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Diphyllin and its natural derivatives were identified as potent vacuolar H

We investigated the role of zinc-finger protein 281 (ZNF281), a novel molecule, in ethanol-induced hepatocyte senescence and uncovered the potential mechanism. Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol-fed mice livers and ethanol-treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol-caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence-associated β-galactosidase-positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence-associated secretory phenotype and proinflammatory cytokines (IL-1β and IL-6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence-associated proteins including p53, p21, p16, high mobility group AT-hook 1, and phospho-histone H2A.X and telomerase-associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol-induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2-PINK1/Parkin signalling-mediated mitophagy. Mechanistically, ZNF281 directly bound to 5'-GGCGGCGGGCGG-3' motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno-associated virus encoding ZNF281 shRNA protected mice from alcohol feeding-caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.

On-road tailpipe volatile organic compounds (VOCs) were sampled from light-duty diesel trucks (LDDTs) compliant with Euro III to V, and a total of 102 VOC species were quantified. The composition characteristics and carbon number distributions were investigated, and the contribution of individual VOC to ozone formation potentials (OFPs) was weighted. Results showed that alkanes were the major VOC species, accounting for approximately 65.5%. VOC emissions decreased significantly as the standards became stricter, especially for alkanes and aromatics; and the VOC emissions on highway were much lower than those on urban roads. Carbon number distribution of VOCs was mainly concentrated in C3‐C4 and C10‐C12. Aromatics were the major contributors to ozone formation, taking up 49.3‐57.6% of the total OFPs, and naphthalene, 1-butene, dodecane, 1,2,3-trimethylbenzene and 2-propenal were the top five species. The information provided insight into the tailpipe VOC emission characteristics and may help decision makers drafting related emission policies.

The objective of this study was to investigate the feasibility of the bolus administration of PLS via skin by using dissolving microneedles of palonosetron hydrochloride (PLS-DMNs). Tip-loaded PLS-DMNs were fabricated by a casting method using sodium hyaluronate (HA) as DMNs-forming polymer. PLS-DMNs were shown to have a content of 118.5 ± 8.7 μg per piece with sufficient mechanical strength for insertion into pig skin ex vivo. In situ dissolution of PLS-DMNs was achieved within 5 min and 83.2 % of PLS was delivered. In vitro studies showed that PLS-DMNs provided much higher PLS permeation than that after passive permeation using a PLS hydrogel. Moreover, the application of 30 min-iontophoresis at the beginning of PLS-DMNs administration further enhanced PLS delivery. In vivo pharmacokinetic studies were carried out in rats. The area under the curve (AUC) and the time to reach the peak (T

Alzheimer’s disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of “senile” plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a “lost link” in understanding and treating AD and call for future work.

Vehicular emissions have become a primary anthropogenic source of urban atmospheric volatile halogenated hydrocarbons (VHCs) with the rapid increase of vehicle population, while characteristics of the VHC emissions from different vehicles were rarely systematically investigated. In this study, the on-road tailpipe emissions were sampled from seven in-use vehicles, including two light-duty gasoline vehicles (LDGV), three light-duty diesel trucks (LDDT), one heavy-duty diesel truck (HDDT), and a liquefied petroleum gas-electric hybrid bus (LPGB), using a portable emission measurement system (PEMS) combined with summa canisters, and 35 individual VHC species were identified by a gas chromatography mass spectrometry detector (GC-MSD). Results showed that VHC emissions under urban driving conditions were much higher than those on the suburban roads and highways. The VHC emission factors of LDGV were 1.2 ± 0.34 mg/km and 3.6 ± 1.5, 6.8 ± 0.89, and 1.6 ± 0.28 mg/km for LDDT, HDDT, and LPGB, respectively. For the LDGV, chlorobenzene, 1,2-dichloroethane, and hexachlorobutadiene were the top three VHC species. 1,2-Dichloroethane, trichloromethane, and methyl chloride were the main VHC constituents in the LDDT. Chlorobenzene was the most abundant VOC species for the HDDT, followed by 1,2-dichloroethane and 1,4-dichlorobenzene. The major species for LPGB were 1,2,4-trichlorobenzene, carbon tetrachloride, and benzyl chloride. The major tailpipe VHC species obtained in this study were partial consistent with previous studies with different test methods. The results provide an initial evaluation of the tailpipe VHC emissions, which may provide experimental data support for the refined source apportionment of atmospheric VHCs and the control of vehicular VHCs.

The obligate intracellular bacterium Chlamydia trachomatis is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited C. trachomatis in a dose-dependent manner in vitro. Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC50 values from 7.25 to 9.73 μM. The compounds disturbed the whole intracellular life cycle of C. trachomatis, mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.

The Wnt/β-catenin signaling pathway is dysregulated in diseases and Wnt inhibitors like PRI-724 are in clinical development. This study evaluated the regulatory actions of PRI-724 and other Wnt inhibitors on the transport activity of human renal Organic anion transporters (OATs) and Organic anion transporting polypeptides (OATPs). The substrate uptake by OAT4 and OATP2B1 was markedly decreased by PRI-724 (Vmax/Km: ∼26% and ∼17% of corresponding control), with less pronounced decreases in OAT1, OAT3 and OAT1A2. PRI-724 decreased the plasma membrane expression of inhibited OATs/OATPs but didn't affect their total cellular expression. Two model Wnt inhibitors - FH535 and 21H7 - were also tested in comparative studies. Like PRI-724, they also strongly decreased the activities and membrane expression of multiple OATs/OATPs. In contrast, FH535 didn't affect the substrate uptake by organic cation transporters. In control studies, the EGFR inhibitor lapatinib did not inhibit the function of some OATs/OATPs. Together these findings suggest that Wnt inhibitors selectively modulate the function of multiple organic anions transporters, so their clinical use may have unanticipated effects on drug entry into cells. These findings are pertinent to current clinical trials that have been designed to understand the safety and efficacy of new Wnt inhibitor drugs.

Chronic alcohol consumption can cause alcoholic liver disease (ALD), leading to morbidity and mortality worldwide. Complex disease progression of ALD varies from alcoholic fatty liver to alcoholic steatohepatitis, eventually contributing to fibrosis and cirrhosis. Accumulating evidence revealed that necroptosis, a way of programmed cell death different from apoptosis and traditional necrosis, is involved in the underlying pathogenic molecular mechanism of ALD. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase have been implicated as key mediators to execute necroptosis. Also, necroptosis has gained increasing attention due to its potential association with primary pathological hallmarks of ALD, including oxidative stress, hepatic steatosis and inflammation. This review summarizes the recent progress on the roles and mechanisms of necroptosis and focuses on the crosstalk between necroptosis and the other pathogenesis of ALD, providing a theoretical basis for targeting necroptosis as a novel treatment for ALD.

A surge in the size of the automobile population has caused vehicular emissions to become a major source of urban atmospheric pollution. Elevating standards is an effective method of controlling vehicular emissions and improving air quality. Light-duty vehicles are the major contributors to HC and CO emissions as they constitute a large proportion of all vehicles. Consequently, controlling light-duty vehicular emissions has been the primary means of air pollution prevention in China. This paper first reviews the progress of emission control standards in mainland China. Second, it analyzes features of the China 6 emissions standards, namely the continuation of European standards, the harmony of global technology regulations, and fusion with the standards of the USA. This is followed by a description and discussion of the status of research on mainstream after-treatment technologies such as the gasoline particulate filter, lean-NOx trap, and selective catalytic reduction. Finally, this study argues that the technical routes for implementing three-way catalysts, gasoline particulate filters, and onboard refueling vapor recovery in gasoline vehicles and diesel oxidation catalysts, diesel particulate filters, and selective catalyst reduction in diesel vehicles meet China 6 standards. Moreover, onboard diagnostics-based control of light vehicle emissions is introduced, and the development directions of vehicle gasoline (the reduction in sulfur, olefin, and aromatic content and vapor pressure control in summer) and vehicle diesel (an increase in the Cetane number and reduction in the forecasted polycyclic aromatic content) are discussed. State-of-the-art outlook for light-duty vehicle emission control standards in China

Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apical‑basal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66‑X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selection‑mass spectrometry, before

A novel series of 1-substituted phenazines 4a-4l were designed and synthesized via Palladium-catalyzed reactions from 1-phenazine trifluoromethanesulfonate. These phenazines showed antichlamydial activity with IC50 values from 1 to 10 μM. Among them, compounds 4c and 4i exhibited the best antichlamydial activity with IC50 values from 2.06 to 2.74 μM without apparent cytotoxicity to host cells.

Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethanol-incubated hepatocytes via restoring PINK1/parkin-mediated mitophagy. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) was downregulated in ethanol-exposed hepatocytes, which was restored after TMP treatment. In vitro UQCRC2 knockdown lowered the capacities of TMP in reducing mitochondrial ROS accumulation, relieving mitochondria damage, and enhancing PINK1/parkin-mediated mitophagy in ethanol-exposed hepatocytes. Analogously, systematic UQCRC2 knockdown interrupted the actions of TMP to trigger autophagic signal, repress necroptotic signal, and protect against alcoholic liver injury, inflammation, and ROS overproduction. In conclusion, this work concluded that TMP rescued UQCRC2 expression in ethanol-challenged hepatocytes, which contributed to necroptosis inhibition by facilitating PINK1/parkin-mediated mitophagy. These findings uncovered a potential molecular pharmacological mechanism underlying the hepatoprotective action of TMP and suggested TMP as a promising therapeutic candidate for alcoholic liver disease.

Chlamydia trachomatis is an obligate intracellular bacterium whose unique developmental cycle consists of an infectious elementary body and a replicative reticulate body. Progression of this developmental cycle requires temporal control of the transcriptome. In addition to the three chlamydial sigma factors (σ66, σ28, and σ54) that recognize promoter sequences of genes, chlamydial transcription factors are expected to play crucial roles in transcriptional regulation. Here, we investigate the function of GrgA, a Chlamydia-specific transcription factor, in C. trachomatis transcriptomic expression. We show that 10 to 30 min of GrgA overexpression induces 13 genes, which likely comprise the direct regulon of GrgA. Significantly, σ66-dependent genes that code for two important transcription repressors are components of the direct regulon. One of these repressors is Euo, which prevents the expression of late genes during early phases. The other is HrcA, which regulates molecular chaperone expression and controls stress response. The direct regulon also includes a σ28-dependent gene that codes for the putative virulence factor PmpI. Furthermore, overexpression of GrgA leads to decreased expression of almost all tRNAs. Transcriptomic studies suggest that GrgA, Euo, and HrcA have distinct but overlapping indirect regulons. These findings, together with temporal expression patterns of grgA, euo, and hrcA, indicate that a transcriptional regulatory network of these three transcription factors plays critical roles in C. trachomatis growth and development. IMPORTANCEChlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in underdeveloped areas as well as some developed countries. Chlamydia carries genes that encode a limited number of known transcription factors. While Euo is thought to be critical for early chlamydial development, the functions of GrgA and HrcA in the developmental cycle are unclear. Activation of euo and hrcA immediately following GrgA overexpression indicates that GrgA functions as a master transcriptional regulator. In addition, by broadly inhibiting tRNA expression, GrgA serves as a key regulator of chlamydial protein synthesis. Furthermore, by upregulating pmpI, GrgA may act as an upstream virulence determinant. Finally, genes coregulated by GrgA, Euo, and HrcA likely play critical roles in chlamydial growth and developmental control.

On-road exhaust emissions from light-duty vehicles are greatly influenced by driving conditions. In this study, two light-duty passenger cars (LDPCs) and three light-duty diesel trucks (LDDTs) were tested to investigate the on-road emission factors (EFs) with a portable emission measurement system. Emission characteristics of carbon monoxide (CO), hydrocarbons (HC) and nitrogen oxides (NOx) emitted from vehicles at different speeds, accelerations and vehicle specific power (VSP) were analyzed. The results demonstrated that road conditions have significant impacts on regulated gaseous emissions. CO, NOx, and HC emissions from light-duty vehicles on urban roads increased by 1.1–1.5, 1.2–1.4, and 1.9–2.6 times compared with those on suburban and highway roads, respectively. There was a rough positive relationship between transient CO, NOx, and HC emission rates and vehicle speeds, while the EFs decreased significantly with the speed decrease when speed ≤ 20 km/h. The emissions rates of NOx and HC tended to increase and then decrease as the acceleration increased and the peak occurred at 0 m/s2 without considering idling conditions. For HC and CO, the emission rates were low and changed gently with VSP when VSP &lt, 0, while emission rates increased gradually with the VSP increase when VSP &gt, 0. For NOx NOx emission rates were lower and had no obvious change when VSP &lt, 0. However, NOx emissions were positively correlated with VSP, when VSP &gt, 0.

Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.

A Fe3+-specific probe (N-TC) based on Rhodamine B was designed and synthesized. N-TC has a good spectral response to Fe3+ in the EtOH/H2O solution (1:1, v/v, HEPES, 0.5 mM, pH = 7.38) with low detection limits and high binding constants. N-TC displays the reversible “turn-off-on” fluorescence response with 1:1 binding stoichiometry. It is further proven to be practical in sensitively monitoring trace Fe3+ in environmental water specimens. Biological experiments demonstrated that N-TC can be respectively used as a probe for detection of Fe3+ in living cells, animals and plant tissues.

A novel turn-on rhodamine B-based fluorescent chemosensor (RBCS) was designed and synthesized by reacting N-(rhodamine B)lactam-1,2-ethylenediamine and carbon disulfide. Upon addition of Fe3+ in EtOH/H2O solution (2:1, v/v, HEPES buffer, 0.6 mM, pH 7.20), the RBCS displayed a significant fluorescence enhancement at 582 nm and a dramatic color change from colorless to pink, which can be detected by the naked eye. Significantly, the RBCS exhibited a highly selective and sensitive ability toward Fe3+. The detection limit of the probe was 2.05 × 10−7 M. Job's plot indicated the formation of 1:1 complex between the RBCS and Fe3+. Moreover, the practical use of the RBCS is demonstrated by its application in the detection of Fe3+ in HeLa cells.

Two new pyridine-type rhodamine B chemosensors (RBPO and RBPF) used to detect Fe3+ have been designed and synthesized, and the sensing behavior towards various metal ions was evaluated via UV-vis and fluorescence spectroscopic techniques. Both RBPO and RBPF not only have good spectral responses to Fe3+ in an EtOH/H2O solution (3 : 1, v/v, HEPES, 0.5 mM, pH = 7.33) with low detection limits and high binding constants, but also suffer from less interference from common metal cations. The two chemosensors are further proven to be practical in sensitively monitoring trace Fe3+ in real water specimens. Intracellular imaging applications demonstrated that RBPO and RBPF can be used as two fluorescent chemosensors for the detection of Fe3+ in living human breast adenocarcinoma (MCF-7) cells.

Background: Chlamydiae are widespread Gram-negative bacteria that cause a number of human diseases. Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen. Methods: Fourteen novel phenazine derivatives were efficiently synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 4-bromo-1-methoxyphenazine. All the derivatives displayed antichlamydial activity with IC50 values from 1.01-19.77 µM against Chlamydia trachomatis D and L2 for inhibiting progeny formation.Results:C-4 morpholinyl 8a and C-4 phenyl phenazine 9c exhibited stronger antichlamydial activity with no apparent cytotoxicity. Both phenazine derivatives inhibited chlamydial inclusions formation and growth in a dose-dependent manner. They inhibited Chlamydia infection by reducing elementary body infectivity and disturbing Chlamydia growth at the mid-stage of the chlamydial developmental cycle.Conclusion:Our findings suggest C-4 aryl and C-4 amino phenazine derivatives as promising lead molecules for antichlamydials development.

The Chinese government has developed an ambitious project to promote the application of ethanol gasoline (E10) on a national scale since 2017. Given the difference in fuel properties between E10 and traditional gasoline, it is necessary to evaluate the volatile organic compound (VOC) emissions from E10-fuelled vehicles. In this study, a two-week sampling campaign was conducted in an urban tunnel, in which E10-fuelled vehicles were dominant, to evaluate the characteristics of VOC emissions from the mixed fleet. In total, 105 VOC species were identified, and the ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAFP) were estimated. The results showed that for vehicular VOC concentrations in the tunnel, alkanes, oxygenated VOCs (OVOCs) and alkenes were the most abundant VOC groups, with the average proportion being more than 80% of the total VOCs. The fleet-average VOC emission factor (EF) was 14.8 mg/km/veh, which was much lower than that from traditional gasoline-fuelled vehicle fleets, and alkanes, OVOCs, alkenes and aromatics were the major VOC groups. Because of the large number of E10-fuelled vehicles in the mixed fleet, a high proportion of OVOCs among the vehicular VOC emissions was observed. Ethane, acrolein, ethanol, ethylene and toluene were the top five VOC species with the largest EF in VOC emissions from the fleet. Alkenes were the main contributors with an average contribution of 43.9% of the total OFP, whereas aromatics dominated the total SOAFP by 95.8% on average. These results may provide a reference for the extensive application of ethanol gasoline and the development of vehicular emission models.

Background: The brain-gut-microbiome axis has emerged as an important pathway through which perturbations in the gut and/or microbial microenvironment can impact neurological function. Such alterations have been implicated in a variety of neuropsychiatric disorders, including depression, anxiety, and Alzheimer’s Disease (AD) and the use of probiotics as therapy for these diseases remains promising. However, the mechanisms underlying the gut microenvironment’s influence on disease pathogenesis and therapy remain unclear. Objective: The objective of this study is to investigate the effect of a novel probiotic formula, BIOCG, on cognitive function and pathobiological mechanisms, including amyloid processing and dendritic spine dynamics, in a mouse model of AD. Methods: BIOCG was administered for 3 months to 3xTg or 3xTg; Thy1-YFP AD mice and functional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Protein (APP) processing and microglial phenotype were also evaluated. Finally, we sequenced fecal samples following probiotic treatment to assess the impact on gut microbial composition and correlate the changes with the above described measures. Results: Mice treated with BIOCG demonstrated preserved cognitive abilities and stronger Long- Term Potentiation (LTP), spontaneous Excitatory Postsynaptic Currents (sEPSC), and glutamate-induced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed attenuated AD pathogenesis, including reduced Amyloid Beta (Aβ) burden, as well as more mature dendritic spines in the BIOCG-treated. Our finding of changes in microglial number and phenotype in the treatment group suggests that this formulation may mediate its effects via attenuation of neuroinflammation. Sequencing data confirmed that the gut microbiome in treated mice was more varied and harbored a greater proportion of “beneficial” bacteria. Conclusion: Overall, our results indicate that treatment with BIOCG enhances microbial diversity and, through gut-brain axis interactions, attenuates neuroinflammation to produce histologic and functional improvement in AD pathogenesis.

Distribution network refers to the distribution network that distributes electrical energy from transmission grids or power stations on-site or to users according to voltage levels. It has the characteristics of complicated structure and diverse application scenarios. In order to meet different distribution needs, the business systems established by power companies are also various, but they encounter difficulties when they need to interact with each other. Due to the inconsistency of interfaces and data structures, the information exchange between systems it is often difficult to achieve. The emergence of a public information model provides a solution to this problem, and each system can implement system construction by following the standards established by it to achieve efficient information interaction and data sharing between systems. Therefore, modeling the distribution network based on the public information model is of great significance. Based on the research of domestic and foreign distribution network information models, this paper proposes a method for distribution network model design based on common information model (CIM) based on the problems existing in the development of distribution network in China. The network topology algorithm is studied, and finally, a distribution network model based on the public information model is established.

Ambient temperature has substantial impacts on vehicle emissions, but the impacts may differ between traditional and alcohol gasolines. The objective of this study was to investigate the effects of temperature on gaseous and particulate emissions with both traditional and alcohol gasoline. Regulated gaseous, particle mass (PM), particle number (PN) and black carbon (BC) emissions from typical passenger vehicles were separately quantified with gasoline, E10 (10% ethanol and 90% gasoline by volume) and M15 (15% methanol and 85% gasoline by volume) at both 30°C and −7°C. The particulate emissions with all fuels increased significantly with decreased temperature. The PM emissions with E10 were only 48.0%–50.7% of those with gasoline at 30°C but increased to 59.2%–79.4% at −7°C. The PM emissions with M15 were comparable to those with gasoline at 30°C, but at −7°C, the average PM emissions were higher than those with gasoline. The variation trend of PN emissions was similar to that of PM emissions with changes in the fuel and temperature. At 30°C, the BC emissions were lower with E10 and M15 than with gasoline in most cases, but E10 and M15 might emit more BC than gasoline at −7°C, especially M15. The results of the transient PN and BC emission rates show that particulate emissions were dominated mainly by those emitted during the cold-start moment. Overall, the particulate emissions with E10 and M15 were more easily affected by ambient temperature, and the advantages of E10 and M15 in controlling particulate emissions declined as the ambient temperature decreased.

The gasoline direct injection (GDI) engine has substantially penetrated light-duty gasoline vehicles to help reduce fleet-wide fuel consumption across the world. However, increased particle emissions from GDI vehicles rather than the conventional multi-port fuel injection (MPFI) vehicles are of great concern. To investigate the particle emissions for these two categories of gasoline engines, we employed a dynamometer and measured the emissions of solid particle number (PN) and black carbon (BC) for four GDI and four MPFI vehicles under various testing cycles and conditions. Under the reference cycle (30 °C and cold-start WLTC), a strong correlation between solid PN and BC emissions is identified for both GDI and MPFI vehicles, although GDI vehicles without particle filters have significantly higher emissions of solid PN and BC than those of MPFI vehicles. Furthermore, varying the testing conditions by including cold start, low temperature, aggressive driving and air conditioning use all increase the emissions of solid PN and BC. These affecting factors pose more significant changes to particle emissions from MPFI vehicles than GDI vehicles. For example, at −7 °C, the solid PN and BC emissions of MPFI vehicles are increased by 4.17 times and 16.5 times relative to the results under 30 °C, and they are comparable to or higher than the emissions of GDI vehicles. Our results indicate that modern gasoline vehicles available in China’s market are likely to fail to comply with the upcoming PN emission limit (China 6), suggesting a serious need to adopt gasoline particle filters (GPF) for both GDI and MPFI vehicles. Advanced after-treatment technologies and stringent regulations to control particle emissions from gasoline vehicles should fully consider varying real-world conditions to guarantee effective environmental benefits.

Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.

Background/Aims: This study used Rho-associated protein kinase (ROCK) isoform-selective suppression or a ROCK inhibitor to analyze the roles of ROCK1 and ROCK2 in regulating endothelial dysfunction triggered by oxidized low-density lipoprotein (oxLDL). Methods: ROCK1 or ROCK2 expression in human umbilical vein endothelial cells (HUVECs) was suppressed by small interfering RNA (siRNA). HUVECs were pretreated with 30 μM Y27632 (pan ROCK inhibitor) for 30 min before exposure to 200 μg/mL oxLDL for an additional 24 h. Cell viability was determined by the MTT assay, and cell apoptosis was evaluated by the TUNEL assay. Protein expression and phosphorylation were assessed by Western blot analysis. The morphology of total and phosphorylated vimentin (p-vimentin) and the co-localization of vimentin with vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) were detected by the immunofluorescence assay. The adhesion of promonocytic U937 cells to HUVECs was observed by light microscopy. Results: ROCK2 suppression or Y27632 treatment, rather than ROCK1 deletion, effectively reduced endothelial cell apoptosis and preserved cell survival. ROCK2 suppression exhibited improved vimentin and p-vimentin cytoskeleton stability and decreased vimentin cleavage by attenuating caspase-3 activity. In addition, increased p-vimentin expression induced by oxLDL was significantly inhibited by ROCK2 deletion or Y27632 treatment. In contrast, ROCK1 suppression showed no obvious effects on the vimentin cytoskeleton, but significantly regulated the expression of adhesion molecules. Endothelial ICAM-1 or VCAM-1 expression induced by oxLDL was obviously inhibited by ROCK1 suppression or Y27632 treatment. Moreover, the expression of ICAM-1 induced by oxLDL could also be reduced by ROCK2 suppression. Furthermore, ROCK2 deficiency or Y27632 treatment inhibited the redistribution of adhesion molecules and their co-localization with vimentin caused by oxLDL. These effects resulted in the significant inhibition of monocyte-endothelial adhesion induced by oxLDL. Conclusion: The results of this study support the novel concept that ROCK1 is involved in oxLDL-induced cell adhesion by regulating adhesion molecule expression, whereas ROCK2 is required for both endothelial apoptosis and adhesion by regulating both the vimentin cytoskeleton and adhesion molecules. Consequently, ROCK1 and ROCK2 have distinct roles in the regulation of oxLDL-mediated endothelial dysfunction.

A new turn-on fluorescent chemosensor (RBTM) for Fe

Human Organic anion/cation transporters (OATs/OCTs), Organic anion transporting polypeptides (OATPs) and proton-coupled Oligopeptide transporters (PepTs) are important membrane transporters responsible of the cellular influx of drugs in many human key tissues. Inhibitor(s) impacting on the cellular uptake of transporter drug substrates is one of the primary causes of drug-drug interactions that lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In the current study, we selected eighteen antibiotic agents used in infectious disease treatment and comprehensively evaluated their inhibitory effects on the substrate uptake mediated through the essential OATs/OCTs, OATPs and PepTs isoforms. Transport functional assay, dose-response curve and kinetic analysis were performed on the HEK293 cells over-expressing each of these transporter genes. Our data revealed that nitrofurantoin, sulfadiazine and metronidazole significantly inhibited the transport activity of OAT3 (IC50 values of 6.23±1.33μM, 6.65±1.30μM and 6.51±0.99μM; Ki values of 5.86μM, 3.98μM and 6.48μM, respectively). Trimethoprim and ciprofloxacin potently decreased the substrate uptake mediated via OATP1A2 (IC50 values of 9.35±1.10μM and 9.25±1.18μM; Ki values of 8.19μM and 7.64μM, respectively). In addition, these antibiotic agents consistently decreased methotrexate influx via OAT3 and OATP1A2. In summary, our study is the first to show that nitrofurantoin, sulfadiazine and metronidazole are potent inhibitors of OAT3 and trimethoprim is a novel inhibitor of OATP1A2. Our study also provides new evidence for the drug-drug interactions of ciprofloxacin with OATP1A2 drug substrates like methotrexate. Therefore, precautions are required when co-administering these antibiotics with OAT3 or OATP1A2 drug substrates.

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 µM, better than 7.30 µM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 µM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

A new furfuran-based rhodamine B fluorescent probe (RBFF) has been designed and synthesized, and its sensing behavior towards various metal ions was evaluated via UV–vis and fluorescence spectroscopic techniques. RBFF exhibits a highly sensitive and selective “turn-on” fluorescent response toward Fe3+ ion and a fluorescence “turn-off” response when added B4O72− to the RBFF-Fe3+ in the EtOH/H2O solution (1:1, v/v, HEPES, 1 mM, pH 7.20). The detection limit of RBFF for Fe3+ was calculated to be 0.025 μM. The fluorescence microscopy experiment suggested that RBFF could also be served as a biological fluorescence probe for the detection of Fe3+ in human cervical carcinoma cells (HeLa).