Response of Paenibacillus polymyxa SC2 to the stress of polymyxin B and a key ABC transporter YwjA involved.

Polymyxins are cationic peptide antibiotics and regarded as the "final line of defense" against multidrug-resistant bacterial infections. Meanwhile, some polymyxin-resistant strains and the corresponding resistance mechanisms have also been reported. However, the response of the polymyxin-producing strain Paenibacillus polymyxa to polymyxin stress remains unclear. The purpose of this study was to investigate the stress response of gram-positive P. polymyxa SC2 to polymyxin B and to identify functional genes involved in the stress response process. Polymyxin B treatment upregulated the expression of genes related to basal metabolism, transcriptional regulation, transport, and flagella formation and increased intracellular ROS levels, flagellar motility, and biofilm formation in P. polymyxa SC2. Adding magnesium, calcium, and iron alleviated the stress of polymyxin B on P. polymyxa SC2, furthermore, magnesium and calcium could improve the resistance of P. polymyxa SC2 to polymyxin B by promoting biofilm formation. Meanwhile, functional identification of differentially expressed genes indicated that an ABC superfamily transporter YwjA was involved in the stress response to polymyxin B of P. polymyxa SC2. This study provides an important reference for improving the resistance of P. polymyxa to polymyxins and increasing the yield of polymyxins. KEY POINTS: • Phenotypic responses of P. polymyxa to polymyxin B was performed and indicated by RNA-seq • Forming biofilm was a key strategy of P. polymyxa to alleviate polymyxin stress • ABC transporter YwjA was involved in the stress resistance of P. polymyxa to polymyxin B.

Photocatalytic Multisite Functionalization of Unactivated Terminal Alkenes by Merging Polar Cycloaddition and Radical Ring-Opening Process.

Although highly appealing for rapid access of molecular complexity, multi-functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring-opening remote C(sp3)-H functionalization, thus enabling a smooth 1,2,5-trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring-opening process, which is followed by a series of 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site-selective introduction of three different functional groups is accomplished and a broad spectrum of valuable ß-hydroxyl-ε-fluoro-nitrile products are synthesized from readily available terminal alkenes.

Achieving Strong Circularly Polarized Luminescence through Cascade Cationic Insertion in Lead-free Hybrid Metal Halides.

Generating circularly polarized luminescence (CPL) with simultaneous high photoluminescence quantum yield (PLQY) and dissymmetry factor (glum) is difficult due to usually unmatched electric transition dipole moment (µ) and magnetic transition dipole moment (m) of materials. Herein we tackle this issue by playing a "cascade cationic insertion" trick to achieve strong CPL (with PLQY of ~100 %) in lead-free metal halides with high glum values reaching -2.3×10-2 without using any chiral inducers. Achiral solvents of hydrochloric acid (HCl) and N, N-dimethylformamide (DMF) infiltrate the crystal lattice via asymmetric hydrogen bonding, distorting the perovskite structure to induce the "intrinsic" chirality. Surprisingly, additional insertion of Cs+ cation to substitute partial (CH3)2NH2 + transforms the chiral space group to achiral but the crystal maintains chiroptical activity. Further doping of Sb3+ stimulates strong photoluminescence as a result of self-trapped excitons (STEs) formation without disturbing the crystal framework. The chiral perovskites of indium-antimony chlorides embedded on LEDs chips demonstrate promising potential as CPL emitters. Our work presents rare cases of chiroptical activity of highly luminescent perovskites from only achiral building blocks via spontaneous resolution as a result of symmetry breaking.

Clearance of bacteria from lymph nodes in sheep immunized with Brucella suis S2 vaccine is associated with M1 macrophage activation.

Ovine brucellosis is a global zoonotic disease of sheep caused by Brucella melitensis, which inflicts a significant burden on human and animal health. Brucella suis strain S2 (B. suis S2) is a smooth live attenuated vaccine for the prevention of ovine brucellosis in China. However, no previous studies have assessed the immunogenicity of B. suis S2 vaccine after oral immunization in sheep. Here, we attempted to evaluate the ovine immune response over the course of B. suis S2 immunization and to identify in vivo predictors for vaccine development. Body temperature, serum Brucella antibodies, serum cytokines (IL-12p70 and interferon [IFN]-γ), and bacterial load in the mandibular lymph nodes (LN), superficial cervical LN, superficial inguinal LN, and spleen were investigated to determine the safety and efficacy of the vaccine. The abnormal body temperature of sheep occurred within 8 days post-infection (dpi). Brucella suis S2 persisted for a short time (< 21 dpi) in the mandibular LN. The highest level of IL-12p70 was observed at 9 dpi, whereas serum IFN-γ levels peaked at 12 dpi. Transcriptome analysis and quantitative reverse transcription PCR were performed to determine gene expression profiles in the mandibular LN of sheep. Antigen processing and presentation pathway was the dominant pathway related to the dataset. Our studies suggest that the immune response in ovine LN resembled type 1 immunity with the secretion of IL-12p70 and IFN-γ after B.suis S2 immunization and the vaccine may eliminate Brucella via stimulation of M1 macrophages through the course of Th cells.

Prenatal exposure to phthalates and polybrominated diphenyl ethers on neonatal health: A birth cohort study in Guangxi, China.

Few epidemiological studies have focused on prenatal phthalates (PAEs) and polybrominated diphenyl ethers (PBDEs) exposure to neonatal health in China. This study aimed to assess the associations between prenatal PAEs and PBDEs exposure and neonatal health in Guangxi, a Zhuang autonomous region of China. Concentrations of 4 PAEs metabolites (mPAEs) and 5 PBDEs congeners were measured in the serum of 267 healthy pregnant women. Birth outcomes and clinical data of neonates were collected after delivery. Mono-(2-Ethylhexyl) phthalate (MEHP) (81.52%) and BDE47 (35.21%) were the mPAEs and PBDEs congeners with the highest detection rate in serum. Prenatal exposures to mono-n-butyl phthalate (MBP), MEHP, and ΣmPAEs were negatively associated with birth weight (BW), birth length (BL), and gestational age (GA). Higher exposures to MBP, MEHP, and ΣmPAEs were associated with an increased odds ratio (OR) for low birth weight (LBW), but exposure to BDE28 exhibited the opposite effect. Moreover, higher exposures to MBP, MEHP, ΣmPAEs, BDE99, and ΣPBDEswere associated with an increased OR for premature birth (PTB) (P < 0.05). In contrast to MBP exposure, BDE28 exposure was associated with a higher OR for neonatal jaundice (NNJ) (P < 0.05). The interaction analysis showed a positive interaction between monoethyl phthalate (MEP) and BDE28 on the risk of NNJ and positive interaction between ΣmPAEs and BDE47 on the risk of NNJ. In addition, there are ethnicity-specific associations of prenatal PBDEs exposure with neonatal health in individuals of Zhuang and Han nationalities, and boy neonates were more sensitive to prenatal PBDEs exposure than girl neonates. The results revealed that prenatal exposure to mPAEs and PBDEs might have adverse effects on neonatal development, and the effects might be ethnicity- and sex-specific.

Postoperative effect of sufentanil preemptive analgesia combined with psychological intervention on breast cancer patients.

OBJECTIVES: To explore the postoperative effects of sufentanil preemptive analgesia combined with psychological intervention on breast cancer patients undergoing radical surgery. METHODS: 112 female breast cancer patients aged 18-80 years old who underwent radical surgery by the same surgeon were randomly divided into 4 groups, and there were 28 patients in each group. Patients in group A were given 10 µg sufentanil preemptive analgesia combined with perioperative psychological support therapy (PPST), group B had only 10 µg sufentanil preemptive analgesia, group C had only PPST, and group D were under general anesthesia with conventional intubation. Visual analogue scoring (VAS) was used for analgesic evaluation at 2, 12 and 24 h after surgery and compared among the four groups by ANOVA method. RESULTS: The awakening time of patients in group A or B was significantly shorter than that in group C or D, and the awakening time in group C was significantly shorter than that in group D. Moreover, patients in group A had the shortest extubation time, while the group D had the longest extubation time. The VAS scores at different time points showed significant difference, and the VAS scores at 12 and 24 h were significantly lower than those at 2 h (P < 0.05). The VAS scores and the changing trend of VAS scores were varied among the four groups (P < 0.05). In addition, we also found that patients in group A had the longest time to use the first pain medication after surgery, while patients in group D had the shortest time. But the adverse reactions among the four groups showed no difference. CONCLUSIONS: Sufentanil preemptive analgesia combined with psychological intervention can effectively relieve the postoperative pain of breast cancer patients.

Multi-omics analysis reveals BDE47 induces depression-like behaviors in mice by interfering with the 2-arachidonoyl glycerol-associated microbiota-gut-brain axis.

2,2',4,4'-tetrabromodiphenyl ether (BDE47) is a foodborne environmental risk factor for depression, but the pathogenic mechanism has yet to be fully characterized. In this study, we clarified the effect of BDE47 on depression in mice. The abnormal regulation of the microbiome-gut-brain axis is evidenced closely associated with the development of depression. Using RNA sequencing, metabolomics, and 16s rDNA amplicon sequencing, the role of the microbiome-gut-brain axis in depression was also explored. The results showed that BDE47 exposure increased depression-like behaviors in mice but inhibited the learning memory ability of mice. The RNA sequencing analysis showed that BDE47 exposure disrupted dopamine transmission in the brain of mice. Meanwhile, BDE47 exposure reduced protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT), activated astrocytes and microglia cells, and increased protein levels of NLRP3, IL-6, IL-1ß, and TNF-α in the brain of mice. The 16 s rDNA sequencing analysis showed that BDE47 exposure disrupted microbiota communities in the intestinal contents of mice, and faecalibaculum was the most increased genus. Moreover, BDE47 exposure increased the levels of IL-6, IL-1ß, and TNF-α in the colon and serum of mice but decreased the levels of tight junction protein ZO-1 and Occludin in the colon and brain of mice. In addition, the metabolomic analysis revealed that BDE47 exposure induced metabolic disorders of arachidonic acid and neurotransmitter 2-Arachidonoyl glycerol (2-AG) was one of the most decreased metabolites. Correlation analysis further revealed gut microbial dysbiosis, particularly faecalibaculum, is associated with altered gut metabolites and serum cytokines in response to BDE47 exposure. Our results suggest that BDE47 might induce depression-like behavior in mice through gut microbial dysbiosis. The mechanism might be associated with the inhibited 2-AG signaling and increased inflammatory signaling in the gut-brain axis.

Global Existence and Fixed-Time Synchronization of a Hyperchaotic Financial System Governed by Semi-Linear Parabolic Partial Differential Equations Equipped with the Homogeneous Neumann Boundary Condition.

Chaotic nonlinear dynamical systems, in which the generated time series exhibit high entropy values, have been extensively used and play essential roles in tracking accurately the complex fluctuations of the real-world financial markets. We are concerned with a system of semi-linear parabolic partial differential equations supplemented by the homogeneous Neumann boundary condition, which governs a financial system comprising the labor force, the stock, the money, and the production sub-blocks distributed in a certain line segment or planar region. The system derived by removing the terms involved with partial derivatives with respect to space variables from our concerned system was demonstrated to be hyperchaotic. We firstly prove, via Galerkin's method and establishing a priori inequalities, that the initial-boundary value problem for the concerned partial differential equations is globally well posed in Hadamard's sense. Secondly, we design controls for the response system to our concerned financial system, prove under some additional conditions that our concerned system and its controlled response system achieve drive-response fixed-time synchronization, and provide an estimate on the settling time. Several modified energy functionals (i.e., Lyapunov functionals) are constructed to demonstrate the global well-posedness and the fixed-time synchronizability. Finally, we perform several numerical simulations to validate our synchronization theoretical results.

Almost Surely Exponential Convergence Analysis of Time Delayed Uncertain Cellular Neural Networks Driven by Liu Process via Lyapunov-Krasovskii Functional Approach.

As with probability theory, uncertainty theory has been developed, in recent years, to portray indeterminacy phenomena in various application scenarios. We are concerned, in this paper, with the convergence property of state trajectories to equilibrium states (or fixed points) of time delayed uncertain cellular neural networks driven by the Liu process. By applying the classical Banach's fixed-point theorem, we prove, under certain conditions, that the delayed uncertain cellular neural networks, concerned in this paper, have unique equilibrium states (or fixed points). By carefully designing a certain Lyapunov-Krasovskii functional, we provide a convergence criterion, for state trajectories of our concerned uncertain cellular neural networks, based on our developed Lyapunov-Krasovskii functional. We demonstrate under our proposed convergence criterion that the existing equilibrium states (or fixed points) are exponentially stable almost surely, or equivalently that state trajectories converge exponentially to equilibrium states (or fixed points) almost surely. We also provide an example to illustrate graphically and numerically that our theoretical results are all valid. There seem to be rare results concerning the stability of equilibrium states (or fixed points) of neural networks driven by uncertain processes, and our study in this paper would provide some new research clues in this direction. The conservatism of the main criterion obtained in this paper is reduced by introducing quite general positive definite matrices in our designed Lyapunov-Krasovskii functional.

Difluoromethylation of Unactivated Alkenes Using Freon-22 through Tertiary Amine-Borane-Triggered Halogen Atom Transfer.

The application of abundant and inexpensive fluorine feedstock sources to synthesize fluorinated compounds is an appealing yet underexplored strategy. Here, we report a photocatalytic radical hydrodifluoromethylation of unactivated alkenes with an inexpensive industrial chemical, chlorodifluoromethane (ClCF2H, Freon-22). This protocol is realized by merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) with organophotoredox catalysis under blue light irradiation. A broad scope of readily accessible alkenes featuring a variety of functional groups and drug and natural product moieties could be selectively difluoromethylated with good efficiency in a metal-free manner. Combined experimental and computational studies suggest that the key XAT process of ClCF2H is both thermodynamically and kinetically favored over the hydrogen atom transfer pathway owing to the formation of a strong boron-chlorine (B-Cl) bond and the low-lying antibonding orbital of the carbon-chlorine (C-Cl) bond.

Isolation and Genome Sequence of a Novel Phosphate-Solubilizing Rhizobacterium Bacillus altitudinis GQYP101 and Its Effects on Rhizosphere Microbial Community Structure and Functional Traits of Corn Seedling.

Bacillus altitudinis is a widely distributed soil bacterium that has various functional activities, including remediation of contaminated soil, degradation of herbicides, and enhancement of plant growth. B. altitudinis GQYP101 was isolated from the rhizosphere soil of Lycium barbarum L. and demonstrated potential as a plant growth-promoting bacterium. In this work, strain GQYP101 could solubilize phosphorus, and increased the stem diameter, maximum leaf area, and fresh weight of corn in a pot experiment. Nitrogen and phosphorus contents of corn seedlings (aerial part) increased by 100% and 47.9%, respectively, after application of strain GQYP101. Concurrently, nitrogen and phosphorus contents of corn root also increased, by 55.40% and 20.3%, respectively. Furthermore, rhizosphere soil nutrients were altered and the content of available phosphorus increased by 73.2% after application of strain GQYP101. The mechanism by which strain GQYP101 improved plant growth was further investigated by whole genome sequence analysis. Strain GQYP101 comprises a circular chromosome and a linear plasmid. Some key genes of strain GQYP101 were identified that were related to phosphate solubilization, alkaline phosphatase, chemotaxis, and motility. The findings of this study may provide a theoretical basis for strain GQYP101 to enhance crop yield as microbial fertilizer.

Integrated MicroRNA-mRNA Analyses of Distinct Expression Profiles in Hyperoxia-Induced Bronchopulmonary Dysplasia in Neonatal Mice.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease of preterm neonates; the underlying pathogenesis is not fully understood. Recent studies suggested microRNAs (miRNAs) may be involved in BPD. STUDY DESIGN: miRNA and mRNA microarrays were performed to analyze the expression profiles of miRNA and mRNA in BPD and control lung tissues after oxygen and air exposure on day 21. Bioinformatics methods, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), were performed to predict the potential functions of differentially expressed genes. Then, miRNA-mRNA regulatory network was constructed by protein-protein interaction (PPI) data and TarBase data. RESULTS: Our results showed that a total of 192 differentially expressed miRNAs (74 downregulated and 118 upregulated) and 1,225 differentially expressed mRNAs (479 downregulated and 746 upregulated) were identified between BPD mice and normoxia-control mice. GO and KEGG analysis showed that for downregulated genes, the top significant enriched GO terms and KEGG pathways were both mainly related to immune and inflammation processes; for upregulated genes, the top significant enriched GO terms and KEGG pathways were both mainly related to extracellular matrix (ECM) remodeling. PPI network and miRNA-mRNA regulatory network construction revealed that the key genes and pathways associated with inflammation and immune regulation. CONCLUSION: Our findings revealed the integrated miRNA-mRNA data of distinct expression profiles in hyperoxia-induced BPD mice, and may provide some clues of the potential biomarkers for BPD, and provide novel insights into the development of new promising biomarkers for the treatment of BPD. KEY POINTS: · Integrated advanced bioinformatics methods may offer a better way to understand the molecular expression profiles involved in BPD.. · ECM remodeling, inflammation, and immune regulation may be essential to BPD.. · The miRNA-mRNA regulatory network construction may contribute to develop new biomarkers for the treatment of BPD..

Volatile organic compounds from Lysinibacillus macroides regulating the seedling growth of Arabidopsis thaliana.

Volatile organic compounds (VOCs) have the characteristics of long distance propagation, low concentration, perception, and indirect contact between organisms. In this experiment, Lysinibacillus macroides Xi9 was isolated from cassava residue, and the VOCs produced by this strain were analyzed by the SPME-GC-MS method, mainly including alcohols, esters, and alkanes. By inoculation of L. macroides Xi9, VOCs can promote the growth and change the root-system architecture of Arabidopsis seedlings. The results showed that the number of lateral roots, root density, and fresh weight of Arabidopsis seedlings were significantly higher (p ≤ 0.01), and the number of roots hair was also increased after exposure to strain Xi9. Compared with the control group, the transcriptome analysis of Arabidopsis seedlings treated with strain Xi9 for 5 days revealed a total of 508 genes differentially expressed (p < 0.05). After Gene Ontology enrichment analysis, it was found that genes encoding nitrate transport and assimilation, and the lateral root-related gene ANR1 were up-regulated. The content of NO3 - and amino acid in Arabidopsis seedlings were significantly higher from control group (p ≤ 0.01). Plant cell wall-related EXPA family genes and pectin lyase gene were up-regulated, resulting cell elongation of leaf. SAUR41 and up-regulation of its subfamily members, as well as the down-regulation of auxin efflux carrier protein PILS5 and auxin response factor 20 (ARF20) led to the accumulation of auxin. These results indicated that VOCs of strain Xi9 promote Arabidopsis seedlings growth and development by promoting nitrogen uptake, regulating auxin synthesis, and improving cell wall modification. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01268-3.

Interactional mechanisms of Paenibacillus polymyxa SC2 and pepper (Capsicum annuum L.) suggested by transcriptomics.

BACKGROUND: Paenibacillus polymyxa SC2, a bacterium isolated from the rhizosphere soil of pepper (Capsicum annuum L.), promotes growth and biocontrol of pepper. However, the mechanisms of interaction between P. polymyxa SC2 and pepper have not yet been elucidated. This study aimed to investigate the interactional relationship of P. polymyxa SC2 and pepper using transcriptomics. RESULTS: P. polymyxa SC2 promotes growth of pepper stems and leaves in pot experiments in the greenhouse. Under interaction conditions, peppers stimulate the expression of genes related to quorum sensing, chemotaxis, and biofilm formation in P. polymyxa SC2. Peppers induced the expression of polymyxin and fusaricidin biosynthesis genes in P. polymyxa SC2, and these genes were up-regulated 2.93- to 6.13-fold and 2.77- to 7.88-fold, respectively. Under the stimulation of medium which has been used to culture pepper, the bacteriostatic diameter of P. polymyxa SC2 against Xanthomonas citri increased significantly. Concurrently, under the stimulation of P. polymyxa SC2, expression of transcription factor genes WRKY2 and WRKY40 in pepper was up-regulated 1.17-fold and 3.5-fold, respectively. CONCLUSIONS: Through the interaction with pepper, the ability of P. polymyxa SC2 to inhibit pathogens was enhanced. P. polymyxa SC2 also induces systemic resistance in pepper by stimulating expression of corresponding transcription regulators. Furthermore, pepper has effects on chemotaxis and biofilm formation of P. polymyxa SC2. This study provides a basis for studying interactional mechanisms of P. polymyxa SC2 and pepper.

Interface-engineered Co3S4/CoMo2S4nanosheets as efficient bifunctional electrocatalysts for alkaline overall water splitting.

Exploring bifunctional electrocatalysts with high efficiency, inexpensive, and easy integration is still the daunt challenge for the production of hydrogen on a large scale by means of water electrolysis. In this work, a novel free-standing Co3S4/CoMo2S4heterostructure on nickel foam by a facial hydrothermal method is demonstrated to be an effective bifunctional electrocatalyst for overall water splitting (OWS). The synthesized Co3S4/CoMo2S4electrocatalyst achieves ultralow overpotentials of 143 mV@10 mA cm-2for hydrogen evolution reaction (HER) and 221 mV@25 mA cm-2for oxygen evolution reaction (OER), respectively, in 1 M KOH. Moreover, it presents a greatly improved durability and stability under operando electrochemical conditions. When used as catalysts for OWS, the Co3S4/CoMo2S4-3//Co3S4/CoMo2S4-3 electrodes just need 1.514 V to make it to the current density of 10 mA cm-2. It is supposed that the introduction of heterogeneous interface between Co3S4and CoMo2S4could give rise to plentiful active sites and enhanced conductivity, and thus boost excellent catalytic performances. Moreover, the porous feature of free-standing nanosheets on nickel foam could benefits catalytic performances by accelerating charge transport and releasing bubbles rapidly. This work proposes a bifunctional catalyst system with the heterogeneous interface, which could be used in a sustainable green energy system.

Effects of Smoking on ACE2 Expression Pattern: Risk and Severity of SARS-CoV-2 Infection.

BACKGROUND: Respiratory epithelium expressing angiotensin-converting enzyme 2 (ACE2) is the entry for novel coronavirus (SARS-CoV-2), pathogen of the COVID-19 pneumonia outbreak, although a few recent studies have found different ACE2 expression in lung tissue of smokers. The effect of smoking on ACE2 expression and COVID-19 is still not clear. So, we did this research to determine the effect of smoking on ACE2 expression pattern and its relationship with the risk and severity of COVID-19. METHODS: The clinical data of COVID-19 patients with smoking and non-smoking were analyzed, and ACE2 expression of respiratory and digestive mucosa epithelia from smoker and non-smoker patients or healthy subjects were detected by immunohistochemical (IHC) staining. RESULTS: Of all 295 laboratory-confirmed COVID-19 patients, only 24 (8.1%) were current smokers with moderate smoking or above, which accounted for 54.2% of severe cases with higher mortality than non-smokers (8.3% vs. 0.4%, p = 0.018). Data analysis showed the proportion of smokers in COVID-19 patients was lower than that in general population of China (Z = 11.65, P < 0.001). IHC staining showed ACE2 expression in respiratory and digestive epithelia of smokers were generally downregulated. CONCLUSIONS: The proportion of smokers in COVID-19 patients was lower, which may be explained by ACE2 downregulation in respiratory mucosa epithelia. However, smoking COVID-19 patients accounted for a higher proportion in severe cases and higher mortality than for non-smoking COVID-19 patients, which needs to be noted.

Sinapic Acid Alleviated Inflammation-Induced Intestinal Epithelial Barrier Dysfunction in Lipopolysaccharide- (LPS-) Treated Caco-2 Cells.

The integrity and permeability of the intestinal epithelial barrier are important indicators of intestinal health. Impaired intestinal epithelial barrier function and increased intestinal permeability are closely linked to the onset and progression of various intestinal diseases. Sinapic acid (SA) is a phenolic acid that has anti-inflammatory, antihyperglycemic, and antioxidant activities; meanwhile, it is also effective in the protection of inflammatory bowel disease (IBD), but the specific mechanisms remain unclear. Here, we evaluated the anti-inflammatory of SA and investigated its potential therapeutic activity in LPS-induced intestinal epithelial barrier and tight junction (TJ) protein dysfunction. SA improved cell viability; attenuated epithelial permeability; restored the protein and mRNA expression of claudin-1, ZO-1, and occludin; and reversed the redistribution of the ZO-1 and claudin-1 proteins in LPS-treated Caco-2 cells. Moreover, SA reduced the inflammatory response by downregulating the activation of the TLR4/NF-κB pathway and attenuated LPS-induced intestinal barrier dysfunction by decreasing the activation of the MLCK/MLC pathway. This study demonstrated that SA has strong anti-inflammatory activity and can alleviate the occurrence of high intercellular permeability in Caco-2 cells exposed to LPS.

A preliminary study on the mechanism of the neurosteroid-mediated ionotropic receptor dysfunction in neurodevelopmental toxicity induced by decabromodiphenyl ether.

The mechanism of neurodevelopmental toxicity of decabromodiphenyl ether (BDE209) remains unclear. Recent evidence suggests that neurosteroids disorders play a vital role in BDE209 induced-neurodevelopmental toxicity. To explore the mechanism of it, pregnant ICR mice were orally gavaged with 0, 225, and 900 mg kg-1 BDE209 for about 42 days. Spatial learning and memory abilities of offspring were tested on postnatal day (PND) 21. Offspring were euthanized at PND26, the neuronal structure, neurosteroids level, and related proteins including neurosteroids synthase, ionotropic receptors and cAMP-response element binding protein (CREB) pathway were evaluated, as well as Ca2+ concentration and the mitochondrial membrane potential (Mmp). Our results showed that BDE209 impaired learning and memory abilities and disrupted neuronal structure. Meanwhile, BDE209 decreased the pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and allopregnanolone (ALLO) levels in the serum and brain, as well as the mRNA and protein levels of cholesterol-side-chain cleavage enzyme (P450scc), steroid 17α-hy-droxylase (P450C17), 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and steroid 5α-reductase of type I (5α-R) in the hippocampi. Also, BDE209 suppressed mRNA and protein levels of NR1, NR2A and NR2B subunits of the N-methyl-D-aspartic acid receptor (NMDAR) and α1 subunit of the Gamma-amino butyric acid A receptor (GABAAR), but increased the levels of ß2 and γ2 subunits of the GABAAR in the hippocampi. Moreover, BDE209 increased the Ca2+ concentration and phosphorylation extracellular regulated protein kinases (P-ERK) 1/2 level, but decreased the P-CREB and Mmp level in the hippocampi. These results indicate that BDE209 exposure during pregnancy and lactation is possible to affect learning and memory formation of offspring by the neurosteroid-mediated ionotropic receptors dysfunction.

Isobavachalcone inhibits acute myeloid leukemia: Potential role for ROS-dependent mitochondrial apoptosis and differentiation.

Isobavachalcone (IBC) has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. Herein, IBC exhibited significant inhibition on the cell viability, proliferation, and the colony formation ability of AML cells. Moreover, IBC induced mitochondrial apoptosis evidenced by reduced mitochondrial membrane potential, increased Bax level, decreased Bcl-2, Bcl-xL, and Mcl-1 levels, elevated cytochrome c level in the cytosol and increased cleavage of caspase-9, caspase-3, and PARP. Furthermore, IBC obviously promoted the differentiation of AML cells, accompanied by the increase of the phosphorylation of MEK and ERK and the C/EBPα expression as well as the C/EBPß LAP/LIP isoform ratio, which was significantly reversed by U0126, a specific inhibitor of MEK. Notably, IBC enhanced the intracellular ROS level. More importantly, IBC-induced apoptosis and differentiation of HL-60 cells were significantly mitigated by NAC. In addition, IBC also exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Together, our study suggests that the ROS-medicated signaling pathway is highly involved in IBC-induced apoptosis and differentiation of AML cells.

DT-13 induced apoptosis and promoted differentiation of acute myeloid leukemia cells by activating AMPK-KLF2 pathway.

Acute myeloid leukemia (AML) is a malignant disease originating from hematopoietic stem cells (HSC). Chemotherapy and/or HSC transplantation is unsatisfactory due to serious side effects, multidrug resistance, and high relapse rate. Thus, alternative strategies are urgently needed to develop more effective therapies. Liriope muscari baily saponins C (DT-13) is a novel compound isolated from Liriope muscari (Decne.) Baily, and exhibited a potent cytotoxicity against several solid tumors. However, the anti-AML activity of DT-13 and the potential mechanisms are still unknown. This study is the first to demonstrate that DT-13 had preferential cytotoxicity against AML cells, and remarkably inhibited proliferation and colony forming ability. Moreover, DT-13 induced the death receptor pathway-dependent apoptosis of HL-60 and Kasumi-1 cells by up-regulating Fas, FasL, DR5 and TRAIL as well as promoted the cleavage of caspase 8, caspase 3 and PARP. Meanwhile, DT-13 induced the differentiation with morphological change related to myeloid differentiation, elevated NBT and α-NAE positive cell rates, differentiation markers CD11b and CD14 as well as level of transcription factors C/EBPα and C/EBPß. RNA-sequencing analysis revealed that KLF2 may be one of the potential targets regulated by DT-13. Further studies indicated that KLF2 played a critical role in DT-13-induced apoptosis and differentiation. Moreover, activation of AMPK-FOXO was proved to be the upstream of KLF2 pathway that contributed to the induction of apoptosis and differentiation by DT-13. Additionally, restoration of KLF2 by DT-13 was highly correlated with the AMPK-related histone acetylation mechanisms. Finally, DT-13 exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Our study suggests that DT-13 may serve as a novel agent for AML by AMPL-KLF2-mediated apoptosis and differentiation.