Molecular Engineering of Corrole Radicals by Polycyclic Aromatic Fusion: Towards Open-Shell Near-Infrared Materials for Efficient Photothermal Therapy.

Open-shell radicals are promising near-infrared (NIR) photothermal agents (PTAs) owing to their easily accessible narrow band gaps, but their stabilization and functionalization remain challenging. Herein, highly stable π-extended nickel corrole radicals with [4n+1] π systems are synthesized and used to prepare NIR-absorbing PTAs for efficient phototheranostics. The light-harvesting ability of corrole radicals gradually improves as the number of fused benzene rings on ß-pyrrolic locations increases radially, with naphthalene- and anthracene-fused radicals and their one-electron oxidized [4n] π cations exhibiting panchromatic visible-to-NIR absorption. The extremely low doublet excited states of corrole radicals promote heat generation via nonradiative decay. By encapsulating naphthocorrole radicals with amphiphilic polymer, water-soluble nanoparticles Na-NPs are produced, which exhibit outstanding photostability and high photothermal conversion efficiency of 71.8 %. In vivo anti-tumor therapy results indicate that Na-NPs enable photoacoustic imaging of tumors and act as biocompatible PTAs for tumor ablation when triggered by 808 nm laser light. The "aromatic-ring fusion" strategy for energy-gap tuning of corrole radicals opens a new platform for developing robust NIR-absorbing photothermal materials.

Influence of organic cosolvents on hexabromobenzene degradation in solution by montmorillonite-templated subnanoscale zero-valent iron.

Organic cosolvents are commonly used to increase the dissolution of poorly water-soluble organic pollutants into aqueous solutions during environmental remediation. In this study, the influences of five organic cosolvents on hexabromobenzene (HBB) degradation catalyzed by one typical reactive material montmorillonite-templated subnanoscale zero-valent iron (CZVI) were investigated. The results demonstrated that all cosolvents promoted HBB degradation but the degree of promotion was different for different cosolvents, which was associated with inconsistent solvent viscosities, dielectric constant properties, and the extent of interactions between cosolvents with CZVI. Meanwhile, HBB degradation was highly dependent on the volume ratio of cosolvent to water, which increased in the range of 10%-25% but persistently decreased in the range of more than 25%. This might be due to the fact that the cosolvents increased HBB dissolution at low concentrations but reduced the protons supplied by water and the contact between HBB with CZVI at high concentrations. In addition, the freshly-prepared CZVI had higher reactivity to HBB than the freeze-dried CZVI in all water-cosolvent solutions, probably because freeze-drying reduced the interlayer space of CZVI and thus the contact probability between HBB and active reaction sites. Finally, the CZVI-catalyzed HBB degradation mechanism was proposed as the electron transfer between zero-valent iron and HBB, which led to the formation of four debromination products. Overall, this study provides helpful information for the practical application of CZVI in the remediation of persistent organic pollutants in the environment.

Circular RNA hsa_circ_0057452 facilitates keloid progression by targeting the microRNA-1225-3p/AF4/FMR2 family member 4 axis.

The circular RNA, hsa_circ_0057452, is highly expressed in keloids, but its specific mechanism of action remains unknown. The levels of hsa_circ_0057452, microRNA (miR)-1225-3p, and AF4/FMR2 family member 4 (AFF4) in keloid tissues and keloid fibroblasts (KFs) were determined using quantitative reverse transcription-polymerase chain reaction. Changes in KFs viability, proliferation, apoptosis, and migration were investigated using the cell counting kit-8, bromodeoxyuridine, flow cytometry, and Transwell assays. Luciferase, RNA immunoprecipitation, and RNA pull-down assays were performed to identify the binding relationship among hsa_circ_0057452, miR-1225-3p, and AFF4. We found that hsa_circ_0057452 and AFF4 expression levels were upregulated, whereas miR-1225-3p expression levels were downregulated in keloids. Knockdown of hsa_circ_0057452 or AFF4 suppressed the viability, proliferation, and migration of KFs and induced apoptosis, whereas hsa_circ_0057452 overexpression and miR-1225-3p knockdown showed the opposite trend. Furthermore, hsa_circ_0057452 affected the biological behavior of KFs by releasing AFF4 via sponging of miR-1225-3p. Therefore, our results show that hsa_circ_0057452 promotes keloid progression by targeting miR-1225-3p and regulating AFF4 levels.

CAPN3: A muscle­specific calpain with an important role in the pathogenesis of diseases (Review).

Calpains are a family of Ca2+­dependent cysteine proteases that participate in various cellular processes. Calpain 3 (CAPN3) is a classical calpain with unique N­terminus and insertion sequence 1 and 2 domains that confer characteristics such as rapid autolysis, Ca2+­independent activation and Na+ activation of the protease. CAPN3 is the only muscle­specific calpain that has important roles in the promotion of calcium release from skeletal muscle fibers, calcium uptake of sarcoplasmic reticulum, muscle formation and muscle remodeling. Studies have indicated that recessive mutations in CAPN3 cause limb­girdle muscular dystrophy (MD) type 2A and other types of MD; eosinophilic myositis, melanoma and epilepsy are also closely related to CAPN3. In the present review, the characteristics of CAPN3, its biological functions and roles in the pathogenesis of a number of disorders are discussed.

The Roles of Lpar1 in Central Nervous System Disorders and Diseases.

Lysophosphatidic acid receptor 1 (Lpar1), which is found in almost all human tissues but is most abundant in the brain, can couple to G protein-coupled receptors (GPCRs) and participate in regulating cell proliferation, migration, survival, and apoptosis. Endothelial differentiation gene-2 receptor (Edg2), the protein encoded by the Lpar1 gene, is present on various cell types in the central nervous system (CNS), such as neural stem cells (NSCs), oligodendrocytes, neurons, astrocytes, and microglia. Lpar1 deletion causes neurodevelopmental disorders and CNS diseases, such as brain cancer, neuropsychiatric disorders, demyelination diseases, and neuropathic pain. Here, we summarize the possible roles and mechanisms of Lpar1/Edg2 in CNS disorders and diseases and propose that Lpar1/Edg2 might be a potential therapeutic target for CNS disorders and diseases.

Associations among Dietary Omega-3 Polyunsaturated Fatty Acids, the Gut Microbiota, and Intestinal Immunity.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), which are essential fatty acids that humans should obtain from diet, have potential benefits for human health. In addition to altering the structure and function of cell membranes, omega-3 PUFAs (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), and docosapentaenoic acid (DPA)) exert different effects on intestinal immune tolerance and gut microbiota maintenance. Firstly, we review the effect of omega-3 PUFAs on gut microbiota. And the effects of omega-3 PUFAs on intestinal immunity and inflammation were described. Furthermore, the important roles of omega-3 PUFAs in maintaining the balance between gut immunity and the gut microbiota were discussed. Additional factors, such as obesity and diseases (NAFLD, gastrointestinal malignancies or cancer, bacterial and viral infections), which are associated with variability in omega-3 PUFA metabolism, can influence omega-3 PUFAs-microbiome-immune system interactions in the intestinal tract and also play roles in regulating gut immunity. This review identifies several pathways by which the microbiota modulates the gut immune system through omega-3 PUFAs. Omega-3 supplementation can be targeted to specific pathways to prevent and alleviate intestinal diseases, which may help researchers identify innovative diagnostic methods.

The pannexin-1 channel regulates pyroptosis through autophagy in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis. Pyroptosis and autophagy are important mechanisms in the pathogenesis of sepsis, and also pannexin-1 is involved in the occurrence of sepsis. However, role of pannexin-1 in SAE and its relationship with pyroptosis and autophagy are unclear. This study examined the relationship between pannexin-1 and pyroptosis, and further explore the relationship between pyroptosis and autophagy in SAE mice. METHODS: A SAE mouse model was established by cecal ligation and puncture (CLP). Different groups of mice were administrated probenecid (PRB), 3-methyladenine (3-MA), or a vehicle control and the survival rates were monitored at different time points. Cortical pathological changes were examined by hematoxylin and eosin (HE) staining. The expression of cortical pannexin-1 and adenosine monophosphate-activated protein kinase (AMPK), as well as pyroptosis and autophagy related proteins, was detected by Western blotting and immunofluorescence analysis. The ultrastructure of neurons was observed by transmission electron microscopy. RESULTS: Septic mice showed significantly higher rates of mortality and cortical pathological change compared to control mice. In addition, the pannexin-1 and AMPK signaling pathway were activated in the cerebral cortex of the septic mice, coupled with the activation of pyroptosis and incomplete activation of autophagy. Inhibition of pannexin-1 expression reduce the rates of mortality and the cortical pathological changes in the mice, further activated the AMPK signaling pathway, inhibited pyroptosis, and completely activated autophagy. The inhibition of autophagy may cause pyroptosis to reactivate. CONCLUSIONS: The present findings suggested that in SAE mice, pannexin-1 may regulate neuronal pyroptosis through autophagy. Moreover, the regulation of autophagy may be related to the AMPK signaling pathway. Inhibiting pannexin-1 expression in SAE mice may have a neuroprotective effect.

CAPN6 in disease: An emerging therapeutic target (Review).

As a member of the calpain protein family, calpain6 (CAPN6) is highly expressed mainly in the placenta and embryos. It plays a number of important roles in cellular processes, such as the stabilization of microtubules, the maintenance of cell stability, the control of cell movement and the inhibition of apoptosis. In recent years, various studies have found that CAPN6 is one of the contributing factors associated with the tumorigenesis of uterine tumors and osteosarcoma, and that CAPN6 participates in the development of tumors by promoting cell proliferation and angiogenesis, and by inhibiting apoptosis, which is mainly regulated by the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway. Due to its abnormal cellular expression, CAPN6 has also been found to be associated with a number of diseases, such as white matter damage and muscular dystrophy. Therefore, CAPN6 may be a novel therapeutic target for these diseases. In the present review, the role of CAPN6 in disease and its possible use as a target in various therapies are discussed.

Iron nanoparticles encapsulated within nitrogen and sulfur co-doped magnetic porous carbon as an efficient peroxymonosulfate activator to degrade 1-naphthol.

A novel iron nanoparticles encapsulated within nitrogen and sulfur co-doped magnetic porous carbon (Fe-N-S-MPC) was proposed by one-pot pyrolysis strategy to activate peroxymonosulfate (PMS) to degrade 1-naphthol using low-cost lignin as precursors. The Fe-N-S-MPC was characterized for structure and properties by different characterizations. The obtained materials had the morphology of iron nanoparticles encapsulated within nitrogen and sulfur co-doped magnetic porous carbon with rich functional groups and large specific surface area, which made the materials have a good catalytic property. It was proved that the doping of nitrogen and sulfur is pivotal for improving the catalytic performance. The radical quenching experiment confirmed that sulfate radical (SO4-) and hydroxyl radical (OH) are two major reactive oxygen groups. The reaction had phenomenon of the free radicals upsurge in the early stage and the shortage in the later stage. Therefore, a mathematical model was put forward to represent the two-stage reaction kinetics. By adding oxidants in batches, the degradation effect could reach nearly 100% within 30 min. The Fe-N-S-MPC were applied to the degradation of 1-naphthol in soil and showed high degradation performance. This work provided a new type of catalytic material by the high-value utilization of waste for the degradation of organic pollutants.

MicroRNA­93 contributes to the suppression of lung inflammatory responses in LPS­induced acute lung injury in mice via the TLR4/MyD88/NF­κB signaling pathway.

Acute lung injury (ALI) is a severe inflammatory lung disease with a rapid onset. The anti­inflammatory functions of microRNA­93 (miRNA/miR­93) have been described in various types of tissue injury and disease. However, the biological role of miR­93 and its molecular mechanisms underlying the initiation and progression of ALI have not yet been reported, at least to the best of our knowledge. The present study aimed to investigate the regulatory effects exerted by miR­93 in ALI. Using an in vivo murine model of ALI induced by lipopolysaccharide (LPS), miR­93 expression was found to be downregulated in the lung tissues and bronchoalveolar lavage fluid (BALF) compared with the control group. Following agomiR­93 injection, it was observed that agomiR­93 attenuated lung injury, as evidenced by decreased lung permeability, a reduced lung wet/dry weight ratio and an increased survival rate of the mice. Concomitantly, agomiR­93 significantly reduced LPS­induced the interleukin (IL)­6, IL­1ß, and tumor necrosis factor (TNF)­α levels in BALF. Of note, Toll­like receptor 4 (TLR4), an upstream regulator of the nuclear factor (NF)­κB signaling pathway, was directly suppressed by miR­93 in RAW 264.7 cells. Importantly, agomiR­93 induced a significant suppression of the TLR4/myeloid differentiation primary response 88 (MyD88)/NF­κB signaling pathway, as demonstrated by the downregulation of MyD88, and the phosphorylation of IκB­α and p65 in the lung tissues of mice with ALI. Taken together, the findings of the present study indicate that miR­93 attenutes LPS­induced lung injury by regulating the TLR4/MyD88/NF­κB signaling pathway, suggesting that miR­93 may prove to be a potential therapeutic target for ALI.

Biosynthesis-inspired mining and identification of untapped alkaloids in Camptotheca acuminate for enzyme discovery using ultra-high performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry.

Leaves, flowers, fruits and stems (44 sample groups) were collected from mature Camptotheca acuminate during 2017.3-2018.3 and classified by ultra-high performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry based metabolomics. One hundred metabolites including forty-seven alkaloids, fifteen terpenes, thirty-two polyphenols and six other metabolites were rapidly identified through the in-house database alignment at first glance. Thirty-three alkaloids classified into five groups including camptothecin group (CG1-13), pumiloside group (PG1-5), strictosidinic acid group (SG1-3), vincosamide group (VG1-7), and a new hybrid group, vincosamide-camptothecin group (VC1-5) were mined and further characterized by MS/MS analyses. The identification of two untapped biosynthetic precursors, 2-hydroxypumiloside (PG2) and 16­hydroxy­15, 16-dihydrocamptothecoside (CG3), along with sixteen new alkaloids enables us for a better understanding of camptothecin biogenetic reasoning. The underlying enzymes involved in camptothecin biosynthesis were also proposed according to the guiding metabolic map, thus purposefully mining of enzymes involved in the downstream biosynthetic pathway of camptothecin could be initiated with the help of this map.

Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers.

Germline variants of PIP4K2A impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of PIP4K2A in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of PIP4K2A and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with PIP4K2A expression in ALL patients, with known cancer-related genes rankings the top (e.g., RAC2, RBL2, and TFDP1). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. PIP4K2A is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, PIP4K2A and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival (p < 0.05). Our findings reveal the transcriptional regulatory network of PIP4K2A in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.

[One-stage revision operations for infection after hip arthroplasty].

OBJECTIVE: To disscuss the therapeutic method of the postoperative infection after hip arthroplasty and compare the results of one-stage revision and two-stage revision. METHODS: From January 1999 to December 2005, 15 cases of infection after hip arthroplasty were treated, including 10 males and 5 females, with a mean age of 63 years (54-71 years). The locations were left hip in 8 cases and right hip in 7 cases. The first operation was hip prosthesis replacement in 6 cases and tatol hip arthroplasty in 9 cases. Infection occurred after 1 month in 6 cases and after 6 months in 9 cases. The preoperative temperature and ruting blood test were normal, the mean erythrocyte sedimentation rate (ESR) was 61 mm/h (34-80 mm/h), mean C-reactive protein (CRP) was 11.7 mg/L (5.4-21.0 mg/L). The mean Harris score was 33 (25-40). The X-ray films showed that periosteal reaction, osteolysis and loosening of prosthesis occurred. The time from the first operation to revision operation was 1-41 months (mean 7.3 months). The results of bacterial culture were positive in 11 cases. One-stage revision was performed in 10 cases, two-stage revision was performed in 5 cases. RESULTS: Of 15 cases, 6 were classified as early postoperative infection, 9 cases as late chonic infection. The microorganism cultures results of joint aspiration or pus in sinus were positive in 11 cases and negative in 4 cases before operation and during operation; 8 had staphylococcus epidermids infection, 2 escherichia coli infection and 1 staphylococcus aureus infection. Incision of revision operation healed by first intention. No re-infection, swelling and tenderness occurred after 19 months (12-37 months) of follow-up. Pain of hip joint disappeared in 14 cases, and only 1 case had mild pain when walking. ESR and CRP after operation decreased to normal range. The mean Harris score increased significantly to 84.2 (79-92) after revision, showing significant difference when compared with that before operation (P < 0.05). CONCLUSION: For postoperative infection after total hip arthroplasty, it is still possible to have satisfactory clinical outcome by one-stage or two-stage revision as long as clear diaglosis and correct treatment can made.