Curcumin Alleviates Airway Inflammation in Cough-Variant Asthmatic Rats by Modulating M1/M2 Macrophage Polarization.

BACKGROUND: With the increase of environmental pollution and atypical pathogen infections, the incidence of cough variant asthma (CVA) has been increasing annually, making it a pressing issue of the medical community. This study aims to observe the ameliorative effect of curcumin on a rat model of cough variant asthma. METHODS: A rat model of cough variant asthma was induced by sensitization with ovalbumin combined with aluminum hydroxide (Al(OH)3), followed by repeated excitations. The drug was administered on the day of the initial nebulized attack, and gavage was administered for 14 d. Pathological changes in the lung tissues were observed, along with the assessment of cough susceptibility and airway resistance. The number of inflammatory cell eosinophils and leukocytes were determined in alveolar lavage fluid. Additionally, serum inflammatory factors and lung tissues Matrix Metalloproteinase-9 (MMP-9) protein were assessed. The level of M1/M2 macrophages was also detected. RESULTS: Following the administration of curcumin, there was reduced inflammatory infiltration, less disordered arrangement of the lung tissue, and decreased abnormal proliferation of lung tissues in cough variant asthma rats compared to the model group. Curcumin treatment led toa notable reduction in cough frequency, a significant decrease in pro-inflammatory factor concentration levels in serum and inflammatory cell counts in the alveolar lavage fluid, and a marked increase in anti-inflammatory factor levels (p < 0.05). Additionally, curcumin administration led to a significant increase in M2-type macrophage levels, while simultaneously decreasing the levels of M1-type macrophages (p < 0.05). CONCLUSIONS: The administration of curcumin effectively ameliorates ovalbumin-induced airway inflammation in cough-variant asthma rats. This effect is attributed to modulating macrophage polarization towards the anti-inflammatory M2 phenotype, thereby reducing airway inflammation, airway hyperresponsiveness, and lung tissue injury.

Phytochemical component profiling and anti-renal fibrosis effects of crude and salt-stir fried Eucommiae Cortex extracts on renal fibrosis rats caused by high-purine diet.

A prolonged diet laden with purine-rich foods represents a significant contributor to renal fibrosis (RF). Eucommia ulmoides Oliver, a plant homologous to food and medicinal materials, has long been employed to recover kidney function. This investigation presents a strategy integrating chemistry, biochemistry, and metabolomics to evaluate bioactive components and efficiency mechanism of crude and salt-stir fried Eucommiae Cortex (EC) extracts against RF. Firstly, 155 chemical components were identified in the EC extracts and the contents of 19 and 27 compounds decreased and increased respectively after salt-stir frying. Secondly, various biochemical indicators displayed that salt-stir fried EC (SEC) extracts had the optimal anti-RF effects in adenine-induced RF model rats, which were associated with the attenuation of TGF-ß signaling pathway. Finally, untargeted metabolomics analysis demonstrated that after treatments with EC and SEC extracts, 30 and 32 efficacy biomarkers were significantly restored in the RF + EC and RF + SEC groups respectively, involving five metabolic pathways.

Photoelectric H2S Sensing Based on Electrospun Hollow CuO-SnO2 Nanotubes at Room Temperature.

Pure tin oxide (SnO2) as a typical conductometric hydrogen sulfide (H2S) gas-sensing material always suffers from limited sensitivity, elevated operation temperature, and poor selectivity. To overcome these hindrances, in this work, hollow CuO-SnO2 nanotubes were successfully electrospun for room-temperature (25 °C) trace H2S detection under blue light activation. Among all SnO2-based candidates, a pure SnO2 sensor showed no signal, even toward 10 ppm, while the 1% CuO-SnO2 sensor achieved a limit of detection (LoD) value of 2.5 ppm, a large response of 4.7, and a short response/recovery time of 21/61 s toward 10 ppm H2S, as well as nice repeatability, long-term stability, and selectivity. This excellent performance could be ascribed to the one-dimensional (1D) hollow nanostructure, abundant p-n heterojunctions, and the photoelectric effect of the CuO-SnO2 nanotubes. The proposed design strategies cater to the demanding requirements of high sensitivity and low power consumption in future application scenarios such as Internet of Things and smart optoelectronic systems.

Molecular characterization of a novel thioredoxin-related transmembrane protein gene AcTMX3 that plays important roles in antioxidant defence in Arma chinensis diapause.

Protein disulphide isomerase (PDI) possesses disulphide isomerase, oxidoreductase and molecular chaperone activities, and is involved in regulating various physiological processes. However, there are few studies on the function in insect diapause. In this study, we cloned one novel member PDI family (TMX3, thioredoxin-related transmembrane protein 3) in Arma chinensis. The AcTMX3 encodes 426 amino acids that contains a predicted N-terminal signal sequence, a thioredoxin-like domain with the CXXC active site and a potential transmembrane region, which are typical sequence features of TMX3. RT-qPCR results showed that AcTMX3 was mainly expressed in the head under non-diapause conditions, while AcTMX3 was highly expressed in the fat body (central metabolic organ) under diapause conditions. Moreover, temporal expression profile showed that compared with non-diapause conditions, diapause conditions significantly induced AcTMX3 expression, and the expression of AcTMX3 was enhanced at 15°C. Silencing AcTMX3 in A. chinensis significantly inhibited the expression of antioxidant genes (AcTrx2 and AcTrx-like), increased the content of H2O2 and ascorbate and reduced the survival rate of A. chinensis under diapause conditions. Our results suggested that AcTMX3 played an important role in the resistance of A. chinensis to oxidative stress under diapause conditions.

[Active components and mechanism of Wuhu Decoction in intervening RSV-induced asthma based on network pharmacology and in vivo experiment].

This study aims to explore the active components and mechanism of Wuhu Decoction in treating respiratory syncytial virus(RSV)-induced asthma. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry was used to determine the components of Wuhu Decoction in the blood. By utilizing databases, Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis and Gene Ontology(GO) functional analysis were conducted to investigate the targets of the components of Wuhu Decoction in asthma. Furthermore, the information on target proteins, and metabolite-target-pathway was imported into the STRING database to construct a network interaction diagram to identify the core components and key pathways of Wuhu Decoction. In the in vivo experiment, an asthma model was established using RSV combined with ovalbumin(OVA) in mice. The intervention effect of Wuhu Decoction on RSV-induced asthma in mice was validated through lung function tests, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), Western blot, and immunohistochemistry. The results showed that the main components of Wuhu Decoction in the blood were flavonoids, phenylpropanoids, lignans, and terpenoids. The core components of Wuhu Decoction in treating pediatric asthma included(-)-epigallocatechin, kaempferol, isoliquiritigenin, diosmetin, betulinic acid, ursolic acid, daphnetin, aescin. The main pathways targeted by Wuhu Decoction were calcium signaling pathway, neuroactive ligand-receptor interaction, NOD-like receptor signaling pathway, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. The results of in vivo experiments demonstrated that Wuhu Decoction could improve lung function indicators, down-regulate levels of interleukin-6(IL-6), interleukin-17(IL-17), and tumor necrosis factor-alpha(TNF-α), and reduce the expression of proteins such as NOD-like receptor pyrin domain-containing 3(NLRP3), mitogen-activated protein kinase 1(MAPK1), mitogen-activated protein kinase 14(MAPK14), and nuclear factor kappaB subunit 1(NFKB1) in lung tissue, thereby alleviating neutrophilic inflammation and pulmonary congestion. These findings indicate that Wuhu Decoction intervenes in virus-induced asthma through a synergistic effect on multiple components, targets, and pathways, and it can inhibit the activation of the NOD-like receptor signaling pathway, thereby alleviating airway inflammation and injury in asthmatic mice.

Pan­cancer analysis on the role of KMT2C expression in tumor progression and immunotherapy.

Histone lysine N-methyltransferase 2C (KMT2C) is involved in transcriptional regulation and DNA damage repair. Mutations in KMT2C have been implicated in the progression, metastasis, and drug resistance of multiple cancer types. However, the roles of KMT2C in the regulation of tumor prognosis, immune cell infiltration and the immune microenvironment in these multiple cancer types remain unclear. Therefore, in the present study, data from The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for KMT2C expression analyses. Kaplan-Meier and univariate Cox regression analyses were also performed to investigate the prognostic role of KMT2C. In addition, Gene Set Enrichment Analysis (GSEA) was conducted to study the KMT2C-related signaling pathways. Tumor immune estimation resource 2 and single-sample GSEA were conducted to investigate the correlation between KMT2C expression and immune cell infiltrations, and Spearman's analysis was conducted to study the correlations among KMT2C, tumor mutational burden, microsatellite instability, immune regulators, chemokines and immune receptors. Immunohistochemistry of patient kidney tumor samples was performed to verify the correlation between KMT2C and programmed death-ligand 1 (PD-L1) expression. Finally, RNA interference, wound healing and colony formation assays were conducted to evaluate the effects of KMT2C expression on cell proliferation and metastasis. The results of the present study demonstrated that KMT2C was highly expressed in multiple cancer types, was a protective factor in kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma, and a risk factor for lung squamous cell carcinoma and uveal melanoma. In addition, KMT2C levels were negatively correlated with immune-activated pathways and the infiltration of immune cells, and positively correlated with inhibitory immune factors and tumor angiogenesis. Patients with low KMT2C expression had higher objective response rates to immunotherapy, and drug sensitivity analysis indicated that topoisomerase, histone deacetylase, DOT1-like histone H3K79 methyltransferase and G9A nuclear histone lysine methyltransferase inhibitors could potentially be used to treat tumors with high KMT2C expression levels. Finally, the KMT2C and PD-L1 expression levels were shown to be positively correlated, and KMT2C knockdown markedly promoted the proliferation and invasion capacities of A549 cells. In conclusion, the present study revealed that low KMT2C expression may be a promising biomarker for predicting the response of patients with cancer to immunotherapy. Conversely, high KMT2C expression was shown to promote tumor angiogenesis, which may contribute to the formation of the immunosuppressive tumor microenvironment.

Molecular identification of two thioredoxin genes and their function in antioxidant defense in Arma chinensis diapause.

Thioredoxin (Trx), an important part of thioredoxin systems, plays crucial role in maintaining the intracellular redox balance by scavenging reactive oxygen species (ROS). However, few Trxs have been functionally characterized in Arma chinensis, especially in diapause. In this study, diapause induction condition promoted hydrogen peroxide accumulation and increased CAT enzymatic activity and ascorbate content, suggesting that A. chinensis was exposed to high level of ROS. Therefore, we identified AcTrx2 and AcTrx-like, and investigated the relationship with antioxidant defense. It was found that AcTrx2 expression was significantly induced, whereas AcTrx-like expression was the highest on day 10 under diapause conditions. The expression of AcTrx2 and AcTrx-like in fat body, a central metabolic organ of resisting oxidative stress, was significantly increased under diapause conditions, and was significantly improved by 5/15°C (diapause temperature). We investigated the knockdown of AcTrx2 and AcTrx-like in A. chinensis and found that some selected antioxidant genes were upregulated, indicating that the upregulated genes may be functional compensation for AcTrx2 and AcTrx-like silencing. We also found that the enzymatic activities of SOD and CAT, and the metabolite contents of hydrogen peroxide, ascorbate increased after AcTrx2 and AcTrx-like knockdown. These results suggested the AcTrx2 and AcTrx-like may play critical roles in antioxidant defense of A. chinensis diapause.

[Prospective,multi-center,and large-scale hospital centralized monitoring of clinical safety of Reduning Injection in 100249 children cases].

This study utilized a prospective, large-sample, multi-center, and registered key specialty approach of hospitals to monitor the application of Reduning Injection. A total of 100 249 adolescent patients aged 14 years and below who received Reduning Injection were monitored, resulting in 83 cases of adverse events, with 76 of them being classified as adverse drug reaction(ADR). The calculated incidence rate of ADR for Reduning Injection was 0.076%, indicating a very rare ADR. The main symptoms of ADR were pruritus, diarrhea, abdominal pain, vomiting, high fever, dyspnea, convulsion, and chills. All ADR cases were reported for the first time, including three new ADR cases and 73 known ADR cases. The categories of ADR was general ADR. All ADR was mild in severity. There were more males than females in ADR patients. One patient had a history of ADR, and the drug causing ADR was buprofen. The largest number of ADR cases occurred when the dosage of Reduning injection was 5-10 mL. The dropping speed was 30 drops or less per min, and the solvent type was 5% glucose injection. The most common manifestation of ADR patients was pruritus, followed by diarrhea, abdominal pain, vomiting, high fever, dyspnea, convulsions, and chills. 72 patients(94.74% of ADR patients) discontinued the drug, and three patients(3.95% of ADR patients) were given oxygen inhalation. 47 cases(61.84% of ADR patients) were treated with medication, of which dexamethasone was the most used(24 cases, 46.15% of ADR patients). 76 ADR patients were cured or improved. ADRs are more likely to occur when diagnosed with acute bronchitis by western medicine and cough by traditional Chinese medicine(TCM), TCM syndrome type is wind heat syndrome, and the combination medicine is ambroxol hydrochloride and bromhexine hydrochloride injection, ascorbic acid/vitamin C injection. This result provides an evidence-based safety basis for active pharmacovigilance of Reduning Injection in adolescents aged 14 years and below.

Testosterone maintains male longevity and female reproduction in Chrysopa pallens.

Vertebrate testosterone, an androgen present in the testes, is essential for male fertility. Vertebrate-type steroid hormones have been identified in insects, but their function remains unknown. Insect vitellogenin (Vg) is usually a female-specific protein involved in reproductive processes. However, males of some species, such as the green lacewing Chrysopa pallens, have Vg. Here, we demonstrated that the knockdown of C. pallens male Vg by RNAi significantly shortened the lifespan of males, suppressed the reproduction of post-mating females, and strikingly reduced the abundance of several immune-related compounds, including testosterone. LC-MS/MS revealed that C. pallens male testosterone had the same structure and molecular mass as vertebrate testosterone. Topical testosterone application partially restored the lifespan of Vg-deficient males and the reproduction of post-mating females. These results suggest that vertebrate-type testosterone maintains male longevity and female reproduction under the control of the male Vg in C. pallens.

Exposure to ephedrine attenuates Th1/Th2 imbalance underlying OVA-induced asthma through airway epithelial cell-derived exosomal lnc-TRPM2-AS.

Although various anti-inflammatory medications, such as ephedrine, are employed to manage cough-variant asthma, their underlying mechanisms are yet to be fully understood. Recent studies suggest that exosomes derived from airway epithelial cells (AECs) contain components like messenger RNAs (mRNAs), micro-RNAs (miRNAs), and long noncoding RNA (lncRNA), which play roles in the occurrence and progression of airway inflammation. This study investigates the influence of AEC-derived exosomes on the efficacy of ephedrine in treating cough-variant asthma. We established a mouse model of asthma and measured airway resistance and serum inflammatory cell levels. Real-time polymerase chain reaction (RT-qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA) analyses were used to assess gene and protein expression levels. Exosomes were isolated and characterized. RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to examine the interaction between hnRNPA2B1 and lnc-TRPM2-AS1. In the ovalbumin (OVA)-challenged mouse model, ephedrine treatment reduced inflammatory responses, airway resistance, and Th1/Th2 cell imbalance. Exosomes from OVA-treated AECs showed elevated levels of lnc-TRPM2-AS1, which were diminished following ephedrine treatment. The exosomal lnc-TRPM2-AS1 mediated the Th1/Th2 imbalance in CD4+ T cells, with its packaging into exosomes being facilitated by hnRNPA2B1. This study unveils a novel mechanism by which ephedrine ameliorates OVA-induced CD4+ T cell imbalance by suppressing AEC-derived exosomal lnc-TRPM2-AS1. These findings could provide a theoretical framework for using ephedrine in asthma treatment.

Gut microbiota is necessary for pair-housing to protect against post-stroke depression in mice.

The goal of this study is to investigate the role of microbiota-gut-brain axis involved in the protective effect of pair-housing on post-stroke depression (PSD). PSD model was induced by occluding the middle cerebral artery (MCAO) plus restraint stress for four weeks. At three days after MCAO, the mice were restrained 2 h per day. For pair-housing (PH), each mouse was pair housed with a healthy isosexual cohabitor for four weeks. While in the other PH group, their drinking water was replaced with antibiotic water. On day 35 to day 40, anxiety- and depression-like behaviors (sucrose consumption, open field test, forced swim test, and tail-suspension test) were conducted. Results showed pair-housed mice had better performance on anxiety- and depression-like behaviors than the PSD mice, and the richness and diversity of intestinal flora were also improved. However, drinking antibiotic water reversed the effects of pair-housing. Furthermore, pair-housing had an obvious improvement in gut barrier disorder and inflammation caused by PSD. Particularly, they showed significant decreases in CD8 lymphocytes and mRNA levels of pro-inflammatory cytokines (TNF-a, IL-1ß and IL-6), while IL-10 mRNA was upregulated. In addition, pair-housing significantly reduced activated microglia and increased Nissl's body in the hippocampus of PSD mice. However, all these improvements were worse in the pair-housed mice administrated with antibiotic water. We conclude that pair-housing significantly improves PSD in association with enhanced functions of microbiota-gut-brain axis, and homeostasis of gut microbiota is indispensable for the protective effect of pair-housing on PSD.

Effects of WuHuTang on the function and autophagy of dendritic cells treated with exosomes induced by RSV.

ETHNOPHARMACOLOGICAL RELEVANCE: WuHuTang (WHT) is a traditional Chinese medicine compound for treating asthma, and the evidence supports that it has a good effect on acute asthma attacks in children and adults. Respiratory syncytial virus (RSV) is an important factor in the pathogenesis of acute asthma attacks, and the effect on dendritic cells is the key to its pathogenesis. Previous studies have confirmed that the pathogenesis of viruses is related to exosomes. However, there are few studies on the exosomes induced by RSV. Whether WHT can improve the changes caused by RSV-induced exosomes or not is worthy of further exploration. AIM OF THE STUDY: We aim to study the effects of RSV-induced exosomes on the function and autophagy of dendritic cells, and to observe the intervention effect of WHT serum on the above effects. METHODS: The co-culture model of exosomes derived from bone marrow mesenchymal stem cells induced by RSV (BMSCs-Exo-RSV) and dendritic cells was established, and then WHT serum was used to intervene. After 24 h of intervention, the CCK-8 method, flow cytometry, Elisa, RT-qCPR, and Western blot were used to detect the above-mentioned culture model. RESULTS: RSV-induced exosomes had certain effects on viability, apoptosis, and costimulatory molecules generation of dendritic cells. At the same time, the levels of IL-6, IL-12, TNF-α, and autophagy increased, while the levels of IL-4, IL-10, and TGF-ß decreased, and the AKT/TSC/mTOR pathway was inhibited. WHT serum could activate this pathway and reverse the above changes in dendritic cells. CONCLUSION: This study reveals that the pathogenic effect of RSV is related to the exosomes induced by RSV. The exosomes induced by RSV affect the function of dendritic cells by inhibiting the AKT/TSC/mTOR pathway, which can be activated by WHT to reverse the effects caused by RSV-induced exosomes.

Synergistic electrochemical catalysis by high-entropy metal phosphide in lithium-sulfur batteries.

The shuttle effect and sluggish redox kinetics of polysulfides have hindered the development of lithium-sulfur batteries (LSBs) as premier energy storage devices. To address these issues, a high-entropy metal phosphide (NiCoMnFeCrP) was synthesized using the sol-gel method. NiCoMnFeCrP, with its rich metal species, exhibits strong synergistic effects and provides numerous catalytic active sites for the conversion of polysulfides. These active sites, possessing significant polarity, can bond with polysulfides. In situ ultraviolet-visible were conducted to monitor the dynamic changes in species and concentrations of polysulfides, validating the ability of NiCoMnFeCrP to facilitate the conversion of polysulfides. The batteries with the NiCoMnFeCrP catalyst as functional separators exhibited minimal capacity decay rates of 0.04 % and 0.23 % after 100 cycles at 0 °C and 60 °C, respectively. This indicates that the NiCoMnFeCrP catalyst possesses good thermal stability. Meanwhile, its area capacity can reach 4.78 mAh cm-2 at a high sulfur load of 4.54 mg cm-2. In conclusion, NiCoMnFeCrP achieves the objective of mitigating the shuttle effect and accelerating the kinetics of the redox reaction, thereby facilitating the commercialization of LSBs.

Differences in nature killer cell response and interference with mitochondrial DNA induced apoptosis in moxifloxacin environment.

OBJECTIVES: As antibiotics become more prevalent, accuracy and safety are critical. Moxifloxacin (MXF) have been reported to have immunomodulatory effects on a variety of immune cells and even anti-proliferative and pro-apoptotic effects, but the mechanism of action is not fully clear. METHODS: Peripheral blood mononuclear cells (PBMC) from experimental groups of healthy adults (n = 3) were treated with MXF (10ug/ml) in vitro for 24 h. Single-cell sequencing was performed to investigate differences in the response of each immune cell to MXF. Flow cytometry determined differential gene expression in subsets of most damaged NK cells. Pseudo-time analysis identified drivers that influence MXF-stimulated cell differentiation. Detection of mitochondrial DNA and its involvement in the mitochondrial respiratory chain pathway clarifies the origin of MXF-induced stress injury. RESULTS: Moxifloxacin-environmental NK cells are markedly reduced: a new subset of NK cells emerges, and immediate-early-response genes in this subset indicate the presence of an early activation response. The inhibitory receptor-dominant subset shows enhanced activation, leading to increased expression of cytokines and chemokines. The near-mature subset showed greater cytotoxicity and the most pronounced cellular damage. CD56bright cells responded by antagonizing the regulation of activation and inhibitory signals, demonstrating a strong cleavage capacity. The severe depletion of mitochondrial genes was focused on apoptosis induced by the mitochondrial respiratory chain complex. CONCLUSION: NK cells exhibit heightened sensitivity to the MXF environment. Different NK subsets upregulate the expression of cytokines and chemokines through different activation pathways. Concurrently, MXF induces impairment of the mitochondrial oxidative phosphorylation system, culminating in apoptosis.

Oxygen Vacancy-Rich Bimetallic Au@Pt Core-Shell Nanosphere-Functionalized Electrospun ZnFe2O4 Nanofibers for Chemiresistive Breath Acetone Detection.

Sensitive and selective acetone detection is of great significance in the fields of environmental protection, industrial production, and individual health monitoring from exhaled breath. To achieve this goal, bimetallic Au@Pt core-shell nanospheres (BNSs) functionalized-electrospun ZnFe2O4 nanofibers (ZFO NFs) are prepared in this work. Compared to pure NFs-650 analogue, the ZFO NFs/BNSs-2 sensor exhibits a stronger mean response (3.32 vs 1.84), quicker response/recovery speeds (33 s/28 s vs 54 s/42 s), and lower operating temperature (188 vs 273 °C) toward 0.5 ppm acetone. Note that an experimental detection limit of 30 ppb is achieved, which ranks among the best cases reported thus far. Besides the demonstrated excellent repeatability, humidity-enhanced response, and long-term stability, the selectivity toward acetone is remarkably improved after BNSs functionalization. Through material characterizations and DFT calculations, all these improvements could be attributed to the boosted oxygen vacancies and abundant Schottky junctions between ZFO NFs and BNSs, and the synergistic catalytic effect of BNSs. This work offers an alternative strategy to realize selective subppm acetone under high-humidity conditions catering for the future requirements of noninvasive breath diabetes diagnosis in the field of individual healthcare.

Shikonin suppresses rheumatoid arthritis by inducing apoptosis and autophagy via modulation of the AMPK/mTOR/ULK-1 signaling pathway.

BACKGROUND: The overproliferation of fibroblast-like synoviocytes (FLS) contributes to synovial hyperplasia, a pivotal pathological feature of rheumatoid arthritis (RA). Shikonin (SKN), the active compound from Lithospermum erythrorhizon, exerts anti-RA effects by diverse means. However, further research is needed to confirm SKN's in vitro and in vivo anti-proliferative functions and reveal the underlying specific molecular mechanisms. PURPOSE: This study revealed SKN's anti-proliferative effects by inducing both apoptosis and autophagic cell death in RA FLS and adjuvant-induced arthritis (AIA) rat synovium, with involvement of regulating the AMPK/mTOR/ULK-1 pathway. METHODS: SKN's influences on RA FLS were assessed for proliferation, apoptosis, and autophagy with immunofluorescence staining (Ki67, LC3B, P62), EdU incorporation assay, staining assays of Hoechst, Annexin V-FITC/PI, and JC-1, transmission electron microscopy, mCherry-GFP-LC3B puncta assay, and western blot. In AIA rats, SKN's anti-arthritic effects were assessed, and its impacts on synovial proliferation, apoptosis, and autophagy were studied using Ki67 immunohistochemistry, TUNEL, and western blot. The involvement of AMPK/mTOR/ULK-1 pathway was examined via western blot. RESULTS: SKN suppressed RA FLS proliferation with reduced cell viability and decreased Ki67-positive and EdU-positive cells. SKN promoted RA FLS apoptosis, as evidenced by apoptotic nuclear fragmentation, increased Annexin V-FITC/PI-stained cells, reduced mitochondrial potential, elevated Bax/Bcl-2 ratio, and increased cleaved-caspase 3 and cleaved-PARP protein levels. SKN also enhanced RA FLS autophagy, featuring increased LC3B, reduced P62, autophagosome formation, and activated autophagic flux. Autophagy inhibition by 3-MA attenuated SKN's anti-proliferative roles, implying that SKN-induced autophagy contributes to cell death. In vivo, SKN mitigated the severity of rat AIA while also reducing Ki67 expression, inducing apoptosis, and enhancing autophagy within AIA rat synovium. Mechanistically, SKN modulated the AMPK/mTOR/ULK-1 pathway in RA FLS and AIA rat synovium, as shown by elevated P-AMPK and P-ULK-1 expression and decreased P-mTOR expression. This regulation was supported by the reversal of SKN's in vitro and in vivo effects upon co-administration with the AMPK inhibitor compound C. CONCLUSION: SKN exerted in vitro and in vivo anti-proliferative properties by inducing apoptosis and autophagic cell death via modulating the AMPK/mTOR/ULK-1 pathway. Our study revealed novel molecular mechanisms underlying SKN's anti-RA effects.

CPD-002, a novel VEGFR2 inhibitor, relieves rheumatoid arthritis by reducing angiogenesis through the suppression of the VEGFR2/PI3K/AKT signaling pathway.

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.

Functional analysis of adipokinetic hormone signaling in reproductive diapause of Coccinella septempunctata.

BACKGROUND: The ladybeetle, Coccinella septempunctata, an important predator, is widely used to control aphids, whiteflies, mites, thrips, and lepidopteran pests. Diapause control technology is key to extending C. septempunctata shelf-life and commercialization. Lipid accumulation is a major feature of reproductive diapause, but the function of AKH signaling as a regulator of lipid mobilization in reproductive diapause remains unclear. This study aimed to identify and characterize AKH and AKHR genes, and clarify their functions in reproductive diapause. RESULTS: The relative expression levels of CsAKH and CsAKHR were the highest in the head and fat body, respectively, and were significantly decreased under diapause conditions, both in developmental stages and tissues (head, midgut, fat body, and ovary). Furthermore, CsAKH and CsAKHR expression was increased significantly after juvenile hormone (JH) injection, but CsMet silencing significantly inhibited CsAKH and CsAKHR expression, whereas CsMet knockdown blocked the induction effect of JH. CsAKH and CsAKHR knockdown significantly reduced water content, increased lipid storage, and promoted the expression of genes related to lipid synthesis, but significantly blocked ovarian development, and induced forkhead box O (FOXO) gene expression in C. septempunctata under reproduction conditions. By contrast, injection of AKH peptide significantly inhibited FOXO expression, reduced lipid storage, and increased water content in C. septempunctata under diapause conditions. CONCLUSION: These results indicate that CsAKH and CsAKHR are involved in the regulation of lipid accumulation and ovarian development during diapause in C. septempunctata, and provide a promising target for manipulating C. septempunctata diapause. © 2024 Society of Chemical Industry.

The genus Neurigona Rondani, 1856 (Diptera, Dolichopodidae) from Yunnan, China, with descriptions of seven new species and a key to the species of China.

Previously, only three species of the genus Neurigona Rondani of the subfamily Neurigoninae were known from Yunnan Province. Here, we reviewed the species of Neurigona from Yunnan and added the following seven new species: N.apicilatasp. nov., N.basicurvasp. nov., N.brevidigitatasp. nov., N.convexasp. nov., N.huanglianshanasp. nov., N.quadrimaculatasp. nov., and N.ventriprocessasp. nov. All seven new species are sympatric and were collected from below a reservoir in the Huanglianshan Nature Reserve in Yunnan using three Malaise traps in 2019. This suggests a very high species richness in the Yunnan fauna. A key to the species of Neurigona from Chinese mainland is provided.

Cellular and Molecular Mechanisms Underlying Synaptic Subcellular Specificity.

Chemical synapses are essential for neuronal information storage and relay. The synaptic signal received or sent from spatially distinct subcellular compartments often generates different outcomes due to the distance or physical property difference. Therefore, the final output of postsynaptic neurons is determined not only by the type and intensity of synaptic inputs but also by the synaptic subcellular location. How synaptic subcellular specificity is determined has long been the focus of study in the neurodevelopment field. Genetic studies from invertebrates such as Caenorhabditis elegans (C. elegans) have uncovered important molecular and cellular mechanisms required for subcellular specificity. Interestingly, similar molecular mechanisms were found in the mammalian cerebellum, hippocampus, and cerebral cortex. This review summarizes the comprehensive advances in the cellular and molecular mechanisms underlying synaptic subcellular specificity, focusing on studies from C. elegans and rodents.