Integrating network pharmacology and experimental validation to explore the mitophagy-associated pharmacological mechanism of modified Shisiwei Jianzhong decoction against aplastic anemia.

The aim of this work was to investigate the therapeutic effect of modified Shisiwei Jianzhong Decoction (SJD) on aplastic anemia (AA) and its potential pharmacological mechanism from the perspective of mitophagy. A comprehensive approach combining network pharmacology, mendelian randomization, molecular docking and animal experiments was applied to evaluate the properties of SJD against AA. By integrating multiple databases, it was determined that SJD exerted its therapeutic effect on AA by targeting three key targets [mammalian target of rapamycin (MTOR), poly(ADP-ribose) polymerase 1 (PARP1) and Sirtuin 1 (SIRT1)] through four core compounds (quercetin, resveratrol, genistein and curcumin). Mendelian randomization analysis identified MTOR as a risk factor for AA occurrence while PARP1 was a protective factor. Results of animal experiments showed that SJD improved peripheral blood counts and promoted the proliferation of hematopoietic stem cells. Mechanistically, SJD, especially at high dose, played a therapeutic role in AA by activating mitophagy-related proteins PTEN induced kinase 1 (PINK1)/Parkin and inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase (AKT)/MTOR pathway. This study revealed for the first time the core chemical composition of SJD and its pharmacological effects against AA, which can restore hematopoietic function by activating mitophagy. The results provide inspiration for the clinical application of traditional Chinese medicine in AA treatment.

Polymeric Nanoparticles for Drug Delivery.

The recent emergence of nanomedicine has revolutionized the therapeutic landscape and necessitated the creation of more sophisticated drug delivery systems. Polymeric nanoparticles sit at the forefront of numerous promising drug delivery designs, due to their unmatched control over physiochemical properties such as size, shape, architecture, charge, and surface functionality. Furthermore, polymeric nanoparticles have the ability to navigate various biological barriers to precisely target specific sites within the body, encapsulate a diverse range of therapeutic cargo and efficiently release this cargo in response to internal and external stimuli. However, despite these remarkable advantages, the presence of polymeric nanoparticles in wider clinical application is minimal. This review will provide a comprehensive understanding of polymeric nanoparticles as drug delivery vehicles. The biological barriers affecting drug delivery will be outlined first, followed by a comprehensive description of the various nanoparticle designs and preparation methods, beginning with the polymers on which they are based. The review will meticulously explore the current performance of polymeric nanoparticles against a myriad of diseases including cancer, viral and bacterial infections, before finally evaluating the advantages and crucial challenges that will determine their wider clinical potential in the decades to come.

Green Synthesis of PtPdNiFeCu High-Entropy Alloy Nanoparticles for Glucose Detection.

High-entropy alloys have long been used as a new type of alloy material and have attracted widespread concern because of their excellent performance, including their stable microstructure and particular catalytic properties. To design a safer preparation method, we report a novel approach targeting green synthesis, using tea polyphenols to prepare PtPdNiFeCu high-entropy alloy nanoparticles for glucose detection. The fabricated sensors were characterized by transmission electron microscopy and electrochemical experiments. Physical characterization showed that the nanoparticle has better dispersibility, and the average particle size is 7.5 nm. The electrochemical results showed that Tp-PtPdNiFeCu HEA-NPs had a high sensitivity of 1.264 µA mM-1 cm-2, a low detection limit of 4.503 µM, and a wide detection range of 0 - 10 mM. In addition, the sensor has better stability and selectivity for glucose detection.

Peroxynitrite-Scavenging Organosilica Nanomedicines for Light-Controllable NO Release and Precision On-Demand Glaucoma Therapy.

Nitric oxide (NO) is a promising approach for treating ocular hypertension and glaucoma. However, its clinical application is limited by its uncontrollable release and the unwanted overproduction of peroxynitrite. Herein, a denitrifying hollow mesoporous organosilica nanoparticle (HMMN) with framework cohybridization is first constructed to encapsulate S-nitroso-N-acetyl-d,l-penicillamine (SNAP) to produce SNAP@HMMN with dual capacities of selective peroxynitrite removal and controllable NO release. Featuring a large corneal permeability, the well-designed SNAP@HMMN can achieve trans-corneal delivery to reach the target trabecular meshwork (TM)/Schlemm's canal (SC) site. Upon light irradiation, the intraocular pressure (IOP) is appropriately lowered in an adjustable and long-lasting manner while the outflow tissues are protected from nitrative damage, which is expected to realize precision on-demand glaucoma therapy with little biosafety concern, promising significant clinical translational potential.

Targeting Lewis X oligosaccharide-modified liposomes encapsulated with house dust mite allergen Der f 2 to dendritic cells inhibits Th2 immune response.

Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic diseases. However, the long desensitization phase and potentially dangerous allergic side effects limit its broad application. Therefore, safer and more effective vaccines are required. Targeting dendritic cells (DCs) with novel allergen conjugates is a promising strategy for AIT. In this study, a novel vaccine with a DC-targeting effect for AIT was constructed. Liposomes were used as vehicles, and a targeted nanovaccine (Lex-lip-Der f 2) was constructed by loading the recombinant group 2 allergen of Dermatophagoides farinae (Der f 2) and conjugating with the DC-SIGN ligand Lewis X. The effect of the vaccine on DCs and T cell responses and the safety of the vaccine were investigated in vitro. The results showed that the Lex-lip-Der f 2 vaccine was spherical, with size of approximately 128 nm. The protein-loading capacity of the vaccine was 0.106 ± 0.001 mg per mg liposome and protein was gradually released from the liposomes during the first 12 h. Lex-lip-Der f 2 was taken up more efficiently by DCs than non-targeted liposomes or free Der f 2. Besides, Lex-lip-Der f 2 significantly inhibited the release of IL-4, IL-6, and TNF-a from DCs. Accordingly, Der f 2-lip loaded DCs significantly decreased IL-4 levels in autologous naïve CD4+T cells. Moreover, Lex-lip-Der f 2-treated basophils showed lower activation levels. These results suggest that DC-SIGN targeting mediated by Lewis X could inhibit the Th2 cell response and improve vaccine safety, and may be a novel vaccination strategy.

Rapamycin and Low-dose IL-2 Mediate an Immunosuppressive Microenvironment to Inhibit Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

Non-interference delivery of Ce6 and DOX in NIR light-responsive liposomes for synergetic cervical cancer therapy.

Multi-model combination treatment of malignant tumors can make up for the shortcomings of single treatment through multi-target and multi-path to achieve more ideal tumor treatment effect. However, the mutual interference of different drugs in the delivery processin vivoand the difficulty of effective drug accumulation in tumor cells are the bottlenecks of combined therapy. To this project, light-responsive liposomes loading doxorubicin (DOX) and chlorin e6 (Ce6) (DOX-Ce6-Lip) without mutual interference were engineered by thin film hydration method. This kind of nano-drug delivery system increased the drugs concentration accumulated in tumor sites through enhanced permeability and retention effect, and reduced the toxic and side effects of drugs on normal tissuesin vivo. In addition, after entering the tumor cells, Ce6 produced a large number of reactive oxygen species under 660 nm NIR laser irradiation, which further oxidized the unsaturated fatty acid chain in the liposomes and caused the collapse of the liposomes, thus realizing the stimulus-responsive release of Ce6 and DOX. The concentrations of DOX and Ce6 in the tumor cells rapidly reached the peak and achieved a more effective combination of chemotherapy and photodynamic therapy (PDT). Consequently, DOX-Ce6-Lip followed by 660 nm NIR irradiation achieved an efficient tumor growth inhibition of 71.90 ± 3.14%, indicating the versatile potential of chemotherapy and PDT. In conclusion, this study provides a delivery scheme for drugs with different solubilities and an effectively combined anti-tumor therapy method.

Neutrophil CD64 index as a superior indicator for diagnosing, monitoring bacterial infection, and evaluating antibiotic therapy: a case control study.

BACKGROUND: Neutrophil CD64 (nCD64) index has been widely studied as an indication of bacteria-infected diseases, but the exact usage of nCD64 index in monitoring infections remains debated. So this study aims to investigate the functionality of nCD64 index in tracking infections' progression and evaluating antibiotic therapy. METHODS: 160 participants (36 healthy controls, 34 culture-negative patients, 56 respiratory tract infected patients, and 34 bloodstream infected patients) were recruited and divided into groups. Data on nCD64 index, T lymphocyte subsets, and conventional indicators, including white blood cell count, neutrophil to lymphocyte ratio, procalcitonin, and C-reactive protein, were tested and compared. RESULTS: Bacteria-infected patients had significantly higher nCD64 indexes (p < 0.05), especially patients with both bloodstream and respiratory tract infections. The nCD64 index could identify infected patients from culture-negative patients or controls, which conventional indicators cannot achieve. We followed up with 24 infected patients and found that their nCD64 indexes were promptly down-regulated after effective antibiotic therapy (3.16 ± 3.01 vs. 1.20 ± 1.47, p < 0.001). CONCLUSION: The nCD64 index is a sensitive indicator for clinical diagnosis of bacterial infection, especially in monitoring infection and evaluating antibiotics' efficacy. Therefore, nCD64 has the potential to improve diagnostic accuracy and provide rapid feedback on monitoring disease progression in infected patients.

A Double-Chamber "Dandelion" Appearance Sequential Drug Delivery System for Synergistic Treatment of Malignant Tumors.

Introduction: During the combined treatment of tumors, the non-interfering transportation of drugs with different solubilities and the controllable sequential release are the main challenges. Here, we reported a double-chamber "Dandelion" -like sequential drug delivery system to realize the sequential release of different drugs for treating malignant tumors synergistically. Methods: After synthesizing mesoporous silica nanoparticles (MSN) by template method, a hydrophilic chemotherapy drug doxorubicin (DOX) was loaded into the channels of mesoporous silica (MSN) and locked with polydopamine (PDA) coating. Next, ß-cyclodextrin (ß-CDs) was decorated on PDA by Michael addition reaction, and the hydrophobic photosensitizer chlorin e6 (Ce6) was encapsulated into the hydrophobic chambers of ß-CDs. Finally, AS1411 was modified on the surface of PDA and obtained DOX@MSN@PDA-ß-CD/Ce6-AS1411 nanoparticles (DMPCCA) through which orthogonal loading and effective controlled release of different drugs were realized. Results: Under the sequential irradiations of 808 nm and 660 nm near-infrared (NIR) laser, PDA promoted the extensive release of Ce6 firstly while playing the effect of photothermal therapy (PTT), further to achieve the effect of photodynamic therapy (PDT) of Ce6. Meanwhile, the rapid release of DOX loaded in MSN channels showed a time lag of about 5 h after Ce6 release, through which it maximized the chemotherapeutic effect. Besides, the present drug loading nano-platform combined passive tumor-targeting effect given by EPR and active tumor-targeting effect endowed by AS1411 realized PTT-PDT-chemotherapy triple mode synergistic combination. Conclusion: We offer a general solution to address the key limitations for the delivery and sequential release of different drugs with different solubilities.

Aptamer-functionalized quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy.

Chemo-thermotherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. In this study, a novel aptamer functionalized thermosensitive liposome encapsulating hydrophobic drug quercetin was fabricated as an efficient drug delivery system. This aptamer-functionalized quercetin thermosensitive liposomes (AQTSL) combined the merits of high-loading yield, sustained drug release, long-term circulation in the body of PEGylated liposomes, passive targeting provided by 100-200 nm nanoparticles, active targeting and improved internalization effects offered by AS1411 aptamer, and temperature-responsive of quercetin release. In addition, AQTSL tail vein injection combined with 42 °C water bath heating on tumor site (AQTSL + 42 °C)treatment inhibited the tumor growth significantly compared with the normal saline administration (p< 0.01), and the inhibition rate reached 75%. Furthermore, AQTSL + 42 °C treatment also slowed down the tumor growth significantly compared with QTSL combined with 42 °C administration (p< 0.05), confirming that AS1411 decoration on QTSL increased the active targeting and internalization effects of the drug delivery system, and AS1411 aptamer itself might also contribute to the tumor inhibition. These data indicate that AQTSL is a potential carrier candidate for different hydrophobic drugs and tumor targeting delivery, and this kind of targeted drug delivery system combined with temperature responsive drug release mode is expected to achieve an ideal tumor therapy effect.

Layered and orthogonal assembly of hydrophilic drugs and hydrophobic photosensitizers for enhanced cancer therapy.

Combinatorial tumor therapy including chemotherapy and photodynamic therapy (PDT) can compensate for the limitations of each other and significantly increase the therapeutic effect. However, considering the differences of water-soluble characteristics between chemotherapeutic drugs and photosensitizers for photodynamic therapy, simply loading these substances into the same cavities of nanocarriers is rather difficult, leading to the reduced drug loading efficiency. Here, we reported a layered and orthogonal assembly of hydrophilic drugs doxorubicin (Dox) and hydrophobic photosensitizers Chlorin e6 (Ce6) for enhancing the effect of synergistic therapeutics. The assembly was based on polydopamine (PDA) modified with ß-cyclodextrin (ß-CD) through the addition reaction of -HS in HS-ß-CD and-C=C in PDA, then DOX and Ce6 were loaded on the PDA and in the hydrophobic cavities of ß-CDs respectively with superior drug loading efficiencies (38.8 ± 0.8% and 5.4 ± 0.3% for DOX and Ce6). PDA was hydrolyzed completely under the lysosomal acidic condition, leading to the controlled release of DOX. Under NIR irradiations, DOX-based chemotherapy was successfully integrated with PDA-based photothermal and Ce6-based photodynamic therapy. Tumor specific aptamer AS1411-modified assembly provides ideal antitumor effects in vitro and in vivo with excellent biocompatibility. Collectively, this layered and orthogonal assembly offers a generalizable solution for delivering matters with distinct aqueous solubility would find broad applications not only in drug delivery but also in bio-nanotechnology.

Polyoxometalates as chemically and structurally versatile components in self-assembled materials.

Polyoxometalates (POMs) are anionic molecular metal oxides with expansive diversity in terms of their composition, structure, nuclearity and charge. Within this vast collection of compounds are dominant structural motifs (POM platforms), that are amenable to significant chemical tuning with minimal perturbation of the inorganic oxide molecular structure. Consequently, this enables the systematic investigation of these compounds as inorganic additives within materials whereby structure and charge can be tuned independently i.e. [PW12O40]3- vs. [SiW12O40]4- while also investigating the impact of varying the charge balancing cations on self-assembly. The rich surface chemistry of POMs also supports their functionalisation by organic components to yield so-called inorganic-organic hybrids which will be the key focus of this perspective. We will introduce the modifications possible for each POM platform, as well as discussing the range of nanoparticles, microparticles and surfaces that have been developed using both surfactant and polymer building blocks. We will also illustrate important examples of POM-hybrids alongside their potential utility in applications such as imaging, therapeutic delivery and energy storage.

Effect of avatrombopag in the management of severe and refractory chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients, especially after multiple cycles of chemotherapy, which leads to the delayed treatment or reduced dosage. The treatment of CIT is limited for refractory and severe cases. Herein we reported a single-center study of avatrombopag, a type of thrombopoietin receptor agonist (TPO-RA), for the treatment of severe and refractory (S/R) CIT who failed from multi-line treatments. A total of 13 cancer patients with S/R CIT were enrolled at the First Affiliated Hospital of Zhejiang Chinese Medical University from September 2020 to February 2021. All the patients were administered oral avatrombopag at an initial dose of 60 mg/day, which could be decreased as needed, over a period of 8 weeks. Eight (8/13, 61.5%) patients responded to avatrombopag (with a platelet count ≥50 × 109/L and transfusion independent), with a median response time of 27.5 (11-50) days, and the median cumulative day of platelet response was 79 (20-167). Ten of 13 patients (76.9%) no longer required platelet transfusion at the study endpoint. The predictor of response was the level of hemoglobin (HB) at study entry, patients with an HB over 90 g/L achieved a response rate of 88.9%. In addition, platelet count showed 87.5% sensitivity and 100% specificity to predict the treatment response at a cutoff value of 25.5× 109/L at the end of the third week management. No drug-related side effects were noticed during administration. Our study showed that avatrombopag could be a novel and effective drug for the treatment of severe and refractory CIT, especially for those with hemoglobin above 90 g/L. This study was registered at chictr.org.cn as # ChiCTR2100050646.

Iodine-imine Synergistic Promoted Povarov-Type Multicomponent Reaction for the Synthesis of 2,2'-Biquinolines and Their Application to a Copper/Ligand Catalytic System.

An efficient iodine-imine synergistic promoted Povarov-type multicomponent reaction was reported for the synthesis of a practical 2,2'-biquinoline scaffold. The tandem annulation has reconciled iodination, Kornblum oxidation, and Povarov aromatization, where the methyl group of the methyl azaarenes represents uniquely reactive input in the Povarov reaction. This method has broad substrate scope and mild conditions. Furthermore, these 2,2'-biquinoline derivatives had been directly used as bidentate ligands in metal-catalyzed reactions.

Ex Vivo Chemosensitivity Profiling of Acute Myeloid Leukemia and Its Correlation With Clinical Response and Outcome to Chemotherapy.

We evaluated the predictive value of the ex-vivo PharmaFlow PM platform in measuring the pharmacological activity of drug combinations consisting of 20 different chemotherapy regimens (20 Tx) administered in 104 acute myeloid leukemia (AML) patients. The predicted sensitivities of alternative treatments for each patient were ranked in five 20% categories, from resistant to sensitive (Groups 1-5). The complete remission (CR) rates of the five groups were 0%, 12.5%, 38.5%, 50.0%, and 81.3%, respectively. The heat map showed a good relationship between drug sensitivity with CR (Group 4 + 5 vs. Group 1 + 2+3: 77.5% vs. 27.3%, p = 0.002) and the European Leukemia Net risk group (22.6% vs. 63.6%, p = 0.015). The predicted coincidence rate was 90.9% in Group 1 + 2 and 81.3% in Group 5. According to the recommendations of the PharmaFlow PM platform, the CR rate would have increased by about 16.3% in one cycle. The overall survival (OS) was shorter in patients predicted to be resistant (Group 1 + 2 vs. Group 3 + 4+5, p = 0.086). In multivariable analysis, CR after one cycle was an independent prognostic factor for OS [p = 0.001; 95% CI 0.202 (0.080-0.511)], and ex-vivo chemosensitivity was a potential predictive factor for OS [p = 0.078; 95% CI 0.696 (0.465-1.041)]. To conclude, the PharmaFlow PM platform is a rapid and valuable tool for predicting clinical response and outcomes in AML patients.

A Promoted Charge Separation/Transfer System from Cu Single Atoms and C3 N4 Layers for Efficient Photocatalysis.

Establishing highly effective charge transfer channels in carbon nitride (C3 N4 ) for enhancing its photocatalytic activity is still a challenging issue. Herein, for the first time, the engineering of C3 N4 layers with single-atom Cu bonded with compositional N (CuNx ) is demonstrated to address this challenge. The CuNx is formed by intercalation of chlorophyll sodium copper salt into a melamine-based supramolecular precursor followed by controlled pyrolysis. Two groups of CuNx are identified: in one group each of Cu atoms is bonded with three in-plane N atoms, while in the other group each of Cu atoms is bonded with four N atoms of two neighboring C3 N4 layers, thus forming both in-plane and interlayer charge transfer channels. Importantly, ultrafast spectroscopy has further proved that CuNx can greatly improve in-plane and interlayer separation/transfer of charge carriers and in turn boost the photocatalytic efficiency. Consequently, the catalyst exhibits a superior visible-light photocatalytic hydrogen production rate (≈212 µmol h-1 /0.02 g catalyst), 30 times higher than that of bulk C3 N4 . Moreover, it leads to an outstanding conversion rate (92.3%) and selectivity (99.9%) for the oxidation of benzene under visible light.

Retrospective case-control data of serum nitrotyrosine level and clinical biomedical indices in primary glaucoma patients.

From April to December 2017, the case-control data were collected in the Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Fudan University. One hundred primary angle closure glaucoma (PACG), one hundred primary open angle glaucoma (POAG) patients and two hundred control participants were consecutively recruited. The serum nitrotyrosine (NT) levels was not significant different in PACG or POAG patients stratified by gender (1,868.17±427.13 nmol/L vs. 1,768.77±410.17 nmol/L, p>0.05; 1,734.04±460.74 vs. 1,696.46±405.73 nmol/L, p>0.05). Serum NT level was not significantly associated with glaucoma severity in either PACG group or POAG group based on mean deviation (MD) (mild, n=30; moderate, n=24; sever, n=19; blinding, n=27, p>0.05, in Table 3 for PACG; mild, n=9; moderate, n=20; sever, n=21; blinding, n=40; p>0.05, in Table 4 for POAG). Multivariable logistic regression analysis indicated that the risk of developing PACG were significantly associated with serum total triglyceride (TG) and uric acid (UA) levels (OR=1.638, 95%CI: 1.059-2.531, p=0.026 for TG, OR=0.003, 95%CI: 0-0.461, p=0.024 for UA). Serum TG, gamma-glutamyl transferase (GGT) and total bilirubin (TB) levels were significantly associated with POAG (OR=2.00, 95%CI: 1.363-2.934, p<0.001 for TG; OR=0.972, 95%CI: 0.949-0.996, p=0.022 for GGT; OR=1.115, 95%CI: 1.042-1.194, p=0.002 for TB). Descriptions of the data are also available in our recent paper published in Nitric Oxide, "Peroxynitrite is a novel risk factor and treatment target of glaucoma" [1].

Ex-vivo drug testing predicts chemosensitivity in acute myeloid leukemia.

The majority of acute myeloid leukemia (AML) patients will respond to standard chemotherapy, however, resistance is a prevalent problem contributing to incomplete responses, refractory disease, and ultimately patient death. Therefore, choosing more sensitive and effective chemotherapy regimens is of key clinical importance. In order to explore this issue, we investigated and optimized PharmaFlow, an automated flow cytometry method for evaluating the sensitivity of leukemia cells to multiple chemotherapeutic drugs ex vivo. We examined bone marrow samples from 38 Chinese AML patients and incubated them for 48 or 72 h with a panel of 7 single drugs and 6 combinations with cytarabine at different concentrations. Leukemic cell depletion was assessed by PharmaFlow and drug response parameter, called PharmaFlow score, was estimated using population pharmacodynamic models. We identified that most chemotherapeutic drugs and combinations could effectively eliminate pathological cells ex vivo. Estimated drug activities strongly correlated with the patients' duration to achieve clinical remission and PharmaFlow chemosensitivity measured ex vivo was highly predictive of the clinical outcome after chemotherapy. Applying a classification model, we determined a PharmaFlow score of 89.4 as the threshold to predict response to chemotherapy. Using this threshold, we found that in 84.2% of cases patient's cell response ex vivo predicted the observed clinical response and performed similarly or better than prognostic subgroups determined by cytogenetic characteristics. PharmaFlow has the potential to predict chemosensitivity for de novo, secondary and relapsed AML patients prior to treatment and may guide clinicians to tailor treatments and improve patient outcome.

Peroxynitrite is a novel risk factor and treatment target of glaucoma.

To investigate the association between systemic nitrotyrosine (NT) levels and primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) and the mechanism involved. A case control study was conducted in the Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Fudan University from April 2017 to December 2017. A total of 400 participants were consecutively recruited into this study (100 PACG, 100 POAG and 200 controls). Multivariable logistic regression analysis was performed to identify the association between serum NT level and PACG or POAG. Clinical results were validated in cell and animal models. Among 200 glaucoma patients, 101 (50.5%) were women; the age was 57.07 ± 14.51 years. 106 (53%) control participants were women and age was 58.34 ± 14.04 years. Serum levels of NT in PACG and POAG patients are significantly higher than controls (1808.53 ± 417.76 nmol/L vs. 1270.62 ± 454.60 nmol/L, p < 0.001; 1718.63 ± 437.29 nmol/L vs. 1258.38 ± 460.72 nmol/L, p < 0.001). Further, elevated serum NT level increases the risk of developing PACG (OR = 1.003, 95% CI: 1.002 to 1.004, p < 0.001) and POAG (OR = 1.002, 95% CI: 1.002 to 1.003, p < 0.001). Consistent with the clinical data, serum and aqueous humour NT levels are significantly higher in caveolin 1 knockout (Cav1 KO) mice, an animal model of glaucoma. More importantly, peroxynitrite (PN) scavenger MnTMPyP and its transduction molecule PARP inhibitor significantly reduce intraocular pressure in Cav1 KO mice. Our data show for the first time that NT is a systemic risk factor and local treatment target of glaucoma.

Hierarchically Structured Two-Dimensional Bimetallic CoNi-Hexaaminobenzene Coordination Polymers Derived from Co(OH)2 for Enhanced Oxygen Evolution Catalysis.

Conjugated coordination polymers (CPs) with designable and predictable structures have drawn tremendous attention in recent years. However, the poor electrical conductivity and low structural stability seriously restrict their practical applications in electronic devices. Herein, the rational design and synthesis of a hierarchically structured 2D bimetallic CoNi-hexaaminobenzene CPs derived from Co(OH)2 are reported as an efficient oxygen evolution reaction (OER) self-supported electrode. The as-obtained electrode possesses high electrochemical surface area and intrinsic activity, exhibiting high electrochemical catalytic activity, favorable reaction kinetics performance, and strong durability compared with those of the powder catalysts. As a result, the electrode delivers low overpotential of 219 mV @ 10 mA cm-2 and Tafel slope of 42 mV dec-1 as well as 91.3% retention of current density after 24 h of reaction time. The results of density functional theory computations reveal that the synergistic effect of Co and Ni plays an important role in OER. This work not only presents a strategy to fabricate advanced self-supported electrodes with abundant and dense active sites, but also promotes the development of conjugated CPs for electrocatalysis.