Restoring colistin sensitivity in colistin-resistant Salmonella and Escherichia coli: combinatorial use of berberine and EDTA with colistin.

The appearance and prevalence of multidrug-resistance (MDR) Gram-negative bacteria (GNB) have limited our antibiotic capacity to control bacterial infections. The clinical efficacy of colistin (COL), considered as the "last resort" for treating GNB infections, has been severely hindered by its increased use as well as the emergence and prevalence of mobile colistin resistance (MCR)-mediated acquired drug resistance. Identifying promising compounds to restore antibiotic activity is becoming an effective strategy to alleviate the crisis of increasing MDR. We first demonstrated that the combination of berberine (BBR) and EDTA substantially restored COL sensitivity against COL-resistant Salmonella and Escherichia coli. Molecular docking indicated that BBR can interact with MCR-1 and the efflux pump system AcrAB-TolC, and BBR combined with EDTA downregulated the expression level of mcr-1 and tolC. Mechanically, BBR combined with EDTA could increase bacterial membrane damage, inhibit the function of multidrug efflux pump, and promote oxidative damage, thereby boosting the action of COL. In addition, transcriptome analysis found that the combination of BBR and EDTA can accelerate the tricarboxylic acid cycle, inhibit cationic antimicrobial peptide (CAMP) resistance, and attenuate Salmonella virulence. Notably, the combination of BBR and EDTA with COL significantly reduced the bacterial load in the liver and spleen of a mice model infected with Salmonella. Our findings revealed that BBR and EDTA can be used as adjuvants collectively with COL to synergistically reverse the COL resistance of bacteria. IMPORTANCE: Colistin is last-resort antibiotic used to treat serious clinical infections caused by MDR bacterial pathogens. The recent emergence of transferable plasmid-mediated COL resistance gene mcr-1 has raised the specter of a rapid worldwide spread of COL resistance. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. Our research showed that berberine combined with EDTA effectively reversed COL resistance both in vivo and in vitro through multiple modes of action. The discovery of berberine in combination with EDTA as a new and safe COL adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections. Our findings provide a potential therapeutic option using existing antibiotics in combination with antibiotic adjuvants and address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Epidemiological Survey of Hemoglobinopathies Based on Next-Generation Sequencing Platform in Hunan Province, China.

Objective: This study was aimed at investigating the carrier rate of, and molecular variation in, α- and ß-globin gene mutations in Hunan Province. Methods: We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province. Hematological screening was performed, and molecular parameters were assessed. Results: The overall carrier rate of thalassemia was 7.1%, including 4.83% for α-thalassemia, 2.15% for ß-thalassemia, and 0.12% for both α- and ß-thalassemia. The highest carrier rate of thalassemia was in Yongzhou (14.57%). The most abundant genotype of α-thalassemia and ß-thalassemia was -α 3.7/αα (50.23%) and ß IVS-II-654/ß N (28.23%), respectively. Four α-globin mutations [CD108 (ACC>AAC), CAP +29 (G>C), Hb Agrinio and Hb Cervantes] and six ß-globin mutations [CAP +8 (C>T), IVS-II-848 (C>T), -56 (G>C), beta nt-77 (G>C), codon 20/21 (-TGGA) and Hb Knossos] had not previously been identified in China. Furthermore, this study provides the first report of the carrier rates of abnormal hemoglobin variants and α-globin triplication in Hunan Province, which were 0.49% and 1.99%, respectively. Conclusion: Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population. The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.

A finite element model of the shoulder: application to the changes of biomechanical environment induced by postoperative malrotation of humeral shaft fracture.

OBJECTIVES: The humerus fracture is one of the most commonly occurring fractures. In this research, we attempted to evaluate and compare the extent of malrotation and biomechanical environment after surgical treatment of humeral shaft fractures. METHODS: A finite element (FE) model of the shoulder was built based on Computed Tomography (CT) data of a patient with a humeral shaft fracture. The muscle group around the shoulder joint was simulated by spring elements. The changes of shoulder stresses under rotation were analyzed. The biomechanics of the normal shoulder and postoperative malrotation of the humeral shaft was analyzed and compared. RESULTS: During rotations, the maximum stress was centered in the posterosuperior part of the glenoid for the normal shoulder. The von Mises shear stresses were 4.40 MPa and 4.89 MPa at 40° of internal and external rotations, respectively. For internal rotation deformity, the shear contact forces were 7-9 times higher for the shoulder internally rotated 40° than for the normal one. For external rotation deformity, the shear contact forces were about 3-5 times higher for the shoulder with 40° external rotation than the normal one. CONCLUSION: Postoperative malrotation of humeral shaft fracture induced the changes of the biomechanical environment of the shoulders. The peak degree of malrotation was correlated with increased stresses of shoulders, which could be paid attention to in humeral shaft fracture treatment. We hoped to provide information about the biomechanical environment of humeral malrotation.

Cytochrome P450 1A1 enhances inflammatory responses and impedes phagocytosis of bacteria in macrophages during sepsis.

The hydroxylase cytochrome P450 1A1 (CYP1A1) is regulated by the inflammation-limiting aryl hydrocarbon receptor (AhR), but CYP1A1 immune functions remain unclear. We observed CYP1A1 overexpression in peritoneal macrophages (PMs) isolated from mice following LPS or heat-killed Escherichia. coli (E. coli) challenge. CYP1A1 overexpression augmented TNF-α and IL-6 production in RAW264.7 cells (RAW) by enhancing JNK/AP-1 signalling. CYP1A1 overexpression also promoted 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE) production in activated RAW, while a 12(S)-HETE antibody attenuated and 12(S)-HETE alone induced inflammatory responses. Macrophages harbouring hydroxylase-deficient CYP1A1 demonstrated reduced 12(S)-HETE generation and LPS-induced TNF-α/IL-6 secretion. CYP1A1 overexpression also impaired phagocytosis of bacteria via decreasing the expression of scavenger receptor A (SR-A) in PMs. Mice injected with CYP1A1-overexpressing PMs were more susceptible to CLP- or E. coli-induced mortality and bacteria invading, while Rhapontigenin, a selective CYP1A1 inhibitor, improved survival and bacteria clearance of mice in sepsis. CYP1A1 and 12(S)-HETE were also elevated in monocytes and plasma of septic patients and positively correlated with SOFA scores. Macrophage CYP1A1 disruption could be a promising strategy for treating sepsis. Video abstract.

Correction to: Cytochrome P450 1A1 enhances inflammatory responses and impedes phagocytosis of bacteria in macrophages during sepsis.

An amendment to this paper has been published and can be accessed via the original article.

Ellipticine Conveys Protective Effects to Lipopolysaccharide-Activated Macrophages by Targeting the JNK/AP-1 Signaling Pathway.

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.

The program of antiviral agents inhibits virus infection.

Virus infections are the root cause of epidemics in the world. Vaccines and antiviral agents have been the two important methods to control viral diseases; in recent times, RNA-mediated therapeutics and prevention have received much attention. In this review, we provide an overview of the current information regarding the use of vaccines, antiviral agents, and RNA-mediated methods in controlling or preventing viral infections. We stress specifically on the potential of existing RNA-mediated methods in clinical applications.

Development of a New RT-PCR with Multiple Primers for Detecting Southern African Territories Foot-and-mouth Disease Viruses.

INTRODUCTION: The extremely high genetic variation and the continuously emerging variants of foot-and-mouth disease virus (FMDV) of Southern African Territory (SAT) serotypes including SAT1, SAT2, and SAT3 make it necessary to develop a new RT-PCR for general use for monitoring viruses based on the updated genome information. MATERIAL AND METHODS: A FMDV SAT-D8 one-step RT-PCR was established based on the 1D2A2B genes of the SAT serotype viruses with a multiplex primer set. FMDV A, O, C, and Asia 1 serotypes, other vesicular disease viruses, inactivated SAT viruses, and 125 bovine, ovine, caprine and porcine tissue samples collected from the Chinese mainland were included for evaluating the assay. RESULTS: The new RT-PCR was proven to be specific without cross-reactions with Eurasian FMDV, swine vesicular disease virus (SVDV), Seneca valley virus (SVV), or other common viral pathogens of cattle, sheep, goat, and pig. An around 257 bp-sized amplicon clearly appeared when the inactivated SAT viruses were detected. However, all 125 samples collected from FMDV-susceptible animals from the Chinese mainland which has not known SAT epidemics showed negative results. CONCLUSIONS: A FMDV SAT-D8 one-step RT-PCR is a promising method for primary screening for FMDV SAT serotypes.

Effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy.

This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia.A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed.Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery.Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect.

Early prevention of trauma-related infection/sepsis.

Trauma still represents one of the major causes of death worldwide. Despite the reduction of post-traumatic sepsis over the past two decades, the mortality of septic trauma inpatients is still high (19.5-23 %). Early prevention of sepsis development can aid in the subsequent treatment of patients and help improve their outcomes. To date, the prevention of trauma-related infection/sepsis has mainly included infection prevention (e.g., surgical management, prophylactic antibiotics, tetanus vaccination, immunomodulatory interventions) and organ dysfunction prevention (e.g., pharmaceuticals, temporary intravascular shunts, lung-protective strategies, enteral immunonutrition, acupuncture). Overall, more efficient ways should be developed to prevent trauma-related infection/sepsis.

A highly selective colorimetric and fluorescent turn-on chemosensor for Al(3+) based on naphthalimide derivative.

A new chemosensor L based on the naphthalimide moiety was synthesized and characterized. L exhibited the high selectivity and sensitivity for Al(3+) in CH3OH, along with colorimetric and fluorometric dual-signaling responses based on the joint contribution of the ICT and CHEF processes. A 1:1 stoichiometry for the L-Al(3+) complex was formed with an association constant of 7.6×10(4)M(-1), and the limit of detection for Al(3+) was determined as 6.9µM. In addition, L was successfully applied to the determination of Al(3+) in real water samples.

[Preparation, characterization and surface-enhanced Raman properties of agarose gel/gold nanoparticles hybrid].

Agarose gel/gold nanoparticles hybrid was prepared by adding gold nanoparticles to preformed agarose gel. Naniocomposite structures and properties were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and UV-Vis-NIR absorption spectroscopy. Experimental data indicated a uniform distribution of gold nanoparticles adsorbed on agarose gel network And the excellent optical absorption properties were shown. Based on the swelling-contraction characteristics of agarose gel and the adjustable localized surface plasmon resonance (LSPR) of the gold nanoparticles, the nano-composites were used as surface enhanced Raman scattering (SERS) substrate to detect the Raman signal molecules Nile blue A. Results revealed that the porous structure of the agarose gel provided a good carrier for the enrichment of the gold nanoparticles. The gold nanoparticles dynamic hot-spot effect arising from the agarose gel contraction loss of water in the air greatly enhanced the Raman signal.

Analysis of common genetic variants identifies RELN as a risk gene for schizophrenia in Chinese population.

UNLABELLED: Abstract Objectives. Several lines of evidence have shown that both RELN mRNA and protein are possibly down-regulated in the brain of schizophrenia patients. Recent association studies in European populations suggested RELN as a risk gene for schizophrenia. In this study, we test if RELN contributes to the risk of schizophrenia in Chinese population. Methods. We conducted case-control association analysis of 19 representative single nucleotide polymorphisms (SNPs) spanning the entire region of RELN in two independent Han Chinese samples from southwestern China (the Kunming sample and the Yuxi sample). Results. We identified six SNPs significantly associated with schizophrenia in the Kunming sample and four of them remained significant in the combined samples (the P values range from 0.006 to 4.0 × 10(-5)). Haplotype analysis also suggested significant associations for the haplotypes incorporating the six significant SNPs (global P < 1.0 × 10(-5)). Additionally, we also observed several other haplotypes (defined by a different set of SNPs) significantly associated with schizophrenia in the Kunming sample. However, the reported association of rs7341475 in Ashkenazi Jews was not significant in Han Chinese. CONCLUSIONS: Our findings demonstrate that RELN is a susceptibility gene for schizophrenia in Chinese population, and it is likely a common risk gene for schizophrenia in major populations worldwide.

Poly[bis(mu-benzene-1,4-dicarboxylato)bis[mu-6-(4-pyridyl)-5H-imidazolo[4,5-f][1,10]phenanthroline]dilead(II)]: an interpenetrating alpha-Po net.

The asymmetric unit of the title compound, [Pb(2)(C(8)H(4)O(4))(2)(C(18)H(11)N(5))(2)](n), contains two Pb(II) atoms, two benzene-1,4-dicarboxylate (1,4-bdc) dianions and two 6-(4-pyridyl)-5H-imidazolo[4,5-f][1,10]phenanthroline (L) ligands. Each Pb(II) atom is eight-coordinated by three N atoms from two different L ligands and five carboxylate O atoms from three different 1,4-bdc dianions. The two 1,4-bdc dianions (1,4-bdc(1) and 1,4-bdc(2)) show different coordination modes. Each 1,4-bdc(1) coordinates to two Pb(II) atoms in a chelating bis-bidentate mode. Each carboxylate group of the 1,4-bdc(2) anion connects two Pb(II) atoms in a chelating-bridging tridentate mode to form a dinuclear unit. Neighbouring dinuclear units are connected together by the aromatic backbone of the 1,4-bdc dianions and the L ligands into a three-dimensional six-connected alpha-polonium framework. The most striking feature is that two identical three-dimensional single alpha-polonium nets are interlocked with each other, thus leading directly to the formation of a twofold interpenetrated three-dimensional alpha-polonium architecture. The framework is held together in part by strong N-H...O hydrogen bonds between the imidazole NH groups of the L ligands and the carboxylate O atoms of 1,4-bdc dianions within different alpha-polonium nets.

Bis(mu-benzene-1,2-dicarboxylato)bis{aqua[2-(2-chloro-6-fluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline]cadmium(II)} and its zinc(II) analogue.

In the isomorphous title compounds, [Cd(2)(C(8)H(4)O(4))(2)(C(19)H(10)ClFN(4))(2)(H(2)O)(2)] and [Zn(2)(C(8)H(4)O(4))(2)(C(19)H(10)ClFN(4))(2)(H(2)O)(2)], the Cd(II) centre is seven-coordinated by two N atoms from one [2-(2-chloro-6-fluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (L) ligand, one water O atom and four carboxylate O atoms from two different benzene-1,2-dicarboxylate (1,2-bdc) ligands in a distorted pentagonal-bipyramidal coordination, while the Zn(II) centre is six-coordinated by two N atoms from one L ligand, one water O atom and three carboxylate O atoms from two different 1,2-bdc ligands in a distorted octahedral coordination. Each pair of adjacent metal centres is bridged by two 1,2-bdc ligands to form a dimeric structure. In the dimer, each L ligand coordinates one metal centre. The dimer is centrosymmetric, with a crystallographic inversion centre midway between the two metal centres. The aromatic interactions lead the dimers to form a two-dimensional supramolecular architecture. Finally, O-H...O and N-H...O hydrogen bonds reinforce the two-dimensional structures of the two compounds.

catena-Poly[[aqua(11-chloropyrido[2',3':2,3]pyrimidino[5,6-f][1,10]phenanthroline-kappa2N4,N5)cadmium(II)]-mu-benzene-1,4-dicarboxylato-kappa3O1,O1':O4]: an inclined interpenetrating (6,3) network.

The asymmetric unit of the title compound, [Cd(C(8)H(4)O(4))(C(17)H(8)ClN(5))(H(2)O)](n), contains one Cd(II) atom, two half benzene-1,4-dicarboxylate (1,4-bdc) anions, one 11-chloropyrido[2',3':2,3]pyrimidino[5,6-f][1,10]phenanthroline (L) ligand and one coordination water molecule. The 1,4-bdc ligands are on inversion centers at the centroids of the arene rings. The Cd(II) atom is six-coordinated by two N atoms from one L ligand, three carboxylate O atoms from two different 1,4-bdc ligands and one water O atom in a distorted octahedral coordination sphere. Each Cd(II) center is bridged by the 1,4-bdc dianions to give a one-dimensional chain. Pi-pi stacking interactions between L ligands of neighboring chains extend adjacent chains into a two-dimensional supramolecular (6,3) network. Neighboring (6,3) networks are interpenetrated in an unusual inclined mode, resulting in a three-dimensional framework. Additionally, the water-carboxylate O-H...O hydrogen bonds observed in the network consolidate the interpenetrating nets.

Poly[diaqua[mu-1,4-bis(imidazol-1-ylmethyl)benzene-kappa2N3:N3'](mu-trans-cyclohexane-1,4-carboxylato-kappa2O1:O4)manganese(II)]: a three-dimensional hydrogen-bonding alpha-polonium net.

In the title coordination compound, [Mn(C8H10O4)(C14H14N4)(H2O)2]n, each Mn(II) centre occupies an inversion centre. The 1,4-bis(imidazol-1-ylmethyl)benzene (1,4-bix) ligand and the trans-cyclohexane-1,4-dicarboxylate dianion (chdc) both function in bridging modes, linking adjacent Mn(II) centres into a two-dimensional four-connected (4,4) network. These two-dimensional layers are stacked in a parallel mode. Hydrogen bonds between water molecules and carboxylate O atoms link neighbouring (4,4) networks, yielding a three-dimensional alpha-polonium net.