CRISPR/Cas13a-based genome editing for establishing the detection method of H9N2 subtype avian influenza virus.

Avian influenza virus (AIV) subtype H9N2 has significantly threatened the poultry business in recent years by having become the predominant subtype in flocks of chickens, ducks, and pigeons. In addition, the public health aspects of H9N2 AIV pose a significant threat to humans. Early and rapid diagnosis of H9N2 AIV is therefore of great importance. In this study, a new method for the detection of H9N2 AIV based on fluorescence intensity was successfully established using CRISPR/Cas13a technology. The Cas13a protein was first expressed in a prokaryotic system and purified using nickel ion affinity chromatography, resulting in a high-purity Cas13a protein. The best RPA (recombinase polymerase amplification) primer pairs and crRNA were designed and screened, successfully constructing the detection of H9N2 AIV based on CRISPR/Cas13a technology. Optimal concentration of Cas13a and crRNA was determined to optimize the constructed assay. The sensitivity of the optimized detection system is excellent, with a minimum detection limit of 10° copies/µL and didn't react with other avian susceptible viruses, with excellent specificity. The detection method provides the basis for the field detection of the H9N2 AIV.

In situ imaging of intracellular miRNAs in tumour cells by branched hybridisation chain reaction.

The ability to visualise microRNA in situ is crucial for studying microRNAs, their microRNA-associated biological functions and disease diagnosis. Traditional fluorescence in situ hybridisation methods based on paraformaldehyde fixation of microRNAs suffer from release of microRNAs from cells, which limits the sensitivity of in situ hybridisation, making them unsuitable for the detection of small, low-abundance microRNAs. To reduce the loss, microRNAs were covalently cross-linked to proteins within cells by combining EDC and paraformaldehyde, and the target microRNA was used as the initiator chain for a branched hybridisation chain reaction to detect microRNA expression levels in situ. A simplified branched hybridisation chain reaction can be realised by coupling two hybridisation chain reaction circuits with a hairpin linker. Upon forming the primary hybridisation chain reaction product with extended sequence, this sequence reacts with the linker hairpin H3 to release the initiator sequence, resulting in the formation of numerous dendritic branched hybridisation chain reaction products. Imaging results show that this technique can detect microRNAs with high sensitivity and selectivity at both the single-cell and single-molecule levels. Compared with the traditional fluorescence in situ hybridisation technique, this method greatly improves the sensitivity and image resolution of in situ imaging detection. Therefore, we believe that the target-initiated branched hybridisation chain reaction based in situ detection method provides a reliable assay platform for analysing disease-related microRNA expression.

Elucidation of anti-pneumonia pharmacodynamic material basis and potential mechanisms of Xiebai San by combining spectrum-efficacy relationship and surface plasmon resonance.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiebai San (XBS), a classic Chinese prescription, has been used for the clinical treatment of pneumonia-related diseases for thousands of years. However, the anti-pneumonia pharmacodynamic material basis of XBS and its underlying mechanisms remain unclear. AIM OF THE STUDY: This study aimed to comprehensively investigate and verify the anti-pneumonia pharmacodynamic material basis and mechanisms of XBS. MATERIALS AND METHODS: This study explored the anti-pneumonia activity and key pneumonia targets of XBS in lipopolysaccharide (LPS)-induced zebrafish and RAW264.7 cells in vivo and in vitro through transcriptomics, western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The chemical fingerprint of XBS was established using high-performance liquid chromatography, and the similarities and areas of characteristic peaks of 15 batches of XBS were analyzed. Based on the spectrum-efficacy relationship, the potential anti-inflammatory components were screened according to their peak areas and efficacy using principal component analysis (PCA), bivariate correlation, and partial least squares regression analysis. Active components that bind to core targets were further screened based on surface plasmon resonance (SPR). The binding mode of proteins and components was simulated via molecular docking, which enabled the identification of the primary active components of XBS, thereby elucidating its anti-pneumonia properties. Finally, the anti-inflammatory activities of these components were verified in vitro. RESULTS: XBS decreased neutrophil aggregation in zebrafish and nitric oxide (NO) secretion in RAW264.7 cells as well as suppressed the release of downstream inflammatory cytokines such as iNOS, TNF-α, IL-1ß, IL-18, and CXCL10 related to TNF and JAK-STAT signaling pathways. The phosphorylation of IκBα, Akt, and Stat3 was alleviated after XBS in cells. The fingerprint similarities of 15 batches of XBS ranged from 0.381 to 0.994, with a large difference. A total of 15 characteristic peaks were identified, and the relative standard deviation of their peak areas ranged from 24.1% to 70.7%. The results of in vitro anti-inflammatory activities of 15 batches of XBS showed that all samples inhibited the expression levels of NO and nine inflammatory markers. The anti-inflammatory index of 15 batches of XBS was determined to be 0.69-0.96 based on transformation of the anti-inflammatory rate and composite index method via PCA. The spectrum-efficacy relationship model of 15 characteristic peak areas and the anti-inflammatory index showed that 7 main potential active components were related to the anti-inflammatory activity of XBS. Moreover, four components (mulberroside A, isoquercitrin, liquiritigenin, and glycyrrhizic acid) screened based on SPR had different affinities toward TNFR1, Akt1, and Stat3 proteins, and the binding modes were elucidated via molecular docking. Finally, in LPS-induced RAW264.7 cells, all four active components (at a concentration of 60 µM) significantly inhibited the expression levels of NO and inflammatory markers. CONCLUSIONS: Based on the comprehensive strategy of spectrum-efficacy relationship and SPR, mulberroside A, isoquercitrin, liquiritigenin, and glycyrrhizic acid were identified as the primary pharmacodynamic active components involved in the anti-pneumonia activity of XBS and were found to intervene in TNF and JAK-STAT signaling pathways.

Geniposide alleviates heart failure with preserved ejection fraction in mice by regulating cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3ß, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 µM) significantly alleviated H2O2-induced oxidative stress through the MMP2/SIRT1/GSK3ß pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3ß, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3ß signaling pathway.

[Analysis of Ozone and VOCs Pollution Characteristics, Sources, and Abatement Control Strategies in Hebi].

In order to control the increasing ozone （O3） pollution in Hebi, Henan Province, clarifying the pollution characteristics of ozone and its precursors is vital. Therefore, we conducted a comprehensive analysis of O3 pollution utilizing the OFP-PMF-EKMA method combined with online hourly resolution monitoring data of conventional pollutants and volatile organic compounds （VOCs） in the summer of 2022 （June-September）. Ozone formation potential （OFP） was used to identify the key VOCs species, and the PMF model was used to identify the VOCs emission sources, whereas EKMA curves and scenario analysis were used to identify the main ozone control area in Hebi and to determine the reduction ratio of VOCs and NOx in a scientifically refined way. In 2022, Hebi had persistent O3 pollution, with the highest concentration in June. Conditions of high temperature, low humidity, and low atmospheric pressure contributed to the O3 accumulation. Aromatic and oxygenated volatile organic compounds （OVOCs） contributed significantly to the OFP and VOCs fraction, which were the dominant active substance and concentration dominant species. The results of the VOCs source analysis indicated that vehicle exhaust sources （25.3%） were the main source of atmospheric VOCs, followed by process sources （17.7%） and biomass combustion sources （17.6%）. Thus, emission sources associated with the combustion of fossil fuels and industrial production emissions were the most urgent sources of atmospheric VOCs to be controlled in Hebi. The O3 generation in Hebi occurred in the VOCs-sensitive zones, and the emission reduction results showed that a synergistic emission reduction of VOCs and nitrogen oxide （NOx） could effectively control O3 pollution with a 75% reduction in VOCs and a 10% reduction in NOx.

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

Identification and bioactivity evaluation of twelve previously undescribed depsidone derivatives from Garcinia oligantha.

Phytochemical studies on the leaves and twigs of Garcinia oligantha Merr. led to the isolation of twelve previously undescribed depsidone derivatives (oliganthdepsidones A-L, 1-12). Their structures were elucidated by extensive spectroscopic analysis including 1H and 13C NMR, HSQC, HMBC and NOESY along with HRESIMS. The structures of oliganthdepsidones G and J were finally determined using DFT-NMR chemical shift calculations and DP4+ methods. Cytotoxicity test in four human cancer cell lines indicated that oliganthdepsidone F had relatively strong cytotoxic effect against A375 (melanoma), A549 (lung cancer), HepG2 (liver cancer), and MCF-7 (breast cancer) cell lines with IC50 of 18.71, 15.44, 10.92, and 15.90 µM, respectively. The dose- and time-dependent antiproliferative effects of oliganthdepsidone F on these cell lines were also observed by CCK-8 test. As determined by fluorescent microscopy and flow cytometry in these cell lines, oliganthdepsidone F could promote cell apoptosis, leading to the inhibition of cell proliferation. The results of wound healing assay and transwell assay showed that oliganthdepsidone F could inhibit the migration and invasion of A549 and MCF-7 cell lines in a concentration-dependent manner.

Eikenella corrodens isolated from pleural effusion: A case report.

BACKGROUND: The bacterium Eikenella, classified as a gram-negative member of the phylum Proteobacteria, is distinguished by its rarity, corrosive nature, facultative anaerobic properties, and conditional pathogenicity. It represents the sole species within its genus-Eikenella corrodens (E. corrodens)-and can be found colonizing both human and animal oral and nasopharyngeal regions. Additionally, it occasionally inhabits the gastrointestinal or urogenital tracts. However, its slow growth rate can be attributed to its high nutritional requirements. However, there is an uneven distribution of construction and diagnostic capacity in China which poses undeniable challenges for the clinical examination and analysis of this case, especially in the basic hospitals. CASE SUMMARY: Here we presented a case of empyema associated with E. corrodens infection in a 67-year-old male patient without any previous history of infectious diseases in our primary hospital in Dongguan district of China. The patient was admitted due to recurrent worsening cough, sputum production, and dyspnea for 3 d, which had persisted for over 20 years. Moreover, the patient experienced a one-hour episode of unconsciousness. Upon admission, immediate comprehensive examinations were conducted on the patient which subsequently led to his admission to the intensive care unit. Meanwhile, the patient presented with drowsiness and profuse sweating along with bilateral conjunctival edema observed during initiation of non-invasive ventilation, suggesting empyema. A significant amount of coffee-colored malodorous pleural fluid was drained during the procedure above and sent to the laboratory department for inspection. Finally, laboratory culture results confirmed the presence of E. corrodens infection in the pleural fluid sample. The patient received antimicrobial therapy until died on day 22 in the hospital. CONCLUSION: In this report, we presented a case of empyema associated with E. corrodens infection. Multiple courses of morphological examination, viable culture analysis, and biochemical identification revealed its difficulties in detecting distinctive characteristics, as well as a detection model worth promoting. It's just that there were still certain deficiencies in terms of morphological assessment, biochemical identification, and drug susceptibility testing.

Microplastic dilemma: Assessing the unexpected trade-offs between biodegradable and non-biodegradable forms on plant health, cadmium uptake, and sediment microbial ecology.

Despite extensive substitution of biodegradable plastics (BPs) for conventional plastics (CPs), research on their environmental ecological consequences as microplastics (MPs) is scarce. This study aimed to fill this gap by investigating the impacts of six prototypical MPs (categorized into BMPs and CMPs) on plant growth, cadmium (Cd) translocation, and bacterial communities in contaminated sediments. Results showed both BMPs and CMPs hindered plant development; yet interestingly, BMPs provoked more pronounced physiological and biochemical changes alongside increased oxidative stress due to reactive oxygen species accumulation. Notably, most MP types promoted the absorption of Cd by plant roots potentially via a "dilution effect". BMPs also induced larger shifts in soil microbial metabolic functions compared to CMPs. Ramlibacter was identified as a key biomarker distinguishing BMPs from CMPs, with link to multiple N metabolic pathways and N assimilation. This study offers novel insights into intricate biochemical mechanisms and environmental chemistry behaviors underpinning MP-Cd interactions within the plant-microbe-sediment system, emphasizing BMPs' higher potential ecological risks based on their significant effects on plant health and microbial ecology. This work contributes to enhancing the comprehensive understanding of their ecological implications and potential threats to environmental security.

Case report: A novel compound heterozygous variant in the COL4A3 gene was identified in a patient with autosomal recessive Alport syndrome.

Alport syndrome (AS), a hereditary kidney disease with a high risk for renal failure, is attributed to pathogenic variants in genes COL4A3, COL4A4, and COL4A5 that encode type IV collagen. Next-generation sequencing (NGS) is increasingly applied to the diagnosis of AS, but complex genotype-phenotype correlation, that is, identifying the significance of variants, is still a huge clinical challenge. In this study, we reported the case of a 27-year-old Chinese woman with a family history of hematuria and proteinuria. Notably, the proband is the only one in her family with renal insufficiency. NGS was performed in this family, and it was revealed that the proband was a compound heterozygote for two variants in the COL4A3 gene: c.2990G>A inherited from her father and c.4981C>T inherited from her mother. We modeled the spatial structure of the corresponding protein and assumed that structural abnormalities led to the breakdown of type IV collagen networks, a major component of the glomerular basement membrane. Thus, the proband was diagnosed with autosomal recessive AS, characterized by severe defects of the glomerular basement membrane. Hence, the proband showed a loss of renal function. This case presentation emphasizes the importance of NGS for AS diagnosis and introduces a novel genotype of AS.

Carbonized wood fiber-supported S, N-codoped carbon layer-coated multinary metal sulfide nanoarchitecture for efficient oxygen evolution reaction at ampere-level current density.

Multinary metal sulfides (MMSs) are highly suitable candidates for the application of electrocatalysis as they offer numerous parameters for optimizing the electronic structure and catalytic sites. Herein, a stable nanoarchitecture consisting of MMSs ((NiCoCrMnFe)Sx) nanoparticles embedded in S, N-codoped carbon (SNC) layers derived from metal organic framework (MOF) and supported on carbonized wood fibers (CWF) was fabricated by directly carbonization. Benefiting from this carbon-coated configuration, along with the synergistic effects within multinary metal systems, (NiCoCrMnFe)Sx@SNC/CWF delivers an exceptionally low overpotential of 260 mV at a high current density of 1000 mA cm-2, a small Tafel slope of 48.5 mV dec-1, and robust electrocatalytic stability. Furthermore, the (NiCoCrMnFe)Sx@SNC/CWF used as the cathode of rechargeable Zn-air batteries demonstrates higher power density and remarkable durability, surpassing that of commercial RuO2. Thus, we showcase the feasibility and advantages of employing highly efficient and durable MMSs materials for low-cost and sustainable energy conversion.

ARL13B promotes cell cycle through the sonic hedgehog signaling pathway to alleviate nerve damage during cerebral ischemia/reperfusion in rats.

Cerebral ischemia/reperfusion (CIRI) is a leading cause of death worldwide. A small GTPase known as ADP-ribosylation factor-like protein 13B (ARL13B) is essential in several illnesses. The role of ARL13B in CIRI remains unknown, though. A middle cerebral artery occlusion/reperfusion (MCAO/R) in rats as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) models in PC12 cells were constructed. The neuroprotective effects of ARL13B against MCAO/R were evaluated using neurological scores, TTC staining, rotarod testing, H&E staining, and Nissl staining. To detect the expression of proteins associated with the SHH pathway and apoptosis, western blotting and immunofluorescence were employed. Apoptosis was detected using TUNEL assays and flow cytometry. There was increased expression of ARL13B in cerebral ischemia/reperfusion models. However, ARL13B knockdown aggravated CIRI nerve injury by inhibiting the sonic hedgehog (SHH) pathway. In addition, the use of SHH pathway agonist (SAG) can increased ARL13B expression, reverse the effects of ARL13B knockdown exacerbating CIRI nerve injury. ARL13B alleviated cerebral infarction and pathological injury and played a protective role against MCAO/R. Furthermore, ARL13B significantly increased the expression of SHH pathway-related proteins and the anti-apoptotic protein BCL-2, while decreased the expression of pro-apoptotic protein BAX, thus reducing apoptosis. The results from the OGD/R model in PC12 cells were consistent with those obtained in vivo. Surprisingly, we demonstrated that ARL13B regulates the cell cycle to protect against CIRI nerve injury. Our findings indicate that ARL13B protects against CIRI by reducing apoptosis through SHH-dependent pathway activation, and suggest that ARL13B plays a crucial role in CIRI pathogenesis.

Iron Plaque: A Shield against Soil Contamination and Key to Sustainable Agriculture.

Soils play a dominant role in supporting the survival and growth of crops and they are also extremely important for human health and food safety. At present, the contamination of soil by heavy metals remains a globally concerning environmental issue that needs to be resolved. In the environment, iron plaque, naturally occurring on the root surface of wetland plants, is found to be equipped with an excellent ability at blocking the migration of heavy metals from soils to plants, which can be further developed as an environmentally friendly strategy for soil remediation to ensure food security. Because of its large surface-to-volume porous structure, iron plaque exhibits high binding affinity to heavy metals. Moreover, iron plaque can be seen as a reservoir to store nutrients to support the growth of plants. In this review, the formation process of iron plaque, the ecological role that iron plaque plays in the environment and the interaction between iron plaque, plants and microbes, are summarized.

The Surface Confinement of FeO Assists in the Generation of Singlet Oxygen and High-Valent Metal-Oxo Species for Enhanced Fenton-Like Catalysis.

Transition metal compounds (TMCs) have long been potential candidate catalysts in persulfate-based advanced oxidation process (PS-AOPs) due to their Fenton-like catalyze ability for radical generation. However, the mechanism involved in TMCs-catalyzed nonradical PS-AOPs remains obscure. Herein, the growth of FeO on the Fe3O4/carbon precursor is regulated by restricted pyrolysis of MIL-88A template to activate peroxymonosulfate (PMS) for tetracycline (TC) removal. The higher FeO incorporation conferred a 2.6 times higher degradation performance than that catalyzed by Fe3O4 and also a higher interference resistance to anions or natural organic matter. Unexpectedly, the quenching experiment, probe method, and electron paramagnetic resonance quantitatively revealed that the FeO reassigned high nonradical species (1O2 and FeIV═O) generation to replace original radical system created by Fe3O4. Density functional theory calculation interpreted that PMS molecular on strongly-adsorbed (200) and (220) facets of FeO enjoyed unique polarized electronic reception for surface confinement effect, thus the retained peroxide bond energetically supported the production of 1O2 and FeIV═O. This work promotes the mechanism understanding of TMCs-induced surface-catalyzed persulfate activation and enables them better perform catalytic properties in wastewater treatment.

Complete genome sequence of Pseudomonas aeruginosa L3, a bacterium with Mn(II) oxidative property isolated from heavy metal-contaminated soils.

Pseudomonas aeruginosa L3, isolated from heavy metal-contaminated soils, possesses the ability of Mn(II) oxidation. To further enhance the understanding of genes involved in Mn(II) oxidation, the complete genome of this strain was sequenced and annotated, which has a total size of 6.39 Mb with a G + C content of 66.39%.

Effects of aquatic exercise intervention on executive function and brain-derived neurotrophic factor of children with autism spectrum disorder.

BACKGROUND: Limited knowledge exists regarding the effectiveness of aquatic exercise intervention for improving executive function (EF) in children with autism spectrum disorder (ASD). Additionally, the impact of aquatic exercise on brain-derived neurotrophic factor (BDNF) in children with ASD requires further investigation. AIMS: This study aimed to explore the effects of a 12-week aquatic exercise intervention on core EF and BDNF levels in children with ASD. METHODS AND PROCEDURES: Thirty children with ASD were assigned to an experimental or control group. The experimental group underwent a 12-week aquatic exercise intervention, while the control group engaged in supervised free activities. Pre- and post-intervention assessments measured EF and BDNF levels. OUTCOMES AND RESULTS: The experimental group showed significant improvements (p < 0.05) in inhibition control, cognitive flexibility, and BDNF levels. However, working memory did not significantly improve. The control group exhibited no significant changes in EF or BDNF levels. CONCLUSIONS AND IMPLICATIONS: Aquatic exercise appears to be a beneficial intervention for cognitive development in children with ASD, as it enhances inhibition control, cognitive flexibility, and BDNF levels in children with ASD. Furthermore, the observed improvements in EF following aquatic exercise intervention in children with ASD may be associated with increased BDNF levels.

Design and Synthesis of Marine Polybrominated Diphenyl Ether Derivatives as Potential Anti-Inflammatory Agents.

Natural polybrominated diphenyl ethers are generally isolated from sponges and possess a broad range of biological activities. Through screening of our marine natural product library, we discovered that polybrominated diphenyl ethers 5 and 6 exhibit considerable anti-inflammatory activity. In order to expand our repertoire of derivatives for further biological activity studies, we designed and synthesized a series of 5-related polybrominated diphenyl ethers. Importantly, compound 5a showed comparable anti-inflammatory activity while much lower cytotoxicity on lipopolysaccharide (LPS)-induced RAW264.7 cells. Additionally, western blotting analysis showed that 5a reduced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK). Besides, molecular docking experiments were conducted to predict and elucidate the potential mechanisms underlying the varying anti-inflammatory activities exhibited by compounds 5a, 5, and 6.

Doped Cu0 and sulfidation induced transition from R-O• to •OH in peracetic acid activation by sulfidated nano zero-valent iron-copper.

Peracetic acid (PAA) has emerged as a new effective oxidant for various contaminants degradation through advanced oxidation process (AOP). In this study, sulfidated nano zero-valent iron-copper (S-nZVIC) with low Cu doping and sulfidation was synthesized for PAA activation, resulting in more efficient degradation of sulfamethoxazole (SMX, 20 µM) and other contaminants using a low dose of catalyst (0.05 g/L) and oxidant (100 µM). The characterization results suggested that S-nZVIC presented a more uniform size and distribution with fewer metal oxides, as the agglomeration and oxidation were inhibited. More significantly, doped Cu0 and sulfidation significantly enhanced the generation and contribution of •OH but decreased that of R-O• in S-nZVIC/PAA/SMX system compared with that of nZVIC and S-nZVI, accounting for the relatively high degradation efficiency of 97.7% in S-nZVIC/PAA/SMX system compared with 85.7% and 78.9% in nZVIC/PAA/SMX and S-nZVI/PAA/SMX system, respectively. The mechanisms underlying these changes were that (i) doped Cu° could promote the regeneration of Fe(Ⅱ) for strengthened PAA activation through mediating Fe(Ⅱ)/Fe(Ⅲ) cycle by Cu(Ⅰ)/Cu(Ⅱ) cycle; (ii) S species might consume part of R-O•, resulting in a decreased contribution of R-O• in SMX degradation; (iii) sulfidation increased the electrical conductivity, thus facilitating the electron transfer from S-nZVIC to PAA. Consequently, the dominant reactive oxygen species transited from R-O• to •OH to degrade SMX more efficiently. The degradation pathways, intermediate products and toxicity were further analyzed through density functional theory (DFT) calculations, liquid chromatography-mass spectrometry (LC-MS) and T.E.S.T software analysis, which proved the environmental friendliness of this process. In addition, S-nZVIC exhibited high stability, recyclability and degradation efficiency over a wide pH range (3.0∼9.0). This work provides a new insight into the rational design and modification of nano zero-valent metals for efficient wastewater treatment through adjusting the dominant reactive oxygen species (ROS) into the more active free radicals.

Uterine Commensal Peptostreptococcus Species Contribute to IDO1 Induction in Endometrial Cancer via Indoleacrylic Acid.

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition.

BACKGROUND: SGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in SGLT2i effects on cardiac hypertrophy. METHODS: Isolated hearts from db/db mice were perfused with 1 µM EMPA, and STK phosphorylation sites were examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced in H9c2 cells with 50 µM phenylephrine (PE), and the role of the most affected STK (p90 ribosomal S6 kinase (RSK)) and NHE1 activity in hypertrophy and the protection by EMPA was evaluated. RESULTS: In db/db mice hearts, EMPA most markedly reduced STK phosphorylation sites regulated by RSKL1, a member of the RSK family, and by Aurora A and B kinases. GO and KEGG analysis suggested that EMPA inhibits hypertrophy, cell cycle, cell senescence and FOXO pathways, illustrating inhibition of growth pathways. EMPA prevented PE-induced hypertrophy as evaluated by BNP and cell surface area in H9c2 cells. EMPA blocked PE-induced activation of NHE1. The specific NHE1 inhibitor Cariporide also prevented PE-induced hypertrophy without added effect of EMPA. EMPA blocked PE-induced RSK phosphorylation. The RSK inhibitor BIX02565 also suppressed PE-induced hypertrophy without added effect of EMPA. Cariporide mimicked EMPA's effects on PE-treated RSK phosphorylation. BIX02565 decreased PE-induced NHE1 activity, with no further decrease by EMPA. CONCLUSIONS: RSK inhibition by EMPA appears as a novel direct cardiac target of SGLT2i. Direct cardiac effects of EMPA exert their anti-hypertrophic effect through NHE-inhibition and subsequent RSK pathway inhibition.