane sulfur in the cytoplasm of the living cells. The results illustrated that the endogenous and exogenous sulfane sulfur level changed depending on different cell lines. BD-diSH was also capable of imaging the level changes of sulfane sulfur in mice. The above applications make our new probe a potential chemical tool for the study of physiological and pathological functions of sulfur sulfide in living cells and in vivo.