Monosodium Urate Crystal-Induced Pyroptotic Cell Death in Neutrophil and Macrophage Facilitates the Pathological Progress of Gout.

Monosodium urate (MSU) crystal deposition in joints can lead to the infiltration of neutrophils and macrophages, and their activation plays a critical role in the pathological progress of gout. However, the role of MSU crystal physicochemical properties in inducing cell death in neutrophil and macrophage is still unclear. In this study, MSU crystals of different sizes are synthesized to explore the role of pyroptosis in gout. It is demonstrated that MSU crystals induce size-dependent pyroptotic cell death in bone marrow-derived neutrophils (BMNs) and bone marrow-derived macrophages (BMDMs) by triggering NLRP3 inflammasome-dependent caspase-1 activation and subsequent formation of N-GSDMD. Furthermore, it is demonstrated that the size of MSU crystal also determines the formation of neutrophil extracellular traps (NETs) and aggregated neutrophil extracellular traps (aggNETs), which are promoted by the addition of interleukin-1ß (IL-1ß). Based on these mechanistic understandings, it is shown that N-GSDMD oligomerization inhibitor, dimethyl fumarate (DMF), inhibits MSU crystal-induced pyroptosis in BMNs and J774A.1 cells, and it further alleviates the acute inflammatory response in MSU crystals-induced gout mice model. This study elucidates that MSU crystal-induced pyroptosis in neutrophil and macrophage is critical for the pathological progress of gout, and provides a new therapeutic approach for the treatment of gout.

POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer.

OBJECTIVE: This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells. METHODS: GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry. RESULTS: GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells. CONCLUSION: Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.

Simultaneous detection of SO2 and viscosity in drug-induced inflammation in live cells and zebrafish.

The viscosity within cells is a crucial microenvironmental factor, and sulfur dioxide (SO2 ) has essential functions in regulating cellular apoptosis and inflammation. Some evidence has been confirmed that changes in viscosity and overexposure of SO2 within the cell may cause detrimental effects including, but not limited to, respiratory and cardiovascular illnesses, inflammation, fatty liver, and various types of cancer. Therefore, precise monitoring of SO2 and viscosity in biological entities holds immense practical importance. Therefore, in this research, we developed a versatile fluorescent TCF-Cou that enables the dual detection of SO2 and viscosity in the living system. Probe TCF-Cou possessed a response to viscosity and SO2 through red and green emissions. The alteration of SO2 and viscosity levels in live cells and zebrafish were also monitored using probe TCF-Cou. We hope that this fluorescent probe could be a potential tool for revealing the related pathological and physiological processes through monitoring the changes in SO2 and viscosity.

Fluorescent dyes based on rhodamine derivatives for bioimaging and therapeutics: recent progress, challenges, and prospects.

Since their inception, rhodamine dyes have been extensively applied in biotechnology as fluorescent markers or for the detection of biomolecules owing to their good optical physical properties. Accordingly, they have emerged as a powerful tool for the visualization of living systems. In addition to fluorescence bioimaging, the molecular design of rhodamine derivatives with disease therapeutic functions (e.g., cancer and bacterial infection) has recently attracted increased research attention, which is significantly important for the construction of molecular libraries for diagnostic and therapeutic integration. However, reviews focusing on integrated design strategies for rhodamine dye-based diagnosis and treatment and their wide application in disease treatment are extremely rare. In this review, first, a brief history of the development of rhodamine fluorescent dyes, the transformation of rhodamine fluorescent dyes from bioimaging to disease therapy, and the concept of optics-based diagnosis and treatment integration and its significance to human development are presented. Next, a systematic review of several excellent rhodamine-based derivatives for bioimaging, as well as for disease diagnosis and treatment, is presented. Finally, the challenges in practical integration of rhodamine-based diagnostic and treatment dyes and the future outlook of clinical translation are also discussed.

Stratum affects the distribution of soil selenium bioavailability by modulating the soil physicochemical properties: A case study in a Se-enriched area, China.

The soil selenium (Se) content and bioavailability are important for human health. In this regard, knowing the factors driving the concentration of total Se and bioavailable Se in soils is essential to map Se, enhance foodstuffs' Se content, and improve the Se nutritional status of humans. In this study, total Se and Se bioavailability (i.e., phosphate extracted Se) in surface soils (0-20 cm) developed on different strata were analyzed in a Se-enriched region of Southwest China. Furthermore, the interaction between the stratum and soil properties was assessed and how did the stratum effect on the concentration and spatial distribution of Se bioavailability in soils was investigated. Results showed that the median concentration of total Se in soils was 0.308 mg/kg, which is higher than China's soil background. The mean proportion of phosphate extracted Se in total Se was 12.2 %. The values of total Se, phosphate extracted Se, and soil organic matter (SOM) in soils increased with the increasing stratum age. In contrast, the coefficient of weathering and eluviation (BA) values decreased. The analysis of statistics and Geodetector revealed that the SOM, stratum, and BA were the dominant controlling factors for the contents and distributions of soil total Se and phosphate extracted Se. This study provided strong evidence that the soil properties that affected the total Se and Se bioavailability were modulated by the local geological background, and had important practical implications for addressing Se malnutrition and developing the Se-rich resource in the study region and similar geological settings in different parts of the globe.

The Longitudinal Associations Between Parental Autonomy Support, Autonomy and Peer Resistance.

Adolescents' autonomy is considered to be shaped within family and peer contexts. However, the specific dynamics of the within-person associations between parental autonomy support, adolescents' general autonomy, and peer resistance over time remain unclear. To address this, random-intercept cross-lagged panel models were employed in a sample of 290 Dutch youth in early adolescence (Mage = 11.58, SD = 0.44 at T1; 49.3% boys) and 220 Dutch youth in middle to late adolescence (Mage = 17.79, SD = 1.47 at T1; 25.0% boys), who were followed over two years across four time points. Results showed that changes in adolescents' general autonomy were concurrently associated with changes in their parental autonomy support and peer resistance at the within-person level. However, these associations were not observed longitudinally over a six-month period. These findings suggest that increases in supportive parenting and peer resistance co-occur with increases in adolescents' autonomy within individuals.

Activatable Near-Infrared Versatile Fluorescent and Chemiluminescent Dyes Based on the Dicyanomethylene-4H-pyran Scaffold: From Design to Imaging and Theranostics.

Activatable fluorescent and chemiluminescent dyes with near-infrared emission have indispensable roles in the fields of bioimaging, molecular prodrugs, and phototheranostic agents. As one of the most popular fluorophore scaffolds, the dicyanomethylene-4H-pyran scaffold has been applied to fabricate a large number of versatile activatable optical dyes for analytes detection and diseases diagnosis and treatment by virtue of its high photostability, large Stokes shift, considerable two-photon absorption cross-section, and structural modifiability. This review discusses the molecular design strategies, recognition mechanisms, and both in vitro and in vivo bio-applications (especially for diagnosis and therapy of tumors) of activatable dicyanomethylene-4H-pyran dyes. The final section describes the current shortcomings and future development prospects of this topic.

An ER-targeted, Viscosity-sensitive Hemicyanine Dye for the Diagnosis of Nonalcoholic Fatty Liver and Photodynamic Cancer Therapy by Activating Pyroptosis Pathway.

The concept of molecular design, integrating diagnostic and therapeutic functions, aligns with the general trend of modern medical advancement. Herein, we rationally designed the smart molecule ER-ZS for endoplasmic reticulum (ER)-targeted diagnosis and treatment in cell and animal models by combining hemicyanine dyes with ER-targeted functional groups (p-toluenesulfonamide). Owing to its ability to target the ER with a highly specific response to viscosity, ER-ZS demonstrated substantial fluorescence turn-on only after binding to the ER, independent of other physiological environments. In addition, ER-ZS, being a small molecule, allows for the diagnosis of nonalcoholic fatty liver disease (NAFLD) via liver imaging based on high ER stress. Importantly, ER-ZS is a type I photosensitizer, producing O2 ⋅- and ⋅OH under light irradiation. Thus, after irradiating for a certain period, the photodynamic therapy inflicted severe oxidative damage to the ER of tumor cells in hypoxic (2 % O2 ) conditions and activated the unique pyroptosis pathway, demonstrating excellent antitumor capacity in xenograft tumor models. Hence, the proposed strategy will likely shed new light on integrating molecular optics for NAFLD diagnosis and cancer therapy.

Nrf2 Is Involved in Hyperglycemia-induced Abnormal Lung Development through both Antioxidation-Dependent and Antioxidation-Independent Activation.

Accumulating evidence has shown that hyperglycemia during pregnancy negatively affects lung development. However, the pathological mechanism of lung dysplasia caused by hyperglycemia remains unclear. In this study, we demonstrated the phenotypes of the impaired lung epithelial cell differentiation of mouse lungs in pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM), and increased levels of oxidative stress and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways occurred. Nrf2 deficiency during pregnancy led to the aforementioned similar and aggravated phenotypes of the poor saccular process as in diabetes, implying the Nrf2 signaling pathway played a very important role in both physiological and pathological conditions. Based on RNA sequencing and luciferase reporter gene analysis, we revealed that Nrf2 could regulate Wnt signaling by targeting Ctnnd2. In summary, we revealed the pathological mechanism of how diabetes affected late lung development during embryogenesis, especially elucidating the bilateral roles of Nrf2-mediated oxidative stress responses and Wnt signaling. This finding also indicated that Nrf2 could potentially be used in preventing or treating pulmonary anomalies induced by hyperglycemia during pregnancy.

Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis.

BACKGROUND: Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood. METHODS: Human placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague-Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors. RESULTS: In this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFß1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats. CONCLUSIONS: Our data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.

An ultra-small bispecific protein augments tumor penetration and treatment for pancreatic cancer.

PURPOSE: The once highly anticipated antibody-based pathway-targeted therapies have not achieved promising outcomes for deadly pancreatic ductal adenocarcinoma (PDAC), mainly due to drugs' low intrinsic anticancer activity and poor penetration across the dense physiological barrier. This study aims to develop an ultra-small-sized, EGFR/VEGF bispecific therapeutic protein to largely penetrate deep tumor tissue and effectively inhibit PDAC tumor growth in vivo. METHODS: The bispecific protein, Bi-fp50, was constructed by a typical synthetic biology method and labeled with fluorescent dyes for in vitro and in vivo imaging. Physicochemical properties, protein dual-binding affinity, and specificity of the Bi-fp50 were evaluated in several PDAC cell lines. In vitro quantitatively and qualitatively anticancer activity of Bi-fp50 was assessed by live/dead staining, MTT assay, and flow cytometry. In vivo pharmacokinetic and biodistribution were evaluated using blood biopsy samples and near-infrared fluorescence imaging. In vivo real-time tracking of Bi-fp50 in the local tumor was conducted by fibered confocal fluorescence microscopy. The subcutaneous PDAC tumor model was used to assess the in vivo antitumor effect of Bi-fp50. RESULTS: Bi-fp50 with an ultra-small size of 50 kDa (5 ~ 6 nm) showed an excellent binding ability to VEGF and EGFR simultaneously and had enhanced, accumulated binding capability for Bxpc3 PDAC cells compared with anti-VEGF scFv and anti-EGFR scFv alone. Additionally, bi-fp50 significantly inhibited the proliferation and growth of Bxpc3 and Aspc1 PDAC cells even under a relatively low concentration (0.3 µM). It showed synergistically enhanced therapeutic effects relative to two individual scFv and Bi-fp50x control in vitro. The half-life of blood clearance of Bi-fp50 was 4.33 ± 0.23 h. After intravenous injection, Bi-fp50 gradually penetrated the deep tumor, widely distributed throughout the whole tissue, and primarily enriched in the tumor with nearly twice the accumulation than scFv2 in the orthotopic PDAC tumor model. Furthermore, the Bi-fp50 protein could induce broad apoptosis in the whole tumor and significantly inhibited tumor growth 3 weeks after injection in vivo without other noticeable side effects. CONCLUSION: The proof-of-concept study demonstrated that the ultra-small-sized, bispecific protein Bi-fp50 could be a potential tumor suppressor and an efficient, safe theranostic tool for treating PDAC tumors.

Persulfate promoted carbamoylation of N-arylacrylamides and N-arylcinnamamides with 4-carbamoyl-Hantzsch esters.

Carbamoyl-Hantzsch esters were used as carbamoyl radical precursors for oxidative carbamoylation of N-arylacrylamides and N-arylcinnamamides in the presence of inexpensive persulfates. This protocol can be applied to a broad range of substrates with various functional groups, providing a variety of 3,3-disubstituted oxindoles and 3,4-disubstituted dihydroquinolin-2(1H)-ones in moderate to good yields via an intermolecular addition/cyclization process.

Mucin1 induced trophoblast dysfunction in gestational diabetes mellitus via Wnt/ß-catenin pathway.

BACKGROUND: To elucidate the role of Mucin1 (MUC1) in the trophoblast function (glucose uptake and apoptosis) of gestational diabetes mellitus (GDM) women through the Wnt/ß-catenin pathway. METHODS: Glucose uptake was analyzed by plasma GLUT1 and GLUT4 levels with ELISA and measured by the expression of GLUT4 and INSR with immunofluorescence and Western blotting. Apoptosis was measured by the expression of Bcl-2 and Caspase3 by Western blotting and flow cytometry. Wnt/ß-catenin signaling measured by Western blotting. In vitro studies were performed using HTR-8/SVneo cells that were cultured and treated with high glucose (HG), sh-MUC1 and FH535 (inhibitor of Wnt/ß-catenin signaling). RESULTS: MUC1 was highly expressed in the placental trophoblasts of GDM, and the Wnt/ß-catenin pathway was activated, along with dysfunction of glucose uptake and apoptosis. MUC1 knockdown resulted in increased invasiveness and decreased apoptosis in trophoblast cells. The initial linkage between MUC1, the Wnt/ß-catenin pathway, and glucose uptake was confirmed by using an HG-exposed HTR-8/SVneo cell model with MUC1 knockdown. MUC1 knockdown inhibited the Wnt/ß-catenin signaling pathway and reversed glucose uptake dysfunction and apoptosis in HG-induced HTR-8/SVneo cells. Meanwhile, inhibition of Wnt/ß-catenin signaling could also reverse the dysfunction of glucose uptake and apoptosis. CONCLUSIONS: In summary, the increased level of MUC1 in GDM could abnormally activate the Wnt/ß-catenin signaling pathway, leading to trophoblast dysfunction, which may impair glucose uptake and induce apoptosis in placental tissues of GDM women.

Effect of pre-use of Dexmedetomidine on the effective inhibitory dose of remimazolam tosilate on positive cardiovascular response in double-lumen endobronchial intubation: a clinical study.

BACKGROUND: Herein, the effect of pre-use of Dexmedetomidine(Dex) on the half-effective dose (ED50) and 95%-effective dose (ED95) of Remimazolam tosilate(RT) in inhibiting the positive cardiovascular response(CR) which means blood pressure or heart rate rises above a critical threshold induced by double-lumen bronchial intubation was evaluated. METHODS: Patients who underwent video-assisted thoracic surgery were divided into groups A (0), B (0.5 µg/kg), and C (1 µg/kg) based on different Dex doses. Group A included subgroups comprising young (A-Y) and elderly (A-O) patients. Neither groups B nor C included elderly patients due of the sedative effect of Dex. Based on the previous subject's CR, the dose of RT was increased or decreased in the next patient using the sequential method. This trial would be terminated when the seventh crossover occurred, at which point the sample size met the stable estimate of the target dose. Heart rate (HR) and mean arterial pressure (MAP) were monitored throughout the trial, and sedation was assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. HR and MAP were recorded at baseline (T1), the end of Dex (T2), and the end of RT (T3), the maximum HR and MAP were recorded within 3 min of intubation from beginning to end (T4). There was a positive CR when the T4 levels rose above 15% of the baseline. The ED50/ED95 and corresponding confidence interval were calculated using probability regression. RESULTS: In total, 114 patients completed the trial. Without the use of Dex, the ED50/ED95 of TR inhibiting the positive CR caused by double-lumen bronchial intubation was 0.198/0.227 and 0.155/0.181 mg/kg in groups A-Y and A-O, respectively. The changes in vital signs from T1 to T3 were similar in the subgroups, indicating that the elderly patients were more sensitive to the dose of RT. The ED50/ED95 of RT inhibiting the positive CR caused by double-lumen endobronchial intubation was 0.122/0.150 and 0.068/0.084 mg/kg in groups B and C, respectively. And, the fluctuation of blood pressure from T3 to T4 was reduced by using Dex. RT was 100% effective in sedation with no significant inhibition of circulation. Apart from one case of hypotension occurred in group A-Y, two cases of low HR in group B, and one case of low HR in group C, no other adverse events were noted. CONCLUSIONS: The optimal dose of RT to inhibit positive CR induced by double-lumen bronchial intubation in elderly patients was 0.18 mg/kg and 0.23 mg/kg in younger patients. When the pre-use dose of Dex was 0.5 µg/kg, the optimal dose to inhibit positive CR of RT was 0.15 mg/kg. And, when the pre-use dose of Dex was 1 µg/kg, the optimal dose of RT was 0.9 mg/kg. CLINICAL TRIAL REGISTRATION: NCT05631028.

Longitudinal associations of parental psychological control and friend support with autonomy during early adolescence.

Although theories suggest transactional associations between adolescents' autonomy and relationships with parents and friends, few studies have examined these within-person effects. This longitudinal study examined the within-person co-development of adolescents' autonomy and relationships with parents and friends. Adolescents (N = 244 Mage = 11.54, SD = 0.43 at T1; 50% boys) participated in a four-wave study across 2 years in the Netherlands. In random-intercept cross-lagged panel models, within-person results showed that higher levels of autonomy predicted less parental psychological control but not vice versa. However, no lagged-effects between friend support and autonomy were found. This study suggests that adolescents' autonomy steers changes in parental psychological control.

Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook.

The discovery of a near-infrared (NIR, 650-900 nm) fluorescent chromophore hemicyanine dye with high structural tailorability is of great significance in the field of detection, bioimaging, and medical therapeutic applications. It exhibits many outstanding advantages including absorption and emission in the NIR region, tunable spectral properties, high photostability as well as a large Stokes shift. These properties are superior to those of conventional fluorogens, such as coumarin, fluorescein, naphthalimides, rhodamine, and cyanine. Researchers have made remarkable progress in developing activity-based multifunctional fluorescent probes based on hemicyanine skeletons for monitoring vital biomolecules in living systems through the output of fluorescence/photoacoustic signals, and integration of diagnosis and treatment of diseases using chemotherapy or photothermal/photodynamic therapy or combination therapy. These achievements prompted researchers to develop more smart fluorescent probes using a hemicyanine fluorogen as a template. In this review, we begin by describing the brief history of the discovery of hemicyanine dyes, synthetic approaches, and design strategies for activity-based functional fluorescent probes. Then, many selected hemicyanine-based probes that can detect ions, small biomolecules, overexpressed enzymes and diagnostic reagents for diseases are systematically highlighted. Finally, potential drawbacks and the outlook for future investigation and clinical medicine transformation of hemicyanine-based activatable functional probes are also discussed.

Correction: Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook.

Correction for 'Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook' by Haidong Li et al., Chem. Soc. Rev., 2022, DOI: 10.1039/d1cs00307k.

Core-Shell Carbon-Based Bifunctional Electrocatalysts Derived from COF@MOF Hybrid for Advanced Rechargeable Zn-Air Batteries.

The development of highly active carbon-based bifunctional electrocatalysts for both the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) is highly desired, but still full of challenges in rechargeable Zn-air batteries. Metal organic frameworks (MOFs) and covalent organic frameworks (COFs) have gained great attention for various applications due to their attractive features of structural tunability, high surface area and high porosity. Herein, a core-shell structured carbon-based hybrid electrocatalyst (H-NSC@Co/NSC), which contains high density active sites of MOF-derived shell (Co/NSC) and COF-derived hollow core (H-NSC), is successfully fabricated by direct pyrolysis of covalently-connected COF@ZIF-67 hybrid. The core-shell H-NSC@Co/NSC hybrid manifests excellent catalytic properties toward both OER and ORR with a small potential gap (∆E = 0.75 V). The H-NSC@Co/NSC assembled Zn-air battery exhibits a high power-density of 204.3 mW cm-2 and stable rechargeability, outperforming that of Pt/C+RuO2 assembled Zn-air battery. Density functional theory calculations reveal that the electronic structure of the carbon frameworks on the Co/NSC shell can be effectively modulated by the embedded Co nanoparticles (NPs), facilitating the adsorption of oxygen intermediates and leading to enhanced catalytic activity. This work will provide a strategy to design highly-efficient electrocatalysts for application in energy conversion and storage.

Gut-Lung Dysbiosis Accompanied by Diabetes Mellitus Leads to Pulmonary Fibrotic Change through the NF-κB Signaling Pathway.

Growing evidence shows that the lungs are an unavoidable target organ of diabetic complications. However, the pathologic mechanisms of diabetic lung injury are still controversial. This study demonstrated the dysbiosis of the gut and lung microbiome, pulmonary alveolar wall thickening, and fibrotic change in streptozotocin-induced diabetic mice and antibiotic-induced gut dysbiosis mice compared with controls. In both animal models, the NF-κB signaling pathway was activated in the lungs. Enhanced pulmonary alveolar well thickening and fibrotic change appeared in the lungs of transgenic mice expressing a constitutively active NF-κB mutant compared with wild type. When lincomycin hydrochloride-induced gut dysbiosis was ameliorated by fecal microbiota transplant, enhanced inflammatory response in the intestine and pulmonary fibrotic change in the lungs were significantly decreased compared with lincomycin hydrochloride-treated mice. Furthermore, the application of fecal microbiota transplant and baicalin could also redress the microbial dysbiosis of the gut and lungs in streptozotocin-induced diabetic mice. Taken together, these data suggest that multiple as yet undefined factors related to microbial dysbiosis of gut and lungs cause pulmonary fibrogenesis associated with diabetes mellitus through an NF-κB signaling pathway.

Reversible Chemical Protein Modification to Endogenous Glutathione and Its Utilities in the Manufacture of Transcellular Pro-Enzymes.

Proteins have been perceived as being an intriguing modality of therapeutics for the treatment of intractable diseases in view of their superlative precision and versatility. Nonetheless, proteins' intrinsic characters, particularly their being hydrophilic macromolecules with unmethodical charges, have imposed the exceeding challenge of seeking transcellular trafficking into cells' interiors. To circumvent this drawback, we have attempted to employ triple-functional amine-reactive 4-(2-((2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)disulfaneyl)ethoxy)-4-oxobutanoic acid for the efficient incorporation of the anionic carboxyl moiety into amine-enriched enzymes, resulting in overall negatively charged pro-enzymes. The resulting pro-enzymes could be readily electrostatically assembled with cationic species [for instance: block copolymers of poly(ethylene glycol)-polylysine] into core-shell architectural delivery nanoparticles for their facilitated endocytosis into cells. Noteworthy is the aforementioned carboxylation chemistry designed to allow facile reversal of the pro-enzymes to the original amine groups due to the thiolysis of intermediate disulfide linkage for subsequent cascade reactions in response to the cytosol-enriched glutathione. Therefore, cytosol-selective structural disassembly for the liberation and activation of the pro-enzymes was accomplished. Our subsequent investigations utilizing ribonuclease A and catalase as the model enzymes demonstrated appreciable transcellular transportation of the active enzymes to the cell interiors, exerting overwhelming cytotoxic potencies and H2O2 scavenging capacities, respectively. Hence, we reported an unprecedented redox-stimulated charge reversal strategy in engineering cytosol-activatable pro-enzymes, manifesting a simple and efficient approach in the manufacture of transcellular proteinic therapeutics, which should be highlighted to promote their wide availability for use with diverse functional proteins as molecular biological tools and precision therapeutics.