A(CoFe)(S2)2/CoFe heterostructure constructed in S, N co-doped carbon nanotubes as an efficient oxygen electrocatalyst for zinc-air battery.

Transition metal alloys can exhibit synergistic intermetallic effects to obtain high activities for oxygen reduction/evolution reactions (ORR/OER). However, due to the insufficient stability of active sites in alkaline electrolytes, conventional alloy catalysts still do not meet practical needs. Herein, by using polypyrrole tubes and cobalt-iron (CoFe) Prussian blue analogs as precursors, CoFe sulfides is in-situ formed on CoFe alloys to construct (CoFe)(S2)2/CoFe heterostructure in sulfur (S) and nitrogen (N) co-doped carbon nanotubes (CoFe@NCNTs-nS) via a low-temperature sulfidation strategy. The as-marked CoFe@NCNTs-12.5S exhibits a comparable ORR activity (half-wave potential of 0.901 V) to Pt/C (0.903 V) and a superior OER activity (overpotential of 272 mV at 10 mA cm-2) to RuO2 (299 mV). CoFe@NCNTs-12.5S also exhibits ultralow charge transfer resistances (ORR-6.36 Ω and OER-0.21 Ω) and an excellent potential difference of 0.617 V. The sulfidation-induced (CoFe)(S2)2/CoFe heterojunctions can accelerate interfacial charge transfer process. Tubular structure not only disperses the (CoFe)(S2)2/CoFe heterostructure, but also reduces the corrosion of active-sites to enhance catalysis stability. Zinc-air battery with CoFe@NCNTs-12.5S achieves a high specific capacity (718.1 mAh g-1), maintaining a voltage gap of 0.957 V after 400 h. This work reveals the potential of interface engineering for boosting ORR/OER activities of alloys via in-situ heterogenization.

Exosomes and Macrophages: Bidirectional Mutual Regulation in the Treatment of Diabetic Complications.

Purpose: The bidirectional regulation of macrophages and exosomes provides a meaningful research direction for the treatment of complications arising from both type 1 and type 2 diabetes mellitus. However, there is currently no comprehensive evaluation of the bidirectional regulatory role of macrophages and exosomes in diabetic complications. In this review, we aim to provide the detailed process of the bidirectional regulation mechanism of macrophages and exosomes, and how macrophage-associated exosomes use this mechanism to make it better applied to clinical practice through biotechnology. Methods: Therefore, we summarized the bidirectional regulation mechanism of macrophages and exosomes and the application based on the bidirectional regulation mechanism from two aspects of inflammation and insulin resistance. Results: As key regulators of the immune system, macrophages are crucial in the progression of diabetic complications due to their significant impact on the regulation of cellular metabolism, inflammation, and insulin sensitivity. Furthermore, exosomes, as innovative mediators of intercellular communication, transport miRNAs, proteins, and various bioactive molecules, influencing the occurrence and progression of diabetic complications through the regulation of inflammation and insulin resistance. The bidirectional regulation between macrophages and exosomes provides a promising pathway for the treatment of diabetic complications aimed at regulating the immune response and improving insulin sensitivity. Conclusions: Understanding the complexity of the interaction between macrophages and exosomes can advance the treatment of diabetic complications and drug development, and bringing more innovative and effective treatment strategies for diabetic complications.

Scoulerine: A natural isoquinoline alkaloid targeting SLC6A3 to treat RCC.

Scoulerine, an isoquinoline alkaloid derived from the corydalis plant, exhibits diverse therapeutic properties against tumors, Alzheimer's disease, and inflammation. This research delves into the pharmacological impact and underlying mechanism of scoulerine on renal cell carcinoma (RCC). Our findings suggest that Scoulerine displays promise as a potential therapeutic agent for RCC, demonstrating notable inhibitory effects in both in vivo and in vitro models. In addition, scoulerine inhibited the viability of 769-P and 786-O cell lines in a time-dependent and dose-dependent manner, and promoted the level of apoptosis associated with B-cell lymphoma-2 associated X protein (Bax). Moreover, the administration of scoulerine resulted in a significant suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Subsequently, utilizing bioinformatics and spatial transcriptomic databases, we identified solute carrier family 6 Member 3 (SLC6A3) as the most promising target of scoulerine. Through experimental validation, we confirmed the functional and therapeutic relevance of SLC6A3 in scoulerine-mediated treatment of RCC. The results of our study indicate a significant affinity between scoulerine and SLC6A3, with competitive inhibition of this interaction leading to a reduction in the inhibitory impact of scoulerine on RCC cell viability. In conclusion, our findings suggest that scoulerine may induce apoptosis in RCC by targeting SLC6A3 and inhibiting the activation of the MAPK signaling pathway, thereby positioning it as a promising natural compound for potential future RCC treatment.

Intrinsic functional defects in B cells of patients with NFKB2 mutations.

Mutations in the human nuclear factor-κB2 gene (NFKB2) are associated with common variable immunodeficiency (CVID) or combined immunodeficiency diseases (CID), characterized by B-cell lymphopenia, hypogammaglobulinemia, and T cell dysfunction. This study investigated whether B cells with NFKB2 mutations exhibit intrinsic impairments in activation, class-switch recombination, and differentiation. We analyzed five patients from four unrelated families with CVID, each carrying a heterozygous NFKB2 mutation: P1 (C.2595_2614del, p.A867Gfs*12), P2 (C.2597G>A, p.S866N), P3 (C.2540dupT, p.R848Efs*38), and P4 and P5 (C.2570_2571insCAGCACA, p.A860Qfs*28). The patients with frameshift mutations (P1, P3, P4, and P5) exhibited truncated proteins detectable in their peripheral blood mononuclear cells, while P2 had a missense mutation. All identified mutations disrupted the processing of p100 into the active p52 form, resulting in NF-κB2 loss-of-function and IκBδ gain-of-function. Clinically, P1, P2, and P3 exhibited B-cell lymphopenia, and all five patients presented with hypogammaglobulinemia. Notably, P2 exhibited a markedly low B-cell count, associated with increased proportions of memory B and IgD-CD27- double negative B cells. In vitro experiments with naïve B cells from P1 and P4 demonstrated decreased survival, impaired activation, and reduced differentiation into CD27+IgD- cells and plasmablasts, while class switch recombination was unaffected. These findings reveal novel B cell-intrinsic functional defects in patients with NFKB2 mutations.

Vascular Biomarkers for Pulmonary Nodule Malignancy: Arteries vs. Veins.

OBJECTIVE: This study aims to investigate the association between the arteries and veins surrounding a pulmonary nodule and its malignancy. METHODS: A dataset of 146 subjects from a LDCT lung cancer screening program was used in this study. AI algorithms were used to automatically segment and quantify nodules and their surrounding macro-vasculature. The macro-vasculature was differentiated into arteries and veins. Vessel branch count, volume, and tortuosity were quantified for arteries and veins at different distances from the nodule surface. Univariate and multivariate logistic regression (LR) analyses were performed, with a special emphasis on the nodules with diameters ranging from 8 to 20 mm. ROC-AUC was used to assess the performance based on the k-fold cross-validation method. Average feature importance was evaluated in several machine learning models. RESULTS: The LR models using macro-vasculature features achieved an AUC of 0.78 (95% CI: 0.71-0.86) for all nodules and an AUC of 0.67 (95% CI: 0.54-0.80) for nodules between 8-20 mm. Models including macro-vasculature features, demographics, and CT-derived nodule features yielded an AUC of 0.91 (95% CI: 0.87-0.96) for all nodules and an AUC of 0.82 (95% CI: 0.71-0.92) for nodules between 8-20 mm. In terms of feature importance, arteries within 5.0 mm from the nodule surface were the highest-ranked among macro-vasculature features and retained their significance even with the inclusion of demographics and CT-derived nodule features. CONCLUSIONS: Arteries within 5.0 mm from the nodule surface emerged as a potential biomarker for effectively discriminating between malignant and benign nodules.

Gut microbiome and metabolites mediate the benefits of caloric restriction in mice after acute kidney injury.

The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii (P. goldsteinii) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii. Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI.

Nesfatin-1 enhances vascular smooth muscle calcification through facilitating BMP-2 osteogenic signaling.

Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

Unveiling the Mechanism of Liangxue Siwu Decoction in Treating Rosacea Through Network Pharmacology and in-vitro Experimental Validation.

Background: Rosacea, a recurring dermatological disorder, demands effective therapeutic approaches. Traditional Chinese medicine, particularly Liangxue Siwu Decoction (LXSWD), has shown promise in managing inflammatory skin diseases, such as rosacea. This study focuses on uncovering LXSWD's specific effects on the inflammatory symptoms of rosacea. Objective: Our research investigates LXSWD's therapeutic effectiveness in rosacea treatment and delves into its underlying mechanisms. Methods: Network pharmacology was utilized to identify LXSWD's key components and their targets in rosacea management, which were then validated by molecular docking. An in vivo rosacea-like model in LL-37-induced mice was developed, subdividing them into control, model, and LXSWD groups. The LXSWD group received oral administration (25.0 g/kg/day) for six days before model induction. Post-treatment evaluations included skin tissue analyses to verify our network pharmacology predictions. Results: Key active ingredients in LXSWD, such as quercetin, kaempferol, and luteolin, were identified alongside central target proteins like TNF and MMPs. Our molecular docking study confirmed the interactions between these ingredients and targets. Analyses through GO and KEGG pathways indicated LXSWD's role in mitigating inflammation, particularly influencing the TNF and IL-17 pathways. LXSWD treatment in vivo markedly alleviated LL-37-induced symptoms in mice, showing a marked reduction in inflammatory cytokines (p < 0.05) and modulation of crucial genes (p < 0.05). These results, supported by immunofluorescence analysis and Western blot, underline the modulatory effects of LXSWD on MMPs, offering significant protection against rosacea's inflammation alterations (p < 0.05). Conclusion: Integrating network pharmacology, molecular docking, and in vivo experiments, this study elucidates LXSWD's potential mechanisms in rosacea treatment. It offers a novel theoretical framework for its clinical use in managing rosacea.

Self-enhanced PTX@HSA-HA loaded functionalized injectable hydrogel for effective local chemo-photothermal therapy in breast cancer.

Breast cancer is a malignant tumor that poses a significant threat to women's health and single therapy fails to play a good oncological therapeutic effect. Synergistic treatment with multiple strategies may make up for the deficiencies and has gained widespread attention. In this study, sulfhydryl-modified hyaluronic acid (HA-SH) was covalently crosslinked with polydopamine (PDA) via a Michael addition reaction to develop an injectable hydrogel, in which PDA can be used not only as a matrix but also as a photothermal agent. After HSA and paclitaxel were spontaneously organized into nanoparticles via hydrophobic interaction, hyaluronic acid with low molecular weight was covalently linked to HSA, thus conferring effectively delivery. This photothermal injectable hydrogel incorporates PTX@HSA-HA nanoparticles, thereby initiating a thermochemotherapeutic response to target malignancy. Our results demonstrated that this injectable hydrogel possesses consistent drug delivery capability in a murine breast cancer model, collaborating with photothermal therapy to effectively suppress tumor growth, represented by low expression of Ki-67 and increasing apoptosis. Photothermal therapy (PTT) can effectively stimulate immune response by increasing IL-6 and TNF-α. Notably, the treatment did not elicit any indications of toxicity. This injectable hydrogel holds significant promise as a multifaceted therapeutic agent that integrates photothermal and chemotherapeutic modalities.

A novel formula for representing the equivalent resistance of the m × n cylindrical resistor network.

The problem of solving the equivalent resistance between two points for resistor networks has important significance in physics. This paper mainly changes and rewrites the formula for calculating the resistance between two points of an unconventional m × n cylindrical resistor network with a zero resistor axis and any two left and right boundaries. To enhance the efficiency of calculating the equivalent resistance between two points, Chebyshev polynomials and hyperbolic cosine functions are employed to represent the new formula. And in the inference process, the famous discrete cosine transform of the third kind (DCT-III) is used to process the matrix. We give the equivalent resistance formula for several special cases, and display them by a three-dimensional graph. Subsequently, the calculation efficiency of the original formula and the rewritten formula are compared. At the end of the paper, a heuristic algorithm suitable for robot path planning on cylindrical environment is proposed.

Effects of attentional focus strategies in drop landing biomechanics of individuals with unilateral functional ankle instability.

Background: Functional Ankle Instability (FAI) is a pervasive condition that can emerge following inadequate management of lateral ankle sprains. It is hallmarked by chronic joint instability and a subsequent deterioration in physical performance. The modulation of motor patterns through attentional focus is a well-established concept in the realm of motor learning and performance optimization. However, the precise manner in which attentional focus can rehabilitate or refine movement patterns in individuals with FAI remains to be fully elucidated. Objective: The primary aim of this study was to evaluate the impact of attentional focus strategies on the biomechanics of single-leg drop landing movements among individuals with FAI. Methods: Eighteen males with unilateral FAI were recruited. Kinematic and kinetic data were collected using an infrared three-dimensional motion capture system and force plates. Participants performed single-leg drop landing tasks under no focus (baseline), internal focus (IF), and external focus (EF) conditions. Biomechanical characteristics, including joint angles, ground reaction forces, and leg stiffness, were assessed. A 2 × 3 [side (unstable and stable) × focus (baseline, IF, and EF)] Repeated Measures Analysis of Variance (RM-ANOVA) analyzed the effects of attentional focus on biomechanical variables in individuals with FAI. Results: No significant interaction effects were observed in this study. At peak vertical ground reaction force (vGRF), the knee flexion angle was significantly influenced by attentional focus, with a markedly greater angle under EF compared to IF (p < 0.001). Additionally, at peak vGRF, the ankle joint plantarflexion angle was significantly smaller with EF than with IF (p < 0.001). Significant main effects of focus were found for peak vGRF and the time to reach peak vGRF, with higher peak vGRF values observed under baseline and IF conditions compared to EF (p < 0.001). Participants reached peak vGRF more quickly under IF (p < 0.001). Leg Stiffness (kleg) was significantly higher under IF compared to EF (p = 0.001). Conclusion: IF enhances joint stability in FAI, whereas EF promotes a conservative landing strategy with increased knee flexion, dispersing impact and minimizing joint stress. Integrating these strategies into FAI rehabilitation programs can optimize lower limb biomechanics and reduce the risk of reinjury.

Development of a fast fluorescent probe for sensitive detection of glutathione in 100 % aqueous solution and its applications in real samples, oxidative stress model and ferroptosis model.

Glutathione (GSH) plays a crucial role in several physiological processes, including anti-oxidation and heavy metal detoxification. GSH is produced endogenously in the human body and can also be obtained through diet. The development of fast, highly sensitive, and multi-application fluorescent probes remains a challenging task. In this study, we have designed and synthesized a coumarin-based fluorescent probe (NFRF) for the sensitive and rapid detection of GSH in 100 % aqueous solution. By loading probe NFRF on the filter paper, the real-time visual detection of GSH is achieved in both daylight and fluorescence modes, providing a convenient, economical and rapid on-site detection tool. Probe NFRF could be used for the detection of GSH in real samples, with recoveries rates of 81.74 %-115.12 %. Notably, the probe imaged changes in GSH concentrations in oxidative stress environments and during ferroptosis. This work provides a prospective method for GSH detection in food and complex biological systems.

mhealth-based interventions to improving liver cancer screening among high-risk populations: a study protocol for a randomized controlled trial.

BACKGROUND: Liver cancer (LC) screening, such as AFP test and abdominal ultrasound, is an effective way to prevent LC, one of the most common cancers worldwide. Despite the proven screening benefits, screening participation among high-risk populations for LC remains low. This suggests that targeted, systematic, and effective interventions should be provided to improve knowledge and awareness related to LC screening, enhance screening intentions, and thereby promote screening behaviors. Telephone is people's main medium of daily communication and mHealth-based programs offer a potential and effective solution for promoting health behaviors. The purpose of this study is to develop and implement a mHealth (WeChat app) based intervention guided by Fogg's Behavior Model (FBM) to augment the knowledge of LC prevention among people at risk of LC and enhance their motivation for screening, and to validate its effectiveness in improving LC screening. METHODS: We propose a two-arm, single-blind randomized controlled trial with 82 at-risk individuals of LC, delivering a 6-month mHealth-based intervention program with optional health counseling. Recruitment will be through tertiary hospitals and community organizations in 4 districts in Heng Yang. In total, 82 individuals at high risk for HCC will be randomized 1:1 to intervention or control (usual care) groups. The intervention group will receive intervention, whose contents are based on the FBM model, via multiple forms of media including PowerPoint presentation, multimedia video, health information booklet and screening message, which is delivered in the WeChat Applet. Control dyads will be provided with usual health education. Outcomes will be assessed at baseline and post-intervention. DISCUSSION: The findings of this study will provide evidence of the benefits of utilizing mHealth-based approaches in intervention development to enhance the effectiveness of screening adherence for high-risk people of LC. Further, the findings would provide reference to the potential incorporation of the targeted intervention in local community organizations. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2400080530) Date registered: 31/1/2024.

Successive Years of Rice Straw Return Increased the Rice Yield and Soil Nutrients While Decreasing the Greenhouse Gas Intensity.

Straw return has important impacts on black soil protection, food security, and environmental protection. One year of straw return (S1) reduces rice yield and increases greenhouse gas (GHG) emissions. However, the effects of successive years of straw return on rice yield, soil nutrients, and GHG emissions in the northeast rice region are still unclear. Therefore, we conducted four successive years of straw return (S4) in a positional experiment to investigate the effects of different years of straw return on rice yield, soil nutrients, and GHG emissions in the northeast rice region. The experimental treatments included the following: no straw return (S0), a year of straw return (S1), two successive years of straw return (S2), three successive years of straw return (S3), and four successive years of straw return (S4). Compared with S1, the rice yields of S2, S3, and S4 increased by 10.89%, 15.46%, and 16.98%, respectively. But only S4 increased by 4.64% compared to S0, while other treatments were lower than S0. S4 increased panicles per m2 and spikelets per panicle by 9.34% and 8.93%, respectively, compared to S1. Panicles per m2 decreased by 8.06% at S4 compared to S0, while spikelets per panicle increased by 13.23%. Compared with S0, the soil organic carbon, total nitrogen, NH4+-N, NO3--N, available phosphorus, and available potassium of S4 increased by 11.68%, 10.15%, 24.62%, 21.38%, 12.33%, and 13.35%, respectively. Successive years of rice straw return decreased GHG intensity (GHGI). Compared with S1, the GHGI of S4, S3, and S2 decreased by 16.2%, 11.84%, and 9.36%, respectively. Thus, S4 increased rice yield and soil nutrients, reducing GHGI.

Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1.

Ferroptosis, a form of cell death characterized by lipid peroxidation, is involved in neurodegenerative diseases such as Alzheimer´s disease (AD). Recent studies have shown that a first-line antimalarial drug artemisinin is effective to counteract AD pathology. In this study, we investigated the protective effect of artemisinin against neuronal ferroptosis and the underlying mechanisms. In hippocampal HT22 cells, pretreatment with artemisinin dose-dependently protected against Erastin-induced cell death with an EC50 value of 5.032 µM, comparable to the ferroptosis inhibitor ferrostatin-1 (EC50 = 4.39 µM). We demonstrated that artemisinin (10 µM) significantly increased the nuclear translocation of Nrf2 and upregulated SLC7A11 and GPX4 in HT22 cells. Knockdown of Nrf2, SLC7A11 or GPX4 prevented the protective action of artemisinin, indicating that its anti-ferroptosis effect is mediated by the Nrf2-SLC7A11-GPX4 pathway. Molecular docking and Co-Immunoprecipitation (Co-IP) analysis revealed that artemisinin competitively binds with KEAP1, promoting the dissociation of KEAP1-Nrf2 complex and inhibiting the ubiquitination of Nrf2. Intrahippocampal injection of imidazole-ketone-Erastin (IKE) induced ferroptosis in mice accompanied by cognitive deficits evidenced by lower preference for exploration of new objects and new object locations in the NOR and NOL tests. Artemisinin (5, 10 mg/kg, i.p.) dose-dependently inhibited IKE-induced ferroptosis in hippocampal CA1 region and ameliorated learning and memory impairments. Moreover, we demonstrated that artemisinin reversed Aß1-42-induced ferroptosis, lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3×Tg mice via the KEAP1-Nrf2 pathway. Our results demonstrate that artemisinin is a novel neuronal ferroptosis inhibitor that targets KEAP1 to activate the Nrf2-SLC7A11-GPX4 pathway.

Genome-wide analysis of the CCT gene family and functional characterization of SlCCT6 in response to drought stress in tomato.

CCT transcription factors are important for photoperiod and abiotic stress regulation in Arabidopsis and rice. However, the CCT gene family has not been reported in tomato. Here, we systematically analyzed this. Thirty-one SlCCT genes were identified and divided into five groups (CMF, TIFY, PRR, S8, and COL), with members unevenly distributed across 12 chromosomes and the third chromosome exhibiting the most distribution. SlCCT was found to interact with an interacting protein (SlGI), transcription factor (MYB), and non-coding RNA (sly-miR156-5p) to jointly regulate the tomato stress response. cis-Acting element analysis of the SlCCT promoter region indicated large stress- and hormone-response elements in this family. Real-time PCR results indicated that SlPRR subfamily genes respond to various abiotic stresses and hormones. Tissue expression analysis revealed that several PRR subfamily genes are highly expressed in flowers, and subcellular localization analysis indicated an SlCCT6 nuclear location. Notably, SlCCT6 expression was significantly induced by drought, and its silencing reduced drought stress tolerance. Moreover, SlCCT6 overexpression enhanced tomato drought resistance by increasing antioxidant enzyme activity and activating stress-related genes, whereas SlCCT6 knockout decreased drought resistance. In conclusion, this provides valuable insights for future research on SlCCT functions.

Silver Nanoparticles Exposure Impairs Cardiac Development by Suppressing the Focal Adhesion Pathway in Zebrafish.

Introduction: The potential toxic effects of wastewater discharges containing silver nanoparticles (AgNPs) and their release into aquatic ecosystems on aquatic organisms are becoming a major concern for environmental and human health. However, the potential risks of AgNPs to aquatic organisms, especially for cardiac development by Focal adhesion pathway, are still poorly understood. Methods: The cardiac development of various concentrations of AgNPs in zebrafish were examined using stereoscopic microscope. The expression levels of cardiac development-related genes were analyzed by qRT-PCR and Whole-mount in situ hybridization (WISH). In addition, Illumina high-throughput global transcriptome analysis was performed to explore the potential signaling pathway involved in the treatment of zebrafish embryos by AgNPs after 72 h. Results: We systematically investigated the cardiac developing toxicity of AgNPs on the embryos of zebrafish. The results demonstrated that 2 or 4 mg/L AgNPs exposure induces cardiac developmental malformations, such as the appearance of pericardial edema phenotype. In addition, after 72 h of exposure, the mRNA levels of cardiac development-related genes, such as myh7, myh6, tpm1, nppa, tbx5, tbx20, myl7 and cmlc1, were significantly lower in AgNPs-treated zebrafish embryos than in control zebrafish embryos. Moreover, RNA sequencing, KEGG (Kyoto Encyclopedia of Genes) and Genomes and GSEA (gene set enrichment analysis) of the DEGs (differentially expressed genes) between the AgNPs-exposed and control groups indicated that the downregulated DEGs were mainly enriched in focal adhesion pathways. Further investigations demonstrated that the mRNA levels of focal adhesion pathway-related genes, such as igf1ra, shc3, grb2b, ptk2aa, akt1, itga4, parvaa, akt3b and vcla, were significantly decreased after AgNPs treatment in zebrafish. Conclusion: Thus, our findings illustrated that AgNPs could impair cardiac development by regulating the focal adhesion pathway in zebrafish.

Role of Kir4.1/Kir5.1 in mediating Angiotensin-II (Ang-II)-induced stimulation of thiazide-sensitive Na-Cl cotransporter.

Background: Angiotensin-II (Ang-II) perfusion stimulates Kir4.1/Kir5.1 in the distal-convoluted-tubule (DCT) and thiazide-sensitive Na-Cl-cotransporter (NCC). However, the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC is not understood. Methods: We used immunoblotting and patch-clamp-experiments to examine whether Ang-II-induced stimulation of NCC is achieved by activation of Kir4.1/Kir5.1 of the DCT using kidney-renal-tubule-specific AT1aR-knockout (Ks-AT1aR-KO), Ks-Kir4.1-knockout and the corresponding wild-type mice. Results: Ang-II perfusion for 1, 3 and 7 days progressively increased phosphor-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II-perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1-day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7-days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K + currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine-kinase-4 (pWNK4), phosphor-ste-20-proline-alanine-rich-kinase (pSPAK), pNCC and tNCC. However, 7-days Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC and tNCC, and increased thiazide-induced natriuresis in kidney-tubule-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice without obvious changes in K + channel activity in the DCT. Conclusions: Short-term Ang-II induced stimulation of pWNK4, pSPAK and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK and pNCC by a Kir4.1/Kir5.1 independent mechanism.

Bacteroides uniformis Ameliorates Carbohydrate and Lipid Metabolism Disorders in Diabetic Mice by Regulating Bile Acid Metabolism via the Gut-Liver Axis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. METHODS: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). RESULTS: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product-vaccarin (VAC)-that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. CONCLUSIONS: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.

The potential toxic effects of estrogen exposure on neural and vascular development in zebrafish.

Estrogens and estrogenic chemicals are endocrine-disrupting chemicals (EDCs). The potential toxicity of EDCs to humans and aquatic organisms has become increasingly concerning. However, at present, the potential toxic mechanisms of EDCs on neural and vascular development are still being fully investigated. During the study, we utilized zebrafish to assess the developmental neural and vascular toxicity of different estrogens. The results indicated that zebrafish treated with different estrogens, especially E2, exhibit developmental malformations, including increased mortality, decreased body length, decreased heart rate, aberrant swimming behavior, and increased developmental malformations, including spinal curvature (SC), yolk edema (YE) and pericaidial edema (PE), in a dose-dependent manner with 72 h-treated. Further morphological evaluation revealed that E2 exposure significantly induced motor neural abnormalities in zebrafish embryos. In addition, treated with these three estrogens also impaired the vascular development in the early stage of zebrafish embryos. Mechanistically, the identification of downstream factors revealed that several key neural and vascular development-related genes, including syn2a, gfap, gap43, shha, kdr, flt1 and flt4, were transcriptionally downregulated after estrogen exposure in zebrafish, suggesting that estrogen exposure might cause neural and vascular toxicity by interfering the mRNA levels of genes relevant to neural and vascular development.