The combination of berberine and isoliquiritigenin synergistically improved adipose inflammation and obesity-induced insulin resistance.

White adipose tissue accumulation and inflammation contribute to obesity by inducing insulin resistance. Herein, we aimed to screen the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for the treatment of insulin resistance and explore the potential synergistic mechanisms. Enzyme-linked immunosorbent assay and quantitative PCR were used to detect expression levels of inflammatory genes in vitro and in vivo. Western blotting and immunohistochemistry were performed to detect protein levels of the insulin signaling pathway and macrophage markers. The effects on obesity-induced insulin resistance were verified using a diet-induced obesity (DIO) mouse model. Interactions between macrophage and adipocyte were assessed using a cellular supernatant transfer assay. Berberine (BBR) and isoliquiritigenin (ISL) alleviated mRNA levels and secretion of inflammatory genes in vitro and in vivo. Furthermore, BBR acted synergistically with ISL to ameliorate obesity and dyslipidemia in DIO mice. Meanwhile, the combination treatment significantly improved glucose intolerance and insulin resistance and decreased M1-macrophage accumulation and infiltration in the adipose tissue. Mechanistically, co-treatment with BBR and ISL upregulated the protein expression of the IRS1-PI3K-Akt insulin signaling pathway, enhanced glucose uptake in adipocyte, and suppressed the interaction between macrophage and adipocyte. BBR and ISL were identified as the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for treating insulin resistance. The synergistic combination of BBR with ISL can be a promising and effective strategy for improving obesity-induced adipose inflammation and insulin resistance.

Effects of a competence-based approach for clerkship teaching under alternating clinical placements: An explanatory sequential mixed-methods research.

BACKGROUND: It is unclear whether alternating placements during clinical clerkship, without an explicit emphasis on clinical competencies, would bring about optimal educational outcomes. METHODS: This is an explanatory sequential mixed-methods research. We enrolled a convenience sample of 41 eight-year programme medical students in Sun Yat-sen University who received alternating placements during clerkship. The effects of competence-based approach (n = 21) versus traditional approach (n = 20) to clerkship teaching were compared. In the quantitative phase, course satisfaction was measured via an online survey and academic performance was determined through final scores on summative assessment. Then, in the qualitative phase, students were invited for semi-structured interviews about their learning experiences, and the transcripts were used for thematic analysis. RESULTS: Quantitative findings showed that students in the study group rated high course satisfaction and performed significantly better in their final scores compared with those in the control group. Qualitative findings from thematic analysis showed that students were relatively neutral about their preference on placement models, but clearly perceived, capitalised, and appreciated that their competencies were being cultivated by an instructor who was regarded as a positive role model. CONCLUSION: A competence-based approach to clerkship teaching resulted in better course satisfaction and academic performance, and was perceived, capitalised, and appreciated by students.

[Identification of HSP70 gene family members in Fritillaria cirrhosa and expression analysis in different tissues under high temperature stress].

The heat shock protein 70 family contains the stress proteins ubiquitous in plants. These proteins are involved in the responses to different abiotic stress conditions and have highly conserved gene sequences. However, little is known about the molecular mechanisms of Fritillaria cirrhosa in response to high-temperature stress. Here, 26 HSP70s, FcHSP70-1 to FcHSP70-26, were identified from the transcriptome data of root, bulb, stem, leaf, and fruit samples of F. cirrhosa. The proteins encoded by FcHSP70s had the lengths ranging from 560 aa to 944 aa, with the molecular weight of 61.64-100.01 kDa and the theoretical isoelectric point between 5.00 and 6.59. The secondary structural elements of HSP70s were mainly random coils and α-helixes. Subcellular localization prediction revealed that FcHSP70s were distributed in mitochondria, chloroplasts, nuclei, endoplasmic reticulum, and cytoplasm. The phylogenetic tree showed that 7 members of the HSP70 family belonged to the Dnak subfamily and 19 members belonged to the HSP110/SSE subfamily. In addition, the qRT-PCR results showed that the expression of FcHSP70-5, FcHSP70-8, FcHSP70-17, FcHSP70-18, and FcHSP70-23 in F. cirrhosa was significantly up-regulated at 35 ℃, which indicated that these genes might play a role in the response to high temperature stress. In addition, compared with other tissues, stems and leaves were sensitive to high temperature stress, with the expression of 18 genes up-regulated by 18.18 and 8.03 folds on average, respectively. These findings provide valuable information about the molecular mechanism of HSP70s of F. cirrhosa in response to high temperature stress.

CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis.

BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.

Chemical Constituents from the deep-sea-derived Fungus Aureobasidium melanogenum LUO5.

Three new C10 and C12 aliphatic δ-lactones (1-3), three new fatty acid methyl esters (4-6), and eight known compounds (7-14) were isolated from the marine Aureobasidium sp. LUO5. Their structures were established by detailed analyses of the NMR, HRESIMS, optical rotation, and ECD data. All isolates were tested for their inhibitory effects on nitric oxide production in LPS-induced BV-2 cells. Notably, compound 4 displayed the strongest inhibitory effect with the IC50 value of 120.3 nM.

Early embryonic failure caused by a novel mutation in the TUBB8 gene: A case report.

BACKGROUND: This study aimed to explore the relationship between gene mutations and early embryonic development arrest and to provide more possibilities for the diagnosis and treatment of repeated implantation failure. CASE SUMMARY: Here, we collected and described the clinical data of a patient with early embryonic development stagnation after repeated in vitro fertilization attempts for primary infertility at the Department Reproductive Center of Zaozhuang Maternal and Child Healthcare Hospital. We also detected the whole-exon gene of the patient's spouse and parents, and conducted bioinformatics analysis to determine the pathogenesis of the gene. CONCLUSION: A novel mutant of the TUBB8 gene [c.602G>T(p.C201F)] was identified, and this mutant provided new data on the genotype-phenotype relationships of related diseases.

Network pharmacology analysis and experimental verification of the antithrombotic active compounds of trichosanthis pericarpium (Gualoupi) in treating coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Trichosanthis pericarpium (TP; Gualoupi, pericarps of Trichosanthes kirilowii Maxim) has been used in traditional Chinese medicine (TCM) to reduce heat, resolve phlegm, promote Qi, and clear chest congestion. It is also an essential herbal ingredient in the "Gualou Xiebai" formula first recorded by Zhang Zhongjing (from the Eastern Han Dynasty) in the famous TCM classic "Jin-Guì-Yào-Lüe" for treating chest impediments. According to its traditional description, Gualou Xiebai is indicated for symptoms of chest impediments, which correspond to coronary heart diseases (CHD). AIM OF THE STUDY: This study aimed to identify the antithrombotic compounds in Gualoupi for the treatment of CHD. MATERIALS AND METHODS: A CHD rat model was established with a combination of high-fat diet and isoproterenol hydrochloride (ISO) administration via subcutaneous multi-point injection in the back of the neck. This model was used to evaluate the antithrombotic effect of two mainstream cultivars of TP ("HaiShi GuaLou" and "WanLou") by analyzing the main components and their effects. Network pharmacology, molecular docking-based studies, and a zebrafish (Danio rerio) thrombosis model induced by phenylhydrazine was used to validate the antithrombosis components of TP. RESULTS: TP significantly reduced the body weight of the CHD rats, improved myocardial ischemia, and reduced collagen deposition and fibrosis around the infarcted tissue. It reduced thrombosis in a dose-dependent manner and significantly reduced inflammation and oxidative stress damage. Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as candidate active TP compounds with antithrombotic effects. The key potential targets of TP in thrombosis treatment were initially identified by molecular docking-based analysis, which showed that the candidate active compounds have a strong binding affinity to the potential targets (protein kinase C alpha type [PKCα], protein kinase C beta type [PKCß], von Willebrand factor [vWF], and prostaglandin-endoperoxide synthase 1 [PTGS1], fibrinogen alpha [Fga], fibrinogen beta [Fgb], fibrinogen gamma [Fgg], coagulation factor II [F2], and coagulation factor VII [F7]). In addition, the candidate active compounds reduced thrombosis, improved oxidative stress damage, and down-regulated the expression of thrombosis-related genes (PKCα, PKCß, vWF, PTGS1, Fga, Fgb, Fgg, F2, and F7) in the zebrafish model. CONCLUSION: Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as the active antithrombotic compounds of TP used to treat CHD. Mechanistically, the active compounds were found to be involved in oxidative stress injury, platelet activation pathway, and complement and coagulation cascade pathways.

A Multilayered GaAs IPD Resonator with Five Airbridges for Sensor System Application.

This work proposes a microwave resonator built from gallium arsenide using integrated passive device (IPD) technology. It consists of a three-layered interlaced spiral structure with airbridges and inner interdigital structures. For integrated systems, IPD technology demonstrated outstanding performance, robustness, and a tiny size at a low cost. The airbridges were made more compact, with overall dimensions of 1590 × 800 µm2 (0.038 × 0.019 λg2). The designed microwave resonator operated at 1.99 GHz with a return loss of 39 dB, an insertion loss of 0.07 dB, and a quality factor of 1.15. Additionally, an experiment was conducted on the properties of the airbridge and how they affected resistance, inductance, and S-parameters in the construction of the resonator. To investigate the impact of airbridges on the structure, E- and H-field distributions of the resonator were simulated. Furthermore, its use in sensing applications was explored. Various concentrations of glucose solutions were used in the experiment. The proposed device featured a minimum detectable concentration of 0.2 mg/mL; high sensitivity, namely, 14.58 MHz/mg·mL-1, with a linear response; and a short response time. Thus, this work proposes a structure that exhibits potential in integrated systems and real-time sensing systems with high sensitivity.

Neural network-based predefined-time bipartite formation tracking control of uncertain heterogeneous Euler-Lagrange systems in task space.

The main problem addressed in this paper is the task-space bipartite formation tracking problem of uncertain heterogeneous Euler-Lagrange systems in predefined time. To solve this problem, an effective hierarchical predefined-time control algorithm is designed. This algorithm utilizes a non-singular sliding surface, allowing for the adjustment of the upper bound of the settling time as a flexible parameter. Key components of the proposed approach include an estimator for the leader's states and a controller tailored to the formation problem. To mitigate the effects of dynamic uncertainties in the system, the radial basis function neural network is integrated into the methodology. Finally, the effectiveness and validity of the proposed algorithm are demonstrated through numerical simulations, showcasing their practical applicability and efficacy.

Occurrence of halogenated organic contaminants in surface sediments of the Yangtze River estuary and its adjacent marine area.

Halogenated organic contaminants, such as chlorinated and brominated polycyclic aromatic hydrocarbons (Cl/Br-PAHs), are some of the most important emerging environmental pollutants. However, empirical data on Cl/Br-PAHs in estuarine and marine ecosystems are limited, rendering assessments of Cl/Br-PAH contamination in estuarine and offshore environments uncertain. Here the occurrence, sources, and ecological risks of 7 Cl-PAHs and 18 Br-PAHs were determined in surface sediments of the Yangtze River Estuary (YRE), a highly urbanized and industrialized area, and its adjacent marine area. The concentrations of Cl-PAHs ranged from 4.50 to 18.38 ng g-1 (average 7.19 ng g-1), while those of Br-PAHs ranged from 4.80 to 61.18 ng g-1 (average 14.11 ng g-1). The dominant Cl-PAH and Br-PAH in surface sediment were 9-chlorofluorene (17.79%) and 9-bromofluorene (58.49%), respectively. The distributions and compositions of Cl/Br-PAHs in the surface sediments varied considerably due to complex hydrodynamic and depositional conditions in the YRE and its adjacent marine area, as well as differences in physicochemical properties of different Cl/Br-PAHs. Positive matrix factorization revealed that the primary sources of Cl/Br-PAHs in the study area were e-waste dismantling (33.6%), waste incineration (23.2%), and metal smelting (11.0%). According to the risk quotient, the Cl/Br-PAHs in sediments posed no toxic risk to aquatic organisms.

Unraveling the pharmacodynamic substances and possible mechanism of Trichosanthis Pericarpium in the treatment of coronary heart disease based on plasma pharmacochemistry, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. AIM OF THE STUDY: The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. MATERIALS AND METHODS: The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. RESULTS: The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1ß, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1ß, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. CONCLUSION: Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1ß, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.

Supramolecular assemblies of Cu(II) with a tetraphenylethene-imidazole ligand for tuning photocatalytic CO2 reduction.

Cu(II) supramolecular assemblies [Cu2(tipe)2(H2O)2](NO3)4·2.5H2O (CuN4) and [Cu2Cl4(tipe)(CH3CN)]·H2O (CuN2Cl2) (tipe = 1,1,2,2-tetrakis(4-(imidazole-1-yl)phenyl)ethene) were synthesized and utilized for photocatalytic CO2 reduction. CuN4 exhibits CO production of up to 891 µmol gcat-1 with a selectivity of 79.9%, while CuN2Cl2 gives low CO production of 206 µmol gcat-1 but with a high selectivity of >99.9% in 5 h. The experimental and DFT calculation results indicate that the coordination environment and non-covalent interactions within the assemblies have a great impact on the photocatalytic CO2 reduction behavior. This work provides useful insights on Cu(II) assembly catalyzed CO2 photoreduction.

Molecules inducing specific cyclin-dependent kinase degradation and their possible use in cancer therapy.

Cyclin-dependent kinases (CDKs) play an important role in the regulation of cell proliferation, and many CDK inhibitors were developed. However, pan-CDK inhibitors failed to be approved due to intolerant toxicity or low efficacy and the use of selective CDK4/6 inhibitors is limited by resistance. Protein degraders have the potential to increase selectivity, efficacy and overcome resistance, which provides a novel strategy for regulating CDKs. In this review, we summarized the function of CDKs in regulating the cell cycle and transcription, and introduced the representative CDK inhibitors. Then we made a detailed introduction about four types of CDKs degraders, including their action mechanisms, research status and application prospects, which could help the development of novel CDKs degraders.

Genome-Wide Network Analysis of Above- and Below-Ground Co-growth in Populus euphratica.

Tree growth is the consequence of developmental interactions between above- and below-ground compartments. However, a comprehensive view of the genetic architecture of growth as a cohesive whole is poorly understood. We propose a systems biology approach for mapping growth trajectories in genome-wide association studies viewing growth as a complex (phenotypic) system in which above- and below-ground components (or traits) interact with each other to mediate systems behavior. We further assume that trait-trait interactions are controlled by a genetic system composed of many different interactive genes and integrate the Lotka-Volterra predator-prey model to dissect phenotypic and genetic systems into pleiotropic and epistatic interaction components by which the detailed genetic mechanism of above- and below-ground co-growth can be charted. We apply the approach to analyze linkage mapping data of Populus euphratica, which is the only tree species that can grow in the desert, and characterize several loci that govern how above- and below-ground growth is cooperated or competed over development. We reconstruct multilayer and multiplex genetic interactome networks for the developmental trajectories of each trait and their developmental covariation. Many significant loci and epistatic effects detected can be annotated to candidate genes for growth and developmental processes. The results from our model may potentially be useful for marker-assisted selection and genetic editing in applied tree breeding programs. The model provides a general tool to characterize a complete picture of pleiotropic and epistatic genetic architecture in growth traits in forest trees and any other organisms.

Computational dissection of genetic variation modulating the response of multiple photosynthetic phenotypes to the light environment.

BACKGROUND: The expression of biological traits is modulated by genetics as well as the environment, and the level of influence exerted by the latter may vary across characteristics. Photosynthetic traits in plants are complex quantitative traits that are regulated by both endogenous genetic factors and external environmental factors such as light intensity and CO2 concentration. The specific processes impacted occur dynamically and continuously as the growth of plants changes. Although studies have been conducted to explore the genetic regulatory mechanisms of individual photosynthetic traits or to evaluate the effects of certain environmental variables on photosynthetic traits, the systematic impact of environmental variables on the dynamic process of integrated plant growth and development has not been fully elucidated. RESULTS: In this paper, we proposed a research framework to investigate the genetic mechanism of high-dimensional complex photosynthetic traits in response to the light environment at the genome level. We established a set of high-dimensional equations incorporating environmental regulators to integrate functional mapping and dynamic screening of gene‒environment complex systems to elucidate the process and pattern of intrinsic genetic regulatory mechanisms of three types of photosynthetic phenotypes of Populus simonii that varied with light intensity. Furthermore, a network structure was established to elucidate the crosstalk among significant QTLs that regulate photosynthetic phenotypic systems. Additionally, the detection of key QTLs governing the response of multiple phenotypes to the light environment, coupled with the intrinsic differences in genotype expression, provides valuable insights into the regulatory mechanisms that drive the transition of photosynthetic activity and photoprotection in the face of varying light intensity gradients. CONCLUSIONS: This paper offers a comprehensive approach to unraveling the genetic architecture of multidimensional variations in photosynthetic phenotypes, considering the combined impact of integrated environmental factors from multiple perspectives.

Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Efficacy and Safety of Bilateral Ultrasound-Guided Erector Spinae Plane Block for Postoperative Analgesia in Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: A meta-analysis of randomized controlled trials was conducted to assess efficacy and safety of bilateral ultrasound-guided erector spinae plane block (ESPB) for postoperative analgesia in patients receiving spine surgery. METHODS: PubMed, Embase, and CENTRAL databases were searched by 2 reviewers independently to identify randomized controlled trials evaluating the efficacy of ultrasound-guided ESPB for pain management in patients undergoing spine surgery. For meta-analysis, mean difference (MD) and 95% confidence interval (CI) were selected for continuous data, and risk ratio (RR) and 95% CI were selected for dichotomous variables. RESULTS: A total of 25 randomized controlled trials including 1917 patients (873 in ESPB group and 874 in control group) were eligible for inclusion. At rest, ESPB was associated with significantly lower pain intensity at 0, 2, 4, 6, 8, 12, 24, and 48 hours compared with the control group. During movement, ESPB was associated with significantly lower pain intensity at 0, 4, 6, 8, 12, 24, and 48 hours compared with the control group. Significantly reduced opioid consumption (MD = -6.29, 95% CI [-8.16, 4.41], P < 0.001), prolonged time for first rescue analgesia (MD = 7.51, 95% CI [3.47, 11.54], P < 0.001), fewer patients needing rescue analgesia (RR = 0.34, 95% CI [0.28, 0.43], P < 0.0001), improved patient satisfaction (MD = 1.34, 95% CI [0.88, 1.80], P < 0.001), and shorter length of hospital stay (MD = -0.38, [95% CI -0.50, -0.26], P < 0.001) were demonstrated after use of ESPB. Additionally, ESPB was associated with decreased risks of any adverse event (RR = 0.51, 95% CI [0.43, 0.60], P < 0.001) and postoperative nausea and vomiting events (RR = 0.39, 95% CI [0.31, 0.49], P < 0.001). CONCLUSIONS: Ultrasound-guided ESPB is an effective adjunctive technique with good tolerability for multimodal analgesia in management of pain in patients undergoing spine surgery.

Tetracycline inhibits tick host reproduction by modulating bacterial microbiota, gene expression and metabolism levels.

BACKGROUND: Ticks are disease vectors that are a matter of worldwide concern. Antibiotic treatments have been used to explore the interactions between ticks and their symbiotic microorganisms. In addition to altering the host microbial community, antibiotics can have toxic effects on the host. RESULTS: In the tick Haemaphysalis longicornis, engorged females showed reproductive disruption after microinjection of tetracycline. Multi-omics approaches were implemented to unravel the mechanisms of tick reproductive inhibition in this study. There were no significant changes in bacterial density in the whole ticks on Day (D)2 or D4 after tetracycline treatment, whereas the bacterial microbial community was significantly altered, especially on D4. The relative abundances of the bacteria Staphylococcus, Bacillus and Pseudomonas decreased after tetracycline treatment, whereas the relative abundances of Coxiella and Rhodococcus increased. Ovarian transcriptional analysis revealed a cumulative effect of tetracycline treatment, as there was a significant increase in the number of differentially expressed genes with treatment time and a higher number of downregulated genes. The tick physiological pathways including lysosome, extracellular matrix (ECM)-receptor interaction, biosynthesis of ubiquinone and other terpenoids-quinones, insect hormone biosynthesis, and focal adhesion were significantly inhibited after 4 days of tetracycline treatment. Metabolite levels were altered after tetracycline treatment and the differences increased with treatment time. The differential metabolites were involved in a variety of physiological pathways; the downregulated metabolites were significantly enriched in the nicotinate and nicotinamide metabolism, galactose metabolism, and ether lipid metabolism pathways. CONCLUSIONS: These findings indicate that tetracycline inhibits tick reproduction through the regulation of tick bacterial communities, gene expression and metabolic levels. The results may provide new strategies for tick control. © 2023 Society of Chemical Industry.

TNFAIP3 Derived from Skeletal Stem Cells Alleviated Rat Osteoarthritis by Inhibiting the Necroptosis of Subchondral Osteoblasts.

Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, the rat anterior cruciate ligament transection OA model was used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necroptotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs-derived tumor necrosis factor α-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3-derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.

Metabolic flux and catabolic kinetics of prebiotic-like dietary polyphenol phlorizin in association with gut microbiota in vitro.

As ubiquitous components among fruits, polyphenols, including flavonoids and phenolic acids, are somewhat embarrassed on their health benefits but low bioavailability, triggering a hotspot on their interaction with microbiota. Due to its structural characteristics similar to flavonoids and phenolic acids, dihydrochalcone phlorizin (PHZ) was selected as a reference, to illustrate its step-by-step metabolic fate associated with microbiota. The results confirmed that the metabolic flux of PHZ starts with its conversion to phloretin (PHT), sequentially followed by the formation of 3-(4-hydroxyphenyl) propionic acid (PHA), and 4-hydroxyphenylacetic acid (4-HPAA). Catabolic characteristics was comparatively elucidated by introducing apparent and potential kinetics. Besides, coupling catabolic processes with microbial changes suggested several potential bacteria involving in PHZ metabolism, as well as those regulated by PHZ and its metabolites. In particular, seven strains from Lactobacillus were selectively isolated and confirmed to be essential for deglycosylation of PHZ, implying a potential synergistic effect between PHZ and Lactobacillus.