C-Reactive Protein: The Most Familiar Stranger.

C-reactive protein (CRP) is a highly conserved pentraxin with pattern recognition receptor-like activities. However, despite being used widely as a clinical marker of inflammation, the in vivo functions of CRP and its roles in health and disease remain largely unestablished. This is, to certain extent, due to the drastically different expression patterns of CRP in mice and rats, raising concerns about whether the functions of CRP are essential and conserved across species and how these model animals should be manipulated to examine the in vivo actions of human CRP. In this review, we discuss recent advances highlighting the essential and conserved functions of CRP across species, and propose that appropriately designed animal models can be used to understand the origin-, conformation-, and localization-dependent actions of human CRP in vivo. The improved model design will contribute to establishing the pathophysiological roles of CRP and facilitate the development of novel CRP-targeting strategies.

Different Reaction Modes Operating in ansa-Half-Sandwich Magnesium Catalysts.

Magnesium-based catalysts are becoming popular for hydroelementation reactions specially using p-block reagents. Based on the seminal report from Schäfer's group (ChemCatChem 2022, 14, e202201007), our study demonstrates that the reaction mechanisms exhibit a far greater degree of complexity than originally presumed. Magnesium has a variety of coordination modes (and access to different hybridizations) which allows this electron-deficient centre to modulate its catalytic power depending on the σ-donor properties of the reagent. DFT calculations demonstrate several reaction channels closely operating in these versatile catalysts. In addition, variations in limiting energy barriers resulting from catalyst modifications were examined as a function of the Hammett constant, thereby predicting enhanced efficiency in reaction conversions.

Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein.

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.

Gas-Phase Characterization of Hypervalent Carbon Compounds Bearing 7-6-7-Ring Skeleton: Penta- versus Tetra-Coordinate Isomers.

In this study, we afford explicit characterizations of the electronic and geometrical structures of recently reported hypervalent penta-coordinate carbon compounds by using gas-phase characterization techniques: photodissociation spectroscopy (PDS) and ion mobility-mass spectrometry (IM-MS). In particular for a compound with moderately electron-donating ligands, bearing p-methylthiophenyl substituents, the coexistence of tetra- and penta-coordinate isomers is confirmed, consistent with solution characterizations. It is in sharp contrast to the exclusive tetra-coordinate form (with normal valence of the central carbon atom) in the single crystal. This suggests that a non-polar environment makes the penta-coordinate structure thermodynamically most stable. This delicate difference between the tetra- and penta-coordinate structures, which depends on the environment, is a close reflection of the lower activation barrier of the SN 2 reaction found in neutral solvent or gas-phase reactions.

Complexation-Triggered Fluctuation of π-Conjugation on an Antiaromatic Dicyanoanthracene Dianion.

The formation of Lewis pairs is an important chemical concept. Recently, the complexation of Lewis acidic tris(pentafluorophenyl)borane with Lewis basic moieties and subsequent reduction has emerged as a fascinating strategy for designing novel reactions and structures. The impact of the complexation and subsequent reduction of antiaromatic systems bearing Lewis base moieties has been investigated. We found how Lewis adduct formation stabilizes an antiaromatic system consisting of 9,10-dicyanoanthracene and tris(pentafluorophenyl)borane by using synthesis, X-ray crystallography, spectroscopic analysis, and quantum chemical calculations.

Synthesis and Characterization of Hypervalent Pentacoordinate Carbon Compounds Bearing a 7-6-7-Ring Skeleton.

To stabilize SN 2 transition state-like penta-coordinate carbon species, triaryl-substituted cationic carbon compounds bearing a moderately flexible 7-6-7-ring skeleton with sulfur donors were synthesized and characterized. Electronic effects of para substituents (R=Cl, F, H, CH3 , SMe, OMe) of the two equatorial aryl groups bound to the cationic central carbon were investigated systematically along with a planar bidentate thioxanthene derivative. X-ray analysis on their solid-state structures showed that the parent (R=H), chloro-, fluoro- and methyl-derivatives were tetracoordinate carbon (sulfonium) structures, while the p-MeO and thioxanthenyl system were pentacoordinate carbocation structures. The Hammett substituent constants for the para substituents (σp + ) correlates well with the bonding in these compounds. The methylthio-derivative with intermediate Hammett substituent constants (p-MeS; σp + =-0.60) showed a tetracooridnate solid-state structure, though solution UV-Vis properties suggested the presence of a penta-coordinate structure. These findings amount to the first unambiguous solution evidence of the hypervalent apical 3c-4e interactions in pentacoordinate carbon compounds.

Redox Activity of IrIII Complexes with Multidentate Ligands Based on Dipyrido-Annulated N-Heterocyclic Carbenes: Access to High Valent and High Spin State with Carbon Donors.

Synthetic strategies to access high-valent iridium complexes usually require use of π donating ligands bearing electronegative atoms (e. g. amide or oxide) or σ donating electropositive atoms (e. g. boryl or hydride). Besides the η5 -(methyl)cyclopentadienyl derivatives, high-valent η1 carbon-ligated iridium complexes are challenging to synthesize. To meet this challenge, this work reports the oxidation behavior of an all-carbon-ligated anionic bis(CCC-pincer) IrIII complex. Being both σ and π donating, the diaryl dipyrido-annulated N-heterocyclic carbene (dpa-NHC) IrIII complex allowed a stepwise 4e- oxidation sequence. The first 2e- oxidation led to an oxidative coupling of two adjacent aryl groups, resulting in formation of a cationic chiral IrIII complex bearing a CCCC-tetradentate ligand. A further 2e- oxidation allowed isolation of a high-valent tricationic complex with a triplet ground state. These results close a synthetic gap for carbon-ligated iridium complexes and demonstrate the electronic tuning potential of organic π ligands for unusual electronic properties.

[Platelet adhesion mediated by von Willebrand factor in patients with premature coronary artery disease].

Aim    To study platelet adhesion mediated by von Willebrand factor (VWF) in patients with premature ischemic heart disease (IHD).Material and methods    This study enrolled 58 patients with stable IHD, including 45 men younger than 55 years with the first manifestation of IHD at the age of <50 years and 13 women younger than 65 years with the first manifestation of IHD at the age of <60 years. The control group consisted of 33 patients, 13 men younger than 55 years and 20 women younger than 65 years without IHD. Platelet adhesion to the collagen surface at the shear rate of 1300 s-1 was studied by evaluating the intensity of scattered laser light from the collagen-coated optical substrate in a flow chamber of a microfluidic device after 15-min circulation of whole blood in the chamber. Decreases in platelet adhesion after addition to the blood of monoclonal antibodies (mAb) to platelet receptors glycoproteins Ib (GPIb) to inhibit the receptor interaction with VWF were compared for patients of both groups. Results    In patients with premature IHD, the decrease in platelet adhesion following the platelet GPIb receptor inhibition was significantly less than in patients of the control group (74.8 % (55.6; 82.7) vs. 28.9 % (-9.8; 50,5), p <0.001). For the entire sample, the median decrease in platelet adhesion following the GPIb receptor inhibition was 62.8 % (52.2; 71.2). With an adjustment for traditional risk factors of IHD, a decrease in platelet adhesion of >62.8% after blocking GPIb receptors increased the likelihood of premature IHD (OR=9.84, 95 % CI: 2.80-34.59; p <0.001).Conclusion    Blocking the interaction of GPIb receptors with VWF in patients with premature IHD and increased shear rate induced a greater decrease in platelet adhesion than in patients without this disease. This suggested that an excessive interaction of VWF with platelets might contribute to the pathogenesis of premature IHD.

Synthesis and Isolation of an Anionic Bis(dipyrido-annulated) N-Heterocyclic Carbene CCC-Pincer Iridium(III) Complex by Facile C-H Bond Activation.

Meridional tridentate N-heterocyclic carbene (NHC)-based pincer ligands contribute to a substantial growth in modern organometallic chemistry in both homogeneous catalysis and luminescence materials. Among all NHC-based pincer ligands, the dianionic LX2-type CCC-pincer ones constitute the smallest subcategory owing to their limited ligand frameworks suitable for complexation. This work reports a one-pot, high-yield synthesis of a homoleptic anionic all-carbon bis-pincer iridium(III) complex (4) directly from a bis(aryl)-substituted dipyrido-annulated (dpaAr2) imidazolium salt and [Ir(COD)Cl]2 via a cascade of deprotonation/C-H activation processes. Both experimental complexation chemistry and computational mechanistic investigation suggest that the large bite angle and π-rich character of the dpaAr2 NHC are responsible for its facile complexation as a dianionic LX2-type CCC-pincer ligand precursor. The all-carbon ligated iridium(III) complex (4) bearing a π-conjugated ligand scaffold showed remarkably low oxidation potentials, which allows future investigations in its redox chemistry and photophysical properties.

Spherand complexes with Li+ and Na+ ions in the gas phase: encapsulation structure and characteristic unimolecular dissociation.

We investigated the complexes of Cram's hexa(p-anisole) spherands (SPR, 1) with Li+ and Na+ ions (1·Li+ and 1·Na+) isolated in the gas phase. Despite the small conformational difference between 1·Li+ and 1·Na+ owing to the rigid framework of 1, ultraviolet photodissociation (UVPD) spectroscopy under cryogenic (∼10 K) conditions yielded clearly distinguishable absorption edges: ∼34 000 and ∼34 500 cm-1 for 1·Li+ and 1·Na+, respectively. The spectral assignment and the preorganization characteristics of the host molecule were compared with those of dibenzo-18-crown-6-ether (DB18C6) complexes, which have more flexible frameworks. Furthermore, we revealed the characteristic unimolecular dissociation of the 1·Li+ complex using UVPD and collision-induced dissociation (CID); the formation of fragment ions with dibenzofuran moieties was detected. This dissociation pattern was ascribed to the efficient release of dimethyl ether molecule(s) from the 1·Li+ complex, which is characteristic of the cyclic skeleton formed with six methoxy groups in the SPR.

Knockdown of lncRNA LINC00707 alleviates LPS-induced injury in MRC-5 cells by acting as a ceRNA of miR-223-5p.

Pneumonia is a common respiratory disease worldwide. Long noncoding RNAs have been implicated in the pathogenesis of pneumonia. However, the effect and mechanism of long intergenic nonprotein-coding RNA (LINC00707) on pneumonia pathogenesis were still unclear. Lipopolysaccharide (LPS) reduced cell viability and promoted apoptosis and inflammation in MRC-5 cells. LINC00707 was increased, and miR-223-5p was decreased in LPS-treated MRC-5 cells. LINC00707 knockdown relieved LPS-triggered injury in MRC-5 cells. LINC00707 directly interacted with miR-223-5p through acting as a miR-223-5p sponge. Moreover, miR-223-5p mediated the regulation of LINC00707 silencing on LPS-stimulated cytotoxicity in MRC-5 cells. p38 mitogen-activated protein kinases and nuclear factor-κB signaling pathways were modulated by the LINC00707/miR-223-5p axis in LPS-induced MRC-5 cells. Our present study indicated that LINC00707 depletion alleviated LPS-induced injury in MRC-5 cells at least partly by acting as a sponge of miR-223-5p, highlighting a new potential therapeutic avenue for pneumonia treatment.

Simultaneous bilateral hallux valgus surgery: Percutaneous or conventional? Early results of a matched study from a tertiary institution.

BACKGROUND: Hallux valgus is bilateral in up to 84 % of cases. In the setting of simultaneous bilateral correction, we aim to evaluate if minimally invasive percutaneous surgery (MIS) provides any advantage compared to conventional open surgery. METHODS: 52 feet (26 patients) undergoing simultaneous bilateral MIS surgery were matched by severity of deformity to 52 feet (26 patients) undergoing simultaneous conventional open surgery. Patients were followed for a minimum of six months. Pre- and post-operative radiographs and clinical records were reviewed. RESULTS: There were no significant differences in pre-operative function or pain between both groups. Post-operatively, the mean hallux valgus angle (HVA) was significantly lower in the MIS group. (HVA MIS - 8.6; Open - 11.8, P = 0.013). There were no significant differences in post-operative outcome and patient satisfaction between both groups. CONCLUSION: This study demonstrates that simultaneous bilateral MIS hallux valgus surgery can be considered for patients with bilateral symptomatic hallux valgus.

In Search of Fulminate Analogues: Ln M≡CP=NR.

The "CPNR" ligand may be viewed as being isolobal with fulminate, CNO; however, attempts to prepare a complex of such a ligand resulted instead in a range of novel imino and aminophosphinocarbyne complexes. Sequential treatment of [Mo(≡CBr)(CO)2 (Tp*)] (Tp*=hydrotris(dimethylpyrazolyl)borate) with nBuLi and ClP=NMes* (Mes*=C6 H2 tBu3 -2,4,6) afforded mixtures of the complexes [Mo(≡CPnBuNHMes*)(CO)2 (Tp*)] and traces of the bimetallic products [Mo2 {µ2 -C2 P2 O(NHMes)2 }(CO)4 (Tp*)2 ] and [Mo2 (µ2 -C2 PNHMes)(CO)4 (Tp*)2 ]. The reaction of [W(≡CBr)(CO)2 (Tp*)] with nBuLi and ClP=NMes* afforded predominantly the mononuclear carbyne [W{≡CP(=NMes*)nBu2 })(CO)2 (Tp*)] and traces of the binuclear complex [W2 (µ-C2 PNHMes)(CO)4 (Tp*)2 ] which is also obtained when tBuLi is used. Although not isolable, the intended complexes [M(≡CPNMes*)(CO)2 (Tp*)] could be generated in situ and spectroscopically characterized via the reactions of the stannyl carbynes [M(≡CSnnBu3 )(CO)2 (Tp*)] and ClP=NMes*. The preceding observations are mechanistically interpreted with reference to a computational interrogation of the model complex [Mo(≡CP=NCH3 )(CO)2 (Tp*)], the LUMO of which has considerable phosphorus character.

C-reactive protein exacerbates epithelial-mesenchymal transition through Wnt/ß-catenin and ERK signaling in streptozocin-induced diabetic nephropathy.

Previous studies have reported the pathogenic role of C-reactive protein (CRP) during diabetic kidney disease (DKD) in human CRP transgenic and Crp-/- mice. However, because humans and mice have inverse acute phase expression patterns of CRP and serum amyloid P component, this could lead to the inaccurate evaluation of CRP function with the above-mentioned CRP transgenic mouse. But different from mice, rats have the same acute phase protein expression pattern as human, which might avoid this problem and be a better choice for CRP function studies. To dispel this doubt and accurately define the role of CRP during diabetic nephropathy, we created the first Crp-/- rat model, which we treated with streptozocin to induce DKD for in vivo studies. Moreover, an established cell line (human kidney 2) was used to further investigate the pathologic mechanisms of CRP. We found that CRP promotes epithelial-mesenchymal transition (EMT) through Wnt/ß-catenin and ERK1/2 signaling, which are dependent on CRP binding to FcγRII on apoptotic cells. By promoting EMT, CRP was demonstrated to accelerate the development of DKD. We thus present convincing evidence demonstrating CRP as a therapeutic target for DKD treatment.-Zhang, L., Shen, Z.-Y., Wang, K., Li, W., Shi, J.-M., Osoro, E. K., Ullah, N., Zhou, Y., Ji, S.-R. C-reactive protein exacerbates epithelial-mesenchymal transition through Wnt/ß-catenin and ERK signaling in streptozocin-induced diabetic nephropathy.

Catalytic Dehydrogenation of Ammonia Borane Mediated by a Pt(0)/Borane Frustrated Lewis Pair: Theoretical Design.

A new efficient metal-based frustrated Lewis pair constructed by (Pt Bu3 )2 Pt and B(C6 F5 )3 was designed through density functional theory calculations for the catalytic dehydrogenation of ammonia borane (AB). The reaction was composed by the successive dehydrogenation of AB and H2 liberation, which occurs through the cooperative functions of the Pt(0) center and the B(C6 F5 )3 moiety. Two equivalents of H2 were predicted to be liberated from each AB molecule. The generation of the second H2 is the rate-determining step, with a Gibbs energy barrier and reaction energy of 27.4 and 12.8 kcal/mol, respectively.

miRNA-574-5p downregulates ZNF70 and influences the progression of human esophageal squamous cell carcinoma through reactive oxygen species generation and MAPK pathway activation.

There is growing evidence shown that microRNAs (miRNAs) are associated with cancer and can play a role in human cancers as oncogenes or tumor suppressor genes. miRNA-574-5p is a candidate oncogene in various types of cancer, but little is known about biological functions of miR-574-5p in esophageal squamous cell carcinoma (ESCC). In this study, we observe that the expression of miR-574-5p is not only increased in human ESCC tissues but also remarkably increased in cell lines correlates with ZNF70. In vitro, we explored the role of miR-574-5p in ESCC progression via transfection of the miR-574-5p inhibitor into ECA-109 cells. The results show miR-574-5p serve as a tumor promoter regulating cells proliferation and apoptosis in ESCC through mitochondrial-mediated reactive oxygen species (ROS) generation and MAPK pathways. Furthermore, ZNF70 has been proved to as a functional target for miR-574-5p to regulate cells poliferation and apoptosis. In summary, these results suggest that miR-574-5p serves as tumor promoter to promote proliferation and inhibit apoptosis of ESCC cells by targeting ZNF70 via mitochondrial-mediated ROS generation and MAPK pathways. The miR-574-5p/ZNF70 pathway provides a new insight into the molecular mechanisms that the occurrence and development of ESCC and it provides a novel therapeutic target for ESCC.

A specific autoantibody against a novel tumour-association antigen derived from human DNA-topoiomerase I is a potential biomarker for early diagnosis and favourable prognosis in patients with colorectal carcinoma.

Context: We previously reported a novel tumour associated antigen (TTA) with molecular weight around 48 kDa and identified the novel TTA as a fragment derived from human DNA-topoiomerase I (TOP1). We termed the novel TAA as TOPO48 and termed autoantibody against the TAA as anti-TOPO48 autoantibody.Objective: To explore the clinical significance of anti-TOPO48 autoantibody in patients with colorectal carcinoma (CRC).Materials and methods: Serum levels of the autoantibody in patients with CRC or benign tumours and healthy volunteers were measured with a specific ELISA.Results: CRC patients at early stage had higher frequency of positive levels of the autoantibody and CRC patients with positive autoantibody levels had higher overall survival rate than those with negative autoantibody levels.Conclusion: The autoantibody is a potential biomarker for early diagnosis and favourable prognosis of CRC.

Long Non-Coding RNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1)Relieves Sepsis-Induced Kidney Injury and Lipopolysaccharide (LPS)-Induced Inflammation in HK-2 Cells.

BACKGROUND Long non-coding RNAs (lncRNAs) play key roles in the development and progression of diseases, including sepsis. Therefore, this study aimed to clarify the role and underlying molecular mechanisms of lncRNA NEAT1 in sepsis. MATERIAL AND METHODS We used real-time quantitative polymerase chain reaction (RT-qPCR) to analyze the expression of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), let-7b-5p, and tumor necrosis factor receptor-associated factor 6 (TRAF6). Western blot assay was used to measure the protein expression levels. After treatment with lipopolysaccharide (LPS), the biological behaviors of human renal tubular epithelial cells (HK-2), such as proliferation and apoptosis, were determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and flow cytometry assays, respectively. The interaction relationship among NEAT1, TRAF6, and let-7b-5p was analyzed by the bioinformatics starBase database and dual-luciferase reporter assay. RESULTS lncRNA NEAT1 was expressed at higher levels in kidney tissues from sepsis patients than in healthy kidney tissues. Interestingly, LPS induced high expression of lncRNA NEAT1 in HK-2 cells in a time- and dose-dependent manner. Furthermore, silencing of NEAT1 weakened LPS-induced apoptosis, inflammation, and inhibition of proliferation, which was overturned by silencing of let-7b-5p. In addition, overexpression of TRAF6 abolished the overexpression of let-7b-5p-induced effects on apoptosis, inflammation, and growth of HK-2 cells exposed to LPS. In summary, NEAT1 regulated TRAF6 expression by sponging let-7b-5p in HK-2 cells, which promotes LPS-induced injury and inflammation in HK-2 cells. CONCLUSIONS Our data show that the lower expression of NEAT1 impeded sepsis development and LPS-induced injury inflammation by targeting let-7b-5p/TRAF6 axis, and NEAT1 may be a target for treatment of sepsis patients.

Luminescent Di- and Tetranuclear Gold Complexes of Bis(diphenylphosphinyl)-Functionalized Dipyrido-Annulated N-Heterocyclic Carbene.

Phosphine-functionalized N-heterocyclic carbene (NHC) ligands are known to complex group 11 metal centers to form multinuclear complexes with photoluminescence properties. This study reports a structurally rigid ortho-substituted dipyrido-annulated NHC with T-shape coordination geometry and its di- and tetranuclear gold(I) complexes. The free ligand as well as all metal complexes are found luminescent at room temperature and phosphorescent at 77 K. Although metal d10-d10 interactions are evident based on their solid-state structures, their effect on the photoemission is limited, most likely due to the weak coordination of the ligand to the metal centers in solution.

Total saponins of Bolbostemma paniculatum (maxim.) Franquet exert antitumor activity against MDA-MB-231 human breast cancer cells via inhibiting PI3K/Akt/mTOR pathway.

BACKGROUND: The aim of the present study was to examine the effects of the Bolbostemma paniculatum (Maxim.) Franquet (BP) active compound, BP total saponins (BPTS), on MDA-MB-231 cells, and investigate the underlying mechanism regarding BPTS-mediated attenuation of the PI3K/Akt/mTOR pathway. METHODS: The effect of BPTS on cytotoxicity, induction of apoptosis and migration on MDA-MB-231 cells at three different concentrations was investigated. A CCK-8 assay, wound-healing assay and flow cytometry were used to demonstrate the effects of BPTS. Additionally, expression of the primary members of the PI3K/Akt/mTOR signaling pathway was assessed using western blotting. To verify the underlying mechanisms, a PI3K inhibitor and an mTOR inhibitor were used. RESULTS: BPTS inhibited proliferation of MDA-MB-231 cells with an IC50 value of 10 µg/mL at 48 h. BPTS inhibited migration of MDA-MB-231 cells, and the western blot results demonstrated that BPTS reduced p-PI3K, p-Akt and p-mTOR protein expression levels in MDA-MB-231 cells. Additionally, the results were confirmed using a PI3K inhibitor and an mTOR inhibitor. BPTS decreased proliferation and migration of MDA-MB-231 cells possibly through inhibiting the PI3K/Akt/mTOR signaling pathway. CONCLUSIONS: The results highlight the therapeutic potential of BPTS for treating patients with triple-negative breast cancer.