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Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

The preparation conditions of zeolite are the key factors affecting the adsorption performance of organic sulfur from natural gas. The influence of crystallization time, pH and Si/Al ratio of ZSM-5...

Emerging documents revealed that E2 enzyme family has been implicated in regulating the progression of numerous human cancers. Ubiquitin-conjugating enzyme E2 J1 (UBE2J1), a member of E2 enzyme family, has been reported to participate in the biological process of medulloblastoma, while little is known about its functionality in endometrial cancer (EC). Gene expression at the mRNA and protein levels were identified using RT-qPCR and western blot analysis, separately. The alteration on cell proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) process was determined through 5-Ethynyl-2ʹ-deoxyuridine, cell adhesion, wound healing and transwell assays as well as western blot analysis. The role of UBE2J1 in xenograft tumor in mice was determined. Luciferase reporter and chromatin immunoprecipitation assays were conducted to reveal the undering mechanism of UBE2J1. Our results indicated that UBE2J1 displayed high level in EC tissues and cells and predicted poor prognosis of EC patients. In addition, UBE2J1 depletion inhibited cell proliferation, adhesion, motion, EMT process invitro, and repressed tumor growth invivo. Rescue assays manifested that ethyl 2-amino-6-chloro-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate treatment reversed the effects of UBE2J1 on PI3K/AKT pathway activation and malignant phenotypes of EC cells. Finally, zinc finger X-chromosomal protein (zfx), with high expression in EC tissues, was verified to activate UBE2J1 transcription by binding to UBE2J1 promoter. In conclusion, all facts signified that zfx-induced upregulation of UBE2J1 accelerated the progression of EC via regulating the PI3K/AKT signaling pathway, which suggested that UBE2J1 might be of great significance in probing into the underlying therapeutic strategies of EC.

Lysosomes are membrane-bound organelles that regulate protein degradation and cellular organelle recycling. Homeostatic alteration by lysosomotropic compounds has been suggested as a potential approach for the treatment of cancer. However, because of the high false-negative rate resulting from strong fluorescent background noise, few luminescent high-throughput screening methods for lysosomotropic compounds have been developed for cancer therapy. Imidazole is a five-membered heterocycle that can act within the acidic interior of lysosomes. To develop an efficient lysosomotropic compound screening system, we introduced an imidazole group to iridium-based complexes and designed a long-lifetime lysosomal probe to monitor lysosomal activity in living cells. By integrating time-resolved emission spectroscopy (TRES) with the novel iridium-based lysosomal probe, a high-throughput screening platform capable of overcoming background fluorescent interference in living cells was developed for discovering lysosomotropic drugs. As a proof-of-concept, 400 FDA/EMA-approved drugs were screened using the TRES system, revealing five compounds as potential lysosomotropic agents. Significantly, the most promising potent lysosomotropic compound (mitoxantrone) identified in this work would have showed less activity if screened using a commercial lysosomal probe because of interference from the intrinsic fluorescence of mitoxantrone. We anticipate that this TRES-based high-throughput screening system could facilitate the development of more lysosomotropic drugs by avoiding false results arising from the intrinsic fluorescence of both bioactive compounds and/or the cell background.

BackgroundMesenchymal stem cells (MSCs) serve as an attractive vehicle for cell-directed enzyme prodrug therapy (CDEPT) due to their unique tumour-nesting ability. Such approach holds high therapeutic potential for treating solid tumours including glioblastoma multiforme (GBM), a devastating disease with limited effective treatment options. Currently, it is a common practice in research and clinical manufacturing to use viruses to deliver therapeutic genes into MSCs. However, this is limited by the inherent issues of safety, high cost and demanding manufacturing processes. The aim of this study is to identify a facile, scalable in production and highly efficient non-viral method to transiently engineer MSCs for prolonged and exceptionally high expression of a fused transgene: yeast cytosine deaminase::uracil phosphoribosyl-transferase::green fluorescent protein (CD::UPRT::GFP).MethodsMSCs were transfected with linear polyethylenimine using a cpg-free plasmid encoding the transgene in the presence of a combination of fusogenic lipids and β tubulin deacetylase inhibitor (Enhancer). Process scalability was evaluated in various planar vessels and microcarrier-based bioreactor. The transfection efficiency was determined with flow cytometry, and the therapeutic efficacy of CD::UPRT::GFP expressing MSCs was evaluated in cocultures with temozolomide (TMZ)-sensitive or TMZ-resistant human glioblastoma cell lines. In the presence of 5-fluorocytosine (5FC), the 5-fluorouracil-mediated cytotoxicity was determined by performing colometric MTS assay. In vivo antitumor effects were examined by local injection into subcutaneous TMZ-resistant tumors implanted in the athymic nude mice.ResultsAt > 90% transfection efficiency, the phenotype, differentiation potential and tumour tropism of MSCs were unaltered. High reproducibility was observed in all scales of transfection. The therapeutically modified MSCs displayed strong cytotoxicity towards both TMZ-sensitive and TMZ-resistant U251-MG and U87-MG cell lines only in the presence of 5FC. The effectiveness of this approach was further validated with other well-characterized and clinically annotated patient-derived GBM cells. Additionally, a long-term suppression (> 30 days) of the growth of a subcutaneous TMZ-resistant U-251MG tumour was demonstrated.ConclusionsCollectively, this highly efficient non-viral workflow could potentially enable the scalable translation of therapeutically engineered MSC for the treatment of TMZ-resistant GBM and other applications beyond the scope of this study.

S100 calcium-binding protein B (S100B) is overexpressed in various malignant tumors, where it regulates cancer cell proliferation and metabolism by physical interactions with other molecules. Interfering with S100B-effector protein interactions is a potential strategy to treat malignant tumors. Although some S100B inhibitors have been discovered by virtual screening (VS), most target the S100B-p53 interaction. Hence, there is scope for the discovery of other S100B-effector protein interaction modulators for malignant tumors. In this review, we provide an overview of S100B-effector protein interaction inhibitor discovery using VS and discuss promising S100B-effector protein interaction targets that permit in silico analysis for drug discovery.

Gastrin-releasing peptide receptor (GRPr) plays proliferative and inflammatory roles in living systems. Here, we report a highly selective GRPr antagonist (JMV594)-tethered iridium(III) complex for probing GRPr in living cancer cells and immune cells. This probe exhibited desirable photophysical properties and also displayed negligible cytotoxicity, overcoming the inherent toxicity of the iridium(III) complex. Its long emission lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using a time-resolved technique. This probe selectively visualized living cancer cells via specific binding to GRPr, while it also modulated the function of GRPr on TNF-α secretion in immune cells. To our knowledge, this is the first peptide-conjugated iridium(III) complex developed as a GRPr bioimaging probe and modulator of GRPr activity. This theranostic agent shows great potential at unmasking the diverse roles of GRPr in living systems.

Brevibacillus brevis GZDF3 is a gram-positive, plant growth-promoting rhizosphere bacterium (PGPR) isolated from the rhizosphere soil of Pinellia ternata (an important herb in traditional Chinese medicine). The GZDF3 strain produces certain active compounds, such as siderophores, which are the final metabolite products of non-ribosomal peptide synthetase (NRPS) and independent non-ribosomal peptide synthetase (NIS) activity. With the present study, we attempted to investigate the siderophore production characteristics and conditions of Bacillus sp. GZDF3. The antibacterial activity of the siderophores on pathogenic fungi was also investigated. Optimal conditions for the synthesis of siderophores were determined by single factor method, using sucrose 15 g/l, asparagine 2 g/l, 32°C, and 48 h. The optimized sucrose asparagine medium significantly increased the production of siderophores, from 27.09% to 54.99%. Moreover, the effects of different kinds of metal ions on siderophore production were explored here. We found that Fe3+ and Cu2+ significantly inhibited the synthesis of siderophores. The preliminary separation and purification of siderophores by immobilized-metal affinity chromatography (IMAC) provides strong antibacterial activity against Candida albicans. The synergistic effect of siderophores and amphotericin B was also demonstrated. Our results have shown that the GZDF3 strain could produce a large amount of siderophores with strong antagonistic activity, which is helpful in the development of new biological control agents.

Protein biomarkers, particularly abnormally expressed receptor proteins, have been proved to be one of the crucial biomarkers for the rapid assessment, diagnosis, prognosis and prediction of specific human diseases. Transition metal based strategies in particular possess delightful strengths in the in-field and real-time visualization of receptor proteins owing to their unique photophysical properties. In this review, we highlight recent advances in the development of detection methods for receptor protein biomarkers using transition metal based approaches, particularly those employing transition metal complexes. We first discuss the strengths and weaknesses of various strategies used for protein biomarker monitoring in live cells. We then describe the principles of the various sensing platforms and their application for receptor protein detection. Finally, we discuss the challenges and future inspirations in this specific field.

Dual-functional theranostics are powerful tools that can allow for the in-field understanding of cancer pathology, yet their use is held back by the paucity of suitable theranostics for living systems. Moreover, typical in vitro screening conditions for probe molecules do not necessarily generate candidates that can function effectively in the natural in cellulo environment, limiting their follow-up use in living systems. We introduce herein a general strategy for the development of an iridium(iii) theranostic by grafting a well-known inhibitor as a “binding unit” onto an iridium(iii) complex precursor as a “signaling unit”. To further optimize their emissive properties, we explored the effect of imaging behavior by incorporating different substituents onto the parental “signaling unit”. This design concept was validated by a series of tailored iridium(iii) theranostics 2a–2h for the visualization and inhibition of EGFR in living cancer cells. By comprehensively assessing the theranostic potency of 2a–2h in both in vitro and in cellulo contexts, probe 2f containing electron-donating methoxy groups on the “signaling unit” was discovered to be the most promising candidate theranostic with desirable photophysical/chemical properties. Probe 2f selectively bound to EGFR in vitro and in cellulo, enabling it to selectively discriminate living EGFR-overexpressing cancer cells from normal cells that express low levels of EGFR with an “always-on” luminescence signal output. In particular, its long-lived lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using time-resolved techniques. Complex 2f simultaneously visualized and inhibited EGFR in a dose-dependent manner, leading to a reduction in the phosphorylation of downstream proteins ERK and MEK, and inhibition of the activity of downstream transcription factor AP1. Notably, complex 2f is comparable to the parental EGFR inhibitor 1b, in terms of both inhibitory activity against EGFR and cytotoxicity against EGFR-overexpressing cancer cells. This tailored dual-functional iridium(iii) theranostic toolkit provides an alternative strategy for the personalized diagnosis and treatment of cancers., In order to optimise dual-functional theranostics for application in living systems, we developed an iridium(iii) theranostic by grafting an inhibitor as a “binding unit” onto an iridium(iii) complex precursor as a “signaling unit”.

A strictly anaerobic, thermophilic, Gram-stain-negative bacterium, named as strain S15T, was isolated from oily sludge of Shengli oilfield in PR China. Cells of strain S15T were straight or slightly curved rods with 0.4–0.8 µm width × 1.4–3 µm length and occurred mostly in pairs or short chains. Endospore-formation was not observed. The strain grew optimally at 55 °C (range from 30–65 °C), pH 6.5 (pH 6.0–8.5) and 0–30 g l−1 NaCl (optimum with 10 g l−1 NaCl). Yeast extract was an essential growth factor for strain S15T. The major cellular fatty acid was iso-C15 : 0 (58.2 %), and the main polar lipids were amino phospholipid (APL), glycolipids (GLs) and phosphatidylethanolamine (PE). The G+C content of DNA of strain S15T was 52.2 mol%. Strain S15T shared 89.8 % 16S rRNA gene similarity with the most related organism Acetomicrobium hydrogeniformans DSM 22491T in the phylum Synergistetes . The paired genomic average amino acid identity (AAI) and percentage of conserved proteins (POCP) values showed relatedness of less than 58.0 and 39.7 % with type strains of the species in the phylum Synergistetes . On the basis of phenotypic, phylogenetic and phylogenomic evidences, strain S15T constitutes a novel species in a novel genus, for the name Thermosynergistes pyruvativorans gen. nov., sp. nov. is proposed. The type strain is S15T (=CCAM 583T=JCM 33159T). Thermosynergistaceae fam. nov. is also proposed.

Circulating tumor cells (CTCs) are an important biomarker for various types of cancers. As CTCs are extremely rare in the bloodstream, the accurate analysis and efficient separation of CTCs is a challenging task. In order to develop new diagnostic approaches for cancer research, understanding the functional characteristics of biomolecules at the single-molecule level in individual cancer cells is required. Meanwhile, microfluidic platforms have emerged as a promising technology for analyzing single molecules and single cells. In this review, we discuss some label-free techniques for biomolecule detection and highlight some reports that have employed combined label-free techniques with microfluidics for individual molecule or cancer cell analysis. Finally, we offer our perspective of the integration of label-free techniques with microfluidic technology on future applications.

Periodate (IO4−) is a widely used reagent in organic synthesis and for biomolecular modification. However, highly sensitive fluorescence detection methods for IO4− are lacking. In this work, we designed and synthesized iridium(III) complexes for the detection of IO4− by the incorporation of a methylthio group to serve as a luminescence trigger. The results showed that complex 1 could detect IO4− in a sensitive and selective manner with a detection limit of 0.077 μM, rendering it more sensitive than reported fluorescence methods. Meanwhile, its inherently long emission lifetime enables its luminescence response to IO4− to be detected even in the presence of organic dyes by the use of time-resolved emission spectroscopy (TRES). This probe was further demonstrated to detect IO4− in living cells. To our knowledge, complex 1 is first long-lived iridium(III)-based probe for the sensitive detection of IO4−, and is also one of few existing imaging probes for IO4−.

The peptidyl-prolyl isomerase Pin1 is correlated with the progression of cervical cancer via regulating numerous oncogenic and tumor suppressor pathways. p65 is a crucial regulator of tumorigenesis that is regulated by Pin1, and p65 signaling suppression can enhance the antitumor efficacy of doxorubicin (DOX). Here, we utilized a structural mimicry approach to synthesize a series of dibenzothiophene analogues and evaluated their ability to inhibit Pin1 activity. Compound 1a was identified as a potent Pin1 inhibitor that inhibited p65 signaling in vitro and in cervical cancer cells. Moreover, compound 1a enhanced the cytotoxicity of DOX in cervical cancer cells via reducing p65 nuclear accumulation and enhancing DOX uptake. These compounds are promising scaffolds for developing more potent Pin1 inhibitors against cervical cancer, either alone or in combination with anticancer drugs such as DOX.

Grafted embryonic central neural tissue pieces can recover function of hemisected spinal cord in neonatal rats and promote axonal growth in adults. However, spinal cord segments from adults have not been used as donor segments for allogeneic transplantation. Here, we utilized adult spinal cord tissue grafts (aSCGs) as donor constructs for repairing complete spinal cord injury (SCI). Moreover, to provide a favourable microenvironment for SCI treatment, a growth factor cocktail containing three growth factors (brain-derived neurotrophic factor, neurotrophin-3 and vascular endothelial growth factor), was applied to the aSCG transplants. We found that the locomotor function was significantly improved 12 weeks after transplantation of aSCGs into the spinal cord lesion site in adult rats. Transplantation of aSCGs combined with these growth factors enhanced neuron and oligodendrocyte survival and functional restoration. These encouraging results indicate that treatment of complete SCI by transplanting aSCGs, especially in the presence of growth factors, has a positive effect on motor functional recovery, and therefore could be considered as a possible therapeutic strategy for SCI.

We have designed for the first time a dual-functional luminescent probe and inhibitor of neuraminidase (NA), a key influenza target. The lead iridium(iii) complex exhibited enhanced inhibition against NA compared to the FDA-approved antiviral drug, oseltamivir, and could detect NA even in the presence of an autofluorescent background.

Four-fold interpenetrating framework 1a can be constructed driven by temperature-controlled SC-SC transformation from 2-fold interpenetrating network 1. Luminescent properties indicated that 1a can be viewed as a luminescent sensor of high-explosives.

Background: Although laryngopharyngeal reflux (LPR) has been implicated in various upper aerodigestive tract and laryngeal diseases, the underlying mechanisms remain elusive. In this study, we investigated the role of gastric acidified pepsin in laryngeal precancerosis. Methods: The in vitro and in vivo effects of acidified pepsin on H+/K+-ATPase expression and autophagy/mitophagy induction in mouse laryngeal epithelial cells were assessed by hematoxylin and eosin staining, immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, and quantitative real-time PCR. Additionally, the levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosal specimens were assessed by immunohistochemical staining. Results: Acidified pepsin (pH=3) enhanced the growth and survival of mouse laryngeal epithelial cells in vitro and promoted laryngeal mucosal thickening and laryngeal epithelial cell growth in vivo. Furthermore, acidified pepsin promoted autophagy/mitophagy induction, accompanied by a significant decrease in mitochondrial membrane potential (MMP). Inhibition of autophagy by chloroquine abolished the ability of acidified pepsin to promote mitophagy and cell growth in laryngeal epithelial cells. Additionally, chloroquine promoted cell apoptosis and further reduced MMP in laryngeal epithelial cells treated with acidified pepsin. The expression levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosa specimens were 51.6%, 48.4%, and 48.4%, respectively. Importantly, the pepsin level was correlated with the H+/K+-ATPase β subunit level. H+/K+-ATPase upregulation in laryngeal epithelial cells in response to acidified pepsin was essential for the mitophagy-promoting effect of acidified pepsin. H+/K+-ATPase knockout or inhibition further reduced MMP in the presence of acidified pepsin. Conclusions: Our findings suggest that in an acidic environment, pepsin promotes laryngeal epithelial cell growth and survival by upregulating H+/K+-ATPase and activating mitophagy, potentially leading to laryngeal precancerosis.

Nanofibers can mimic natural tissue structure by creating a more suitable environment for cells to grow, prompting a wide application of nanofiber materials. In this review, we include relevant studies and characterize the effect of nanofibers on mesenchymal stem cells, as well as factors that affect cell adhesion and osteogenic differentiation. We hypothesize that the process of bone regeneration in vitro is similar to bone formation and healing in vivo, and the closer nanofibers or nanofibrous scaffolds are to natural bone tissue, the better the bone regeneration process will be. In general, cells cultured on nanofibers have a similar gene expression pattern and osteogenic behavior as cells induced by osteogenic supplements in vitro. Genes involved in cell adhesion (focal adhesion kinase (FAK)), cytoskeletal organization, and osteogenic pathways (transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP), mitogen-activated protein kinase (MAPK), and Wnt) are upregulated successively. Cell adhesion and osteogenesis may be influenced by several factors. Nanofibers possess certain physical properties including favorable hydrophilicity, porosity, and swelling properties that promote cell adhesion and growth. Moreover, nanofiber stiffness plays a vital role in cell fate, as cell recruitment for osteogenesis tends to be better on stiffer scaffolds, with associated signaling pathways of integrin and Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Also, hierarchically aligned nanofibers, as well as their combination with functional additives (growth factors, HA particles, etc.), contribute to osteogenesis and bone regeneration. In summary, previous studies have indicated that upon sensing the stiffness of the nanofibrous environment as well as its other characteristics, stem cells change their shape and tension accordingly, regulating downstream pathways followed by adhesion to nanofibers to contribute to osteogenesis. However, additional experiments are needed to identify major signaling pathways in the bone regeneration process, and also to fully investigate its supportive role in fabricating or designing the optimum tissue-mimicking nanofibrous scaffolds.

Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4′,5-trihydroxy-stilbene-3-β-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition., Graphical abstract fx1, Highlights • Fructose decreases miR-200a expression to impair Keap1/Nrf2 pathway in NAFLD. • MiR-200a-driven oxidative stress is a causer in fructose-induced NAFLD. • Polydatin elevates miR-200a to regulate Keap1/Nrf2 pathway in fructose-induced NAFLD. • Polydatin lowers fructose-caused oxidative stress, inflammation and lipid deposition. • Enhancement of miR-200a expression by polydatin is a therapeutic strategy for NAFLD.

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

AIM To study the role of microbial metabolites in the modulation of biochemical and physiological processes in irritable bowel syndrome (IBS). METHODS In the current study, using a metabolomic approach, we analyzed the key metabolites differentially excreted in the feces of control mice and mice with IBS, with or without Clostridium butyricum (C. butyricum) treatment. C57BL/6 mice were divided into control, IBS, and IBS + C. butyricum groups. In the IBS and IBS + C. butyricum groups, the mice were subjected to water avoidance stress (WAS) for 1 h/d for ten days. Gas chromatography/mass spectrometry (GC-MS) together with multivariate analysis was employed to compare the fecal samples between groups. RESULTS WAS exposure established an appropriate model of IBS in mice, with symptoms of visceral hyperalgesia and diarrhea. The differences in the metabolite profiles between the control group and IBS group significantly changed with the progression of IBS (days 0, 5, 10, and 17). A total of 14 differentially excreted metabolites were identified between the control and IBS groups, and phenylethylamine was a major metabolite induced by stress. In addition, phenylalanine metabolism was found to be the most relevant metabolic pathway. Between the IBS group and IBS + C. butyricum group, 10 differentially excreted metabolites were identified. Among these, pantothenate and coenzyme A (CoA) biosynthesis metabolites, as well as steroid hormone biosynthesis metabolites were identified as significantly relevant metabolic pathways. CONCLUSION The metabolic profile of IBS mice is significantly altered compared to control mice. Supplementation with C. butyricum to IBS mice may provide a considerable benefit by modulating host metabolism.

Depression is a common mental disorder in modern society. A traditional Chinese medicine Huanglian-Wendan decoction with potential anti-inflammation is used as a clinical antidepressant. Our previous study showed central and peripheral inflammatory responses in a rat model of depression developed by chronic unpredictable mild stress (CUMS). Here, we investigated the anti-inflammatory activity and mechanism of Huanglian-Wendan decoction in CUMS rats. LC-MS/MS and HPLC were performed to determine the major compounds in water extract of this decoction. This study showed that Huanglian-Wendan decoction significantly increased sucrose consumption and reduced serum levels of interleukin-1 beta (IL-1β), IL-6, and alanine aminotransferase (ALT) in CUMS rats. Moreover, this decoction inhibited nuclear entry of nuclear factor-kappa B (NF-κB) with the reduction of phosphorylated protein of NF-κB (p-NF-κB) and inhibitor of NF-κB alpha (p-IκBα) and downregulated protein of nod-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), cysteinyl aspartate-specific proteinase-1 (Caspase-1), and IL-1β in liver and brain regions of CUMS rats. These findings demonstrated that Huanglian-Wendan decoction had antidepressant activity with hepatoprotection in CUMS rats coinciding with its anti-inflammation in both periphery and central. The inhibitory modulation of NF-κB and NLRP3 inflammasome activation by Huanglian-Wendan decoction may mediate its antidepressant action.

NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53.

The complex and time-consuming character of the current methods to synthesize cuprous catalysts hampers use of such compounds as replacements for noble metal catalysts for the degradation of organic pollutants. Herein, we report on the development of a simple one-pot method for synthesis of Cu2O/Cu nanoparticles. The method was comprised of adding benzyl alcohol during the process of nanoparticle synthesis, where the amount of benzyl alcohol used determined the content of Cu in the obtained nanoparticles. A thorough physicochemical characterization was carried out for the synthesized nanoparticles, where it was found that they could act as catalysts for ultra-fast degradation of phenolics and dyes. Thus, their catalytic activity for the degradation of 4-nitrophenol, methyl orange, and Congo red were evaluated, where pseudo-first-order kinetics were observed. The percentage degradation and rate constant (kapp) values were, respectively, 98% (in 60 s) and kapp= 61.23 × 10−3 s−1 for 4-nitrophenol, 96% (in 100 s) and kapp = 31.5 × 10−3 s−1 for methyl orange, and 97% (in 100 s) and kapp= 35.5 × 10−3 s−1 for Congo red. Comparisons with previously reported cuprous catalysts for degradation of these compounds revealed that the Cu2O/Cu nanoparticles of the present paper exhibited the fastest degradation rates.

By modifying the salicylic-acid moiety with electron-withdrawing or –donating groups, three new terbium complexes (LI·Tb, LII·Tb, LIII·Tb) based on tripodal carboxylate ligands were synthesized. Due to different pull-push electronic effects of ligands, the fluorescence intensities of these terbium complexes significantly varied, that is: LII·Tb > LIII·Tb > LI·Tb. Meanwhile, the characteristic peaks at 492 nm (5D4 → 7F6) and 547 nm (5D4 → 7F5) showed “Off–On–Off” fluorescence response to various pH conditions, which indicated that all of them can be used as the highly sensitive pH fluorescent probes. Notably, using LII·Tb with the best fluorescence performance as a probe, some patients’ urine samples can be easily monitored through the response triggered by pH value. Therefore, LII·Tb has the potential to auxiliarily diagnose some diseases in clinical practice through pH detection of routine urine test.

The aim of the present study was to investigate the role of the cancer‑testis antigen family 45 member A1 (CT45A1) in the proliferation, apoptosis, invasion and metastasis of lung cancer cells, and the associated molecular mechanisms. Western blotting determined that the expression of CT45A1 in normal lung cells was far lower than that observed in lung cancer cells. Following the transfection of CT45A1 small (or short) interfering (si)RNA and its negative control into A549 cells using Lipofectamine 2000, the CT45A1 protein and mRNA levels were determined further by western blotting and reverse transcription‑polymerase chain reaction. Following CT45A1 siRNA transfection, the levels of CT45A1 in lung cancer cells were markedly reduced (P

Disruption of the neurovascular unit (NVU), induced by chronic cerebral hypoperfusion (CCH), has been broadly found in various neurological disorders. SUMO-specific protease 3 (SENP3) is expressed in neurons, astrocytes, and microglia, and regulates a variety of cell events. However, whether SENP3 is involved in neurovascular injury under the condition of CCH is still elusive. To address this issue, we investigated the effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on NVU and the role of SENP3 in this process, as well as the underling mechanisms. The expression of SENP3 was detected by immunochemistry. The function and structure of the NVU was assessed by Western blot analysis and transmission electron microscopy. CCH caused the upregulation of SENP3, the disruption of cell and non-cell components at the protein level within the NVU, and ultrastructural deterioration. The NVU impairment as well as overexpression of SENP3 were reversed by treatment with URB597. These results reveal a novel neuroprotective role in URB597, which implicates URB597 in the amelioration of CCH-induced NVU impairment by inhibiting SENP3.

The stimuli-responsive behavior of supramolecular nanocarriers is crucial for their potential applications as smart drug delivery systems. We hereby constructed a glucose-responsive supramolecular drug delivery system based on the host-guest interaction between a water-soluble pillar[5]arene (WP5) and a pyridylboronic acid derivative (G) for insulin delivery and controlled release under physiological conditions. The approach represents the ideal treatment of diabetes mellitus. The drug loading and in vitro drug release experiments demonstrated that large molecular weight insulin could be encapsulated into the vesicles with high loading efficiency, which, to our knowledge, is the first example of small-size supramolecular vesicles with excellent encapsulation capacity of a large protein molecule. Moreover, FITC-labeled insulin was used to evaluate the release behavior of insulin, and it was demonstrated that high glucose concentration could facilitate the quick release of insulin, suggesting a smart drug delivery system for potential application in controlled insulin release only under hyperglycemic conditions. Finally, we demonstrated that these supramolecular nanocarriers have good cytocompatibility, which is essential for their further biomedical applications. The present study provides a novel strategy for the construction of glucose-responsive smart supramolecular drug delivery systems, which has potential applications for the treatment of diabetes mellitus.

Targeting apoptosis is a principal strategy in the design of anticancer drugs. In recent years, non-platinum-based scaffolds have been exploited as viable candidates for the exploitation of anticancer agents with potentially lower toxicity than the widely used cisplatin analogues. This review highlights the latest advances in developing iridium(III) complexes as anticancer agents that act particularly via targeting apoptotic cell death in cancer cells.

This study aimed to explore potential new drugs in the treatment of ischemic stroke by Connectivity Map (CMap) and to determine the role of luteolin on ischemic stroke according to its effects on matrix metalloproteinase-9 (MMP9) and PI3K/Akt signaling pathway. Based on published gene expression data, differentially expressed genes were obtained by microarray analysis. Potential compounds for ischemic stroke therapy were obtained by CMap analysis. Cytoscape and gene set enrichment analysis (GSEA) were used to discover signaling pathways connected to ischemic stroke. Cell apoptosis and viability were, respectively, evaluated by flow cytometry and an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the expression of MMP9 and the PI3K/Akt signaling pathway-related proteins in human brain microvascular endothelial cells (HBMECs) and tissues. Additionally, the infarct volume after middle cerebral artery occlusion (MCAO) was determined by a TTC (2,3,5-triphenyltetrazolium chloride) assay. The microarray and CMap analyses identified luteolin as a promising compound for future therapies for ischemic stroke. Cytoscape and GSEA showed that the PI3K/Akt signaling pathway was crucial in ischemic stroke. Cell experiments revealed that luteolin enhanced cell viability and downregulated apoptosis via inhibiting MMP9 and activating the PI3K/Akt signaling pathway. Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. These results suggest that luteolin has potential in the treatment of ischemic stroke through inhibiting MMP9 and activating PI3K/Akt signaling pathway., Ischemic stroke: Compound in fruit and vegetables may offer benefit A metabolite commonly found in fruit and vegetables may provide protection against brain damage after a stroke, according to researchers in China. Lei Zhang and co-workers at Sun Yat-sen University in Guangdong employed the Connectivity Map (CMap), a tool for analyzing genome-wide data and identifying connections between diseases, genes, and potential treatments. They confirmed that the metabolite luteolin may benefit patients who have suffered ischemic stroke, which is caused by a blocked artery to the brain. Using an existing database comprising genetic details of stroke patients and controls, the team found that a major signaling pathway is inactivated and an enzyme called MMP9 is increased in stroke victims. Studies in cultured human brain cells and rats showed that luteolin can inhibit MMP9 and reactivate the signaling pathway.

Diabetic retinopathy (DR) is one of the major diseases causing blindness, and microaneurysms in the fundus are the first reliable lesions in its early stage. This paper proposes an object detection method for microaneurysms based on R-CNN, which consists of five steps: image preprocessing, candidate region generation, feature extraction, classification and non-maximal suppression. First, a fundus image preprocessing method and a candidate region generation algorithm for microaneurysms are proposed. Then, the VGG16 network is trained using the transferred fine-tuning model to extract features from candidate samples. Finally, real aneurysms are selected from candidate regions by a classifier. The experimental results in the internationally published database e-ophtha show that the proposed method outperforms other known related methods on the FROC indicator.

The distribution and transfer of sulfide in the thermal reaction process are studied. It has found that different types of sulfur have different distribution patterns in the refining process. Thiophene derivatives with better thermal stability are mainly distributed in the heavy components, while mercaptans and small molecular thioethers with poor thermal stability are mainly distributed in the light components. During the thermal reaction, part of the sulfide will decompose or react to produce sulfide with a smaller molecular weight, which will be transferred to light components or gases. The thermal reaction temperature has a certain effect on the product yield and sulfur content. As the reaction temperature increases, the liquid yield increases and the sulfur content decreases, but the thermal reaction temperature has little effect on the sulfide type distribution.

Polymer membranes with well-controlled and vertically oriented pores are of great importance in the applications for water treatment and tissue engineering. On the basis of two-dimensional solvent freezing, we report environmentally friendly facile fabrication of such membranes from a broad spectrum of polymer resources including poly(vinylidene fluoride), poly(l-lactic acid), polyacrylonitrile, polystyrene, polysulfone and polypropylene. Dimethyl sulfone, diphenyl sulfone, and arachidic acid are selected as green solvents crystallized in the polymer matrices under two-dimensional temperature gradients induced by water at ambient temperature. Parallel Monte Carlo simulations of the lattice polymers demonstrate that the directional process is feasible for each polymer holding suitable interaction with a corresponding solvent. As a typical example of this approach, poly(vinylidene fluoride) membranes exhibit excellent tensile strength, high optical transparence, and outstanding separation performance for the mixtures of yeasts and lactobacilli.

Acute liver injury in the setting of fibrosis is an area of interest in investigations, and remains to be fully elucidated. Previous studies have suggested the beneficial effects of liver fibrosis induced by thioacetamide and partial bile duct ligation against Fas‑mediated acute liver injury. The activation of AKT and extracellular signal-regulated kinase signaling is considered to be crucial in this hepatoprotection. To demonstrate the protection of CCl4‑induced liver fibrosis against lethal challenge, the present study compared the reactivity to lethal doses of D‑galactosamine (D-GalN)/lipopolysaccharide (LPS) between fibrotic mice and control mice groups. The extent of hepatic damage was assessed by survival rate and histopathological analysis. The molecular basis of the fibrosis‑based hepatoprotection was examined, with a particular focus on the translocation and release of high‑mobility group box (HMGB)1 and the inflammatory response triggered by HMGB1. Hepatoprotection induced by fibrosis was demonstrated by improved survival rates (100%, vs. 20%) and improved preservation of liver architecture in fibrotic mice subjected to D‑GalN/LPS, compared with control mice treated in the same way. D‑GalN/LPS evoked the translocation and release of HMGB1, detected by immunohistochemistry, in the control mice, which was significantly inhibited in the fibrotic mice. The gene expression levels of HMGB1‑associated proinflammatory cytokines, including interleukin (IL)‑1β, IL‑6, tumor necrosis factor‑α and IL‑12p40, were markedly inhibited in the fibrotic mice when exposed to D‑GalN/LPS. These findings confirmed that CCl4‑based fibrosis induced hepatoprotection, and provided evidence that fibrosis inhibited the translocation and release of HMGB1, and the proinflammatory response triggered by HMGB1. This alleviated liver damage following exposure to D‑GalN/LPS challenge.

Adipic acid(AA) has a wide range of industrial applications and is enormously demanded. However, there are many disadvantages such as high energy consumption, environmental pollution in the current industrial process. Development of environment-friendly and effective synthetic methods is in urgent need. This review mainly introduces the latest research progresses of green synthetic methods of adipic acid by direct oxidation of cyclohexane using clean oxidants such as O2 (air), H2O2 and O3.

Transition metal complexes have attracted interest in the fields of cancer therapy, medical and environmental detection, and materials of organic light-emitting diodes (OLED). Recently, iridium(iii) complexes have been explored in a reaction based way for luminescence monitoring and imaging due to their salient photophysical properties, including large Stokes shifts, long-lived luminescence and high luminescent quantum yields. This frontier article will introduce recent developments and applications of iridium(iii) complexes as luminescent probes for ions and biomolecules. Our outlook for this class of complexes is also discussed.

Nitric oxide (NO) is an intra- and extracellular messenger with important functions during human physiology process. A long-lived luminescent iridium(III) complex probe 1 has been designed and synthesized for the monitoring of NO controllably released from sodium nitroprusside (SNP). Probe 1 displayed a 15-fold switch-on luminescence in the presence of SNP at 580 nm. The probe exhibited a linear response towards SNP between 5 to 25 μM with detection limit at 0.18 μM. Importantly, the luminescent switch-on detection of NO in HeLa cells was demonstrated. Overall, complex 1 has the potential to be applied for NO tracing in complicated cellular environment.

Pseudomonas putida (P. putida) MnB1 is a widely used model strain in environment science and technology for determining microbial manganese oxidation. Numerous studies have demonstrated that the growth and metabolism of P. putida MnB1 are influenced by various environmental factors. In this study, we investigated the effects of hydrogen peroxide (H2O2) and manganese (Mn2+) on proliferation, Mn2+ acquisition, anti-oxidative system, and biofilm formation of P. putida MnB1. The related orthologs of 4 genes, mco, mntABC, sod, and bifA, were amplified from P. putida GB1 and their involvement were assayed, respectively. We found that P. putida MnB1 degraded H2O2, and quickly recovered for proliferation, but its intracellular oxidative stress state was maintained, with rapid biofilm formation after H2O2 depletion. The data from mco, mntABC, sod and bifA expression levels by qRT-PCR, elucidated a sensitivity toward bifA-mediated biofilm formation, in contrary to intracellular anti-oxidative system under H2O2 exposure. Meanwhile, Mn2+ ion supply inhibited biofilm formation of P. putida MnB1. The expression pattern of these genes showed that Mn2+ ion supply likely functioned to modulate biofilm formation rather than only acting as nutrient substrate for P. putida MnB1. Furthermore, blockade of BifA activity by GTP increased the formation and development of biofilms during H2O2 exposure, while converse response to Mn2+ ion supply was evident. These distinct cellular responses to H2O2 and Mn2+ provide insights on the common mechanism by which environmental microorganisms may be protected from exogenous factors. We postulate that BifA-mediated biofilm formation but not intracellular anti-oxidative system may be a primary protective strategy adopted by P. putida MnB1. These findings will highlight the understanding of microbial adaptation mechanisms to distinct environmental stresses.