Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in Human Induced Pluripotent Stem Cells Chondrocytes Induced by HT-2 Toxin.

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome.

Background: Restless legs syndrome (RLS) is a prevalent sensorimotor nervous system disorder in patients accompanied with insomnia, blood pressure fluctuation, and sympathetic dysfunction. These symptoms may disrupt cerebral hemodynamics. Dynamic cerebral autoregulation (dCA) describes the temporary response of cerebrovascular system to abrupt fluctuations in blood pressure, which keep cerebral blood flow stable and serve as a marker of cerebrovascular system ability. Objective: This research aimed to assess dCA in RLS patients. Methods: In this study, RLS patients were recruited and subsequently classified into four groups (mild, moderate, severe, and very severe) based on the International RLS Rating Scale (IRLS). Healthy controls matched for age and sex were enrolled. All participants were evaluated dCA by assessing phase difference (PD). A portion of patients with RLS was reassessed for dCA after one month of medication therapy (pramipexole [0.125 mg/day] and gabapentin [300 mg/day]). Results: There were altogether 120 patients with RLS and 30 controls completed the polysomnography and dCA assessment. PD was lower in the moderate, severe, and very severe RLS groups than that in the controls and mild RLS groups. Periodic limb movement index (PLMI), arousal index, and IRLS all showed a linear correlation with PD in RLS patients. Additionally, PD increased in RLS patients after therapy. Conclusion: The dCA was compromised in moderate, severe, and very severe RLS patients and was negatively correlated with the IRLS, arousal index, and PLMI. After 1 month of therapy, dCA improved in RLS patients.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

Generating Multi-Depth 3D Holograms Using a Fully Convolutional Neural Network.

Efficiently generating 3D holograms is one of the most challenging research topics in the field of holography. This work introduces a method for generating multi-depth phase-only holograms using a fully convolutional neural network (FCN). The method primarily involves a forward-backward-diffraction framework to compute multi-depth diffraction fields, along with a layer-by-layer replacement method (L2RM) to handle occlusion relationships. The diffraction fields computed by the former are fed into the carefully designed FCN, which leverages its powerful non-linear fitting capability to generate multi-depth holograms of 3D scenes. The latter can smooth the boundaries of different layers in scene reconstruction by complementing information of occluded objects, thus enhancing the reconstruction quality of holograms. The proposed method can generate a multi-depth 3D hologram with a PSNR of 31.8 dB in just 90 ms for a resolution of 2160 × 3840 on the NVIDIA Tesla A100 40G tensor core GPU. Additionally, numerical and experimental results indicate that the generated holograms accurately reconstruct clear 3D scenes with correct occlusion relationships and provide excellent depth focusing.

Dual-step Redox Engineering of Two-Dimensional CoNi-Alloy Embedded B, N-Doped Carbon Layers towards Tunable Electromagnetic Wave Absorption and Light-Weight Infrared Stealth Heat Insulation Devices.

Two-dimensional layered metallic graphite composites as promising electromagnetic wave absorption materials (EWAMs) for their combined properties of abundant interlayer free spaces, rich metallic polarized sites and high conductivity, but the controllable synthesis remains rather challenging. Herein, a dual-step Redox engineering strategy was developed by employing cobalt boron imidazolate framework (Co-BIF) to construct a two-dimensional CoNi-alloy embedded B, N-doped carbon layers (2D-CNC), as a promising EWAM. In the first step, a chemical etching oxidation process on Co-BIF was used to obtain an optimized 2D-CoNi-layered double hydroxide (2D-CoNi-LDH) intermediate and in the second, high-temperature calcination reduction was implemented to modify graphitization the degree of the 2D-CNC. The obtained sample delivers superior reflection loss (RLmin) of -60.1 dB and wide effective absorption bandwidth (EAB) of 6.24 GHz. The synergy mechanisms of interfacial/dipole polarization and magnetic coupling were in-depth evidenced by the hologram and Lorentz electron microscopy, revealing its significant contribution on multireflection and impedance matching. Further theoretical evaluation by COMSOL simulation in different fields based on the dynamic loss process towards the test ring reveals the in situ EW attenuation process. This work presents a strategy to develop multifunctional light-weight infrared stealthy aerogel with superior pressure-resistant, anti-corrosion and heat-insulating properties for future applications. This article is protected by copyright. All rights reserved.

In-situ measurement of urea concentration with an in-fiber SPR-MZI sensor.

A fiber-optic urea sensor based on surface plasmon resonance (SPR) and Mach-Zehnder interference (MZI) combined principle was designed and implemented. By plating gold film on the single-mode-no-core-thin-core-single-mode fiber structure, we successfully excited both SPR and MZI, and constructed two parallel detection channels for simultaneously measurement of urea concentration and temperature. Urease was immobilized on the gold film by metal-organic zeolite skeleton (ZIF-8), which can not only fix a large number of urease to improve measurement sensitivity of urea, but also protect urease activity to ensure the sensor stability. Experimental results indicate that the designed urea sensor with temperature compensation function can detect urea solution with concentration of 1-9 mM, and the sensitivity is 1.4 nm/mM. The proposed measurement method provides a new choice for monitoring urea concentration in the field of medical diagnosis and human health monitoring.

Single-Pd-Site Catalyst Induced by Different Dimensional Nitrogen of N-Doping Carbon for Efficient Hydroaminocarbonylation of Alkynes.

The unsaturated amides are traditionally synthesized by acylation of carboxylic acids or hydration of nitrile compounds but are rarely investigated by hydroaminocarbonylation of alkynes using heterogeneous single-metal-site catalysts (HSMSCs). Herein, single-Pd-site catalysts supported on N-doping carbon (NC) with different nitrogen dimensions inherited from corresponding metal-organic-framework precursors are successfully synthesized. 2D NC-supported single-Pd-site (Pd1/NC-2D) exhibited the best performance with near 100% selectivity and 76% yield of acrylamide for acetylene hydroaminocarbonylation with better stability, superior to those of Pd1/NC-3D, single-metal-site/nanoparticle coexisting catalyst, and nanoparticle catalyst. The coordination environment and molecular evolution of the single-Pd-site during the process of acetylene hydroaminocarbonylation on Pd1/NC-2D are detailly illuminated by various characterizations and density functional theoretical calculations (DFT). DFT also showed the energy barrier of rate-determining step on Pd1/NC-2D is lower than that of Pd1/NC-3D. Furthermore, Pd1/NC-2D catalyst illustrated the general applicability of the hydroaminocarbonylation for various alkynes.

Analysis of clinical features and prognostic factors in Takayasu arteritis involving pulmonary hypertension: A retrospective study.

BACKGROUND: Multiple takayasu arteritis (TA) is a chronic nonspecific large to medium vasculitis disease that mainly accumulates the aorta and its branches. Pulmonary vascular disease is often seen as stenosis and occlusion, and patients may show no moderate to severe pulmonary hypertension (PH). This study aims to summarize the clinical characteristics and analysis of prognostic factors in patients with PH caused by TA. METHODS: Patients diagnosed with aortitis involving the pulmonary artery by pulmonary arteriography or pulmonary artery and total aortic computed tomography arteriography (CTA). All patients underwent detailed clinical assessment, laboratory data collection, and analysis of imaging data. Patients were followed up and factors affecting the prognosis of the pulmonary arteries were analyzed. RESULTS: Most of the patients' complaints were chest tightness, shortness of breath, decreased activity tolerance, hemoptysis and chest pain. 56.90% of the patients were in at the time of admission. Echocardiographic estimation of pulmonary artery systolic pressure was 90.39 ±â€…22.87 mm Hg. In terms of laboratory tests, 39.66%% of the patients had elevated C-reactive protein and erythrocyte sedimentation rate, and amino-terminal natriuretic peptide precursor on admission. In terms of imaging, all patients had pulmonary artery involvement, which was combined with aortic involvement in 31.03%. Nuclide lung perfusion/ventilation imaging of the patients revealed multiple perfusion defects/absences in the segmental and subsegmental distribution of the lungs. Univariate Cox regression model analysis suggested that patients' WHO functional class at admission, age ≧ 51 years at the time of consultation, and amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL were factors affecting the prognosis. Further multifactorial Cox regression model analysis suggested amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL was an independent predictor of poor prognosis with a hazard ratio (HR) value of 5.248. CONCLUSION: Electrocardiogram and echocardiogram may suggest an increased right heart load; some patients have elevated serum inflammatory indexes. Characteristic imaging manifestations include widening of the main pulmonary artery, multiple pulmonary segmental and subsegmental stenoses.

Prediction of hematologic toxicity in luminal type breast cancer patients receiving neoadjuvant chemotherapy using CT L1 level skeletal muscle index.

This study aims to explore the correlation between the CT-L1 and L3 body composition parameters and analyze the relationship between L1 body composition and hematologic toxicity in luminal-type breast cancer patients undergoing neoadjuvant chemotherapy. Data from 140 luminal-type breast cancer patients who underwent surgical treatment after neoadjuvant chemotherapy were analyzed retrospectively. Spearman analysis was used to assess the correlation between CT-L1 and CT-L3 body composition parameters pre-neoadjuvant chemotherapy. Additionally, univariate and multivariate logistic regression analyses were performed to identify factors influencing hematologic toxicity. CT-L1 body composition parameters were positively correlated with CT-L3 body composition parameters in 34 patients. Severe hematological toxicity occurred in 46 cases among the patient cohort. A skeletal muscle index (SMI) of < 32.91 cm2/m2, initial tumor size ≥ 3.335 cm, and a glucose-to-neutrophil ratio (GLR) ≥ 2.88 were identified as independent risk factors for severe hematologic toxicity during neoadjuvant chemotherapy in luminal-type breast cancer patients. The sample size in this study is small, and the predictive capacity of GLR in hematologic toxicity requires further research for comprehensive validation. CT-L1 analysis represents a viable alternative to CT-L3 analysis for body composition assessment. Patients with a low skeletal muscle index were more prone to experiencing severe hematologic toxicity during neoadjuvant chemotherapy.

Exploration of the body from the perspective of acupuncturists: based on the classification of body terms in Huangdi Neijing. / 针灸师视野中的身体.

There is a rich record on body terms in Huangdi Neijing (Yellow Emperor's Inner Classic). The authors classify them into 4 dimensions, including "structure of human body", "constant concern of human body", "symptoms" of disease and "sites" of acupuncture, which corresponds to anatomy, physiology, pathology (including diagnosis) and treatment from the perspective of acupuncture. It is based on the knowledge described by these 4 categories of body terms, acupuncturists recognize the body in treatment. Through the correlation among these terms, the acupuncturists understand acupuncture as a therapeutic technique delivered to "the site of needling" under the guidance of ancient anatomy, physiology and pathology.

ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion.

BACKGROUND: Spinal cord injury (SCI)-induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation-activated microglia after SCI. METHODS: Adult male C57BL/6 ACOD1-/- mice and their wild-type (WT) littermates were subjected to a moderate thoracic spinal cord contusion. The degree of neuroinflammation and OS in the injured spinal cord were assessed using qPCR, western blot, flow cytometry, immunofluorescence, and trans-well assay. We then employed immunoprecipitation-western blot, chromatin immunoprecipitation (ChIP)-PCR, dual-luciferase assay, and immunofluorescence-confocal imaging to examine the molecular mechanisms of ACOD1. Finally, the locomotor function was evaluated with the Basso Mouse Scale and footprint assay. RESULTS: Both in vitro and in vivo, microglia with transcriptional blockage of ACOD1 exhibited more severe levels of neuroinflammation and OS, in which the expression of p62/Keap1/Nrf2 was down-regulated. Furthermore, silencing ACOD1 exacerbated neurological dysfunction in SCI mice. Administration of exogenous Ita or 4-octyl itaconate reduced p62 phosphorylation. Besides, ACOD1 was capable of interacting with phosphorylated p62 to enhance Nrf2 activation, which in turn further promoted transcription of ACOD1. CONCLUSIONS: Here, we identified an unreported ACOD1-p62-Nrf2-ACOD1 feedback loop exerting anti-inflammatory and anti-OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita. KEY POINTS: ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury. ACOD1, not itaconate, interacted with p-p62 to facilitate Nrf2 expression and nuclear translocation. Nrf2 was capable of promoting ACOD1 transcription in microglia.

Optical Fiber Surface Plasmon Resonance Sensor for Glyceryl Tributyrate Detection Based on the PAA/CS Composite Hydrogel Embedding Protease Method.

Glycerol tributyrate as a low-density lipoprotein plays a crucial role in drug development and food safety. In this work, a novel high-stability fiber optic sensor for glyceryl tributyrate based on the poly(acrylic acid) (PAA) and chitosan (CS) composite hydrogel embedding method is first proposed. Compared with traditional functionalization, the lipase in a polymer network structure used in this article can not only avoid chemical reactions that cause damage to the enzyme structure but also avoid the instability of ionic bonds and physical adsorption. Therefore, the PAA/CS hydrogel method proposed in this article can effectively retain enzyme structure. First, the impact of different layers (one to five layers) of PAA/CS on pH sensing performance was explored, and it was determined that layers 1-3 could be used for subsequent sensing experiments. Within the linear detection range of 0.5-10 mM, the detection sensitivities of the one to three layers of the biosensor are divided into 0.65, 0.95, and 1.51 nm/mM, respectively, with the three layers having the best effect. When the number of coating layers is three, the detection limit of the sensor is 0.47 mM, meeting the millimole level detection standard for anticancer requirement. Furthermore, the stability and selectivity of the sensor (in the presence of hemoglobin, urea, cholesterol, acetylcholine, and glucose) were analyzed. The three-layer sensor is used for sample detection. At concentrations of 1-10 mM, the absolute value of the recovery percentage (%) is 82-99%, which can accurately detect samples. The sensor proposed in this paper has the advantages of low sample consumption, high sensitivity, simple structure, and label-free measurement. The enzyme-embedding method provides a new route for rapid and reliable glyceryl tributyrate detection, which has potential applications in food safety as well as the development of anticancer drugs.

Occurrence, distribution, and ecological risk assessment of pharmaceuticals and personal care products in the surface water of Lipu River, China.

Pharmaceuticals and Personal Care Products (PPCPs) are inadvertently released into the aquatic environment, causing detrimental effects on aquatic ecosystem. There is an urgent need of an in-deep investigation on contamination information of PPCPs in aquatic environment as well as the ecological risks to the aquatic ecosystem. This study was carried out in Lipu River basin, China, to investigate the distribution pattern and ecological risks of PPCPs. Results showed that PPCPs pollution is ubiquitous, 29 out of 30 targeted PPCPs were detected in Lipu River. Fourteen PPCPs were detected with a frequency of 100% in all water samples, and ten PPCPs were detected with a frequency of more than 80%. The cumulated PPCPs concentrations ranged from 33.30 ng/L to 99.60 ng/L, with a median value of 47.20 ng/L in Lipu River. Caffeine, flumequine, nifedipine, and lomefloxacin were the predominant PPCPs in study area. Caffeine showed high ecological risk, five and seven individual PPCP showed medium and low ecological risk to algae.

Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, attenuates molecular pathological alterations in learning memory in AD mice.

OBJECTIVE: Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. METHODS: AD mice model was established by lateral ventricular injection with Aß25-35. N15 was daily intraperitoneal administered for 28 days. Morris Water Maze was used to evaluate the neurocognitive function of the mice. The expression of PPARα/γ, brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT3), ADAM10, PS1 and BACE1 were measured by qPCR. Aß amyloid in the hippocampus was measured by Congo red assay. Toluidine blue staining was used to detect the neuronal apoptosis. Protein levels of ADAM10, PS1 and BACE1 were determined using immunoblotting. RESULTS: N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aß amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. CONCLUSION: N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD.

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Exploring spatio-temporal impact of COVID-19 on citywide taxi demand: A case study of New York City.

Coronavirus disease 2019 (COVID-19) has brought dramatic changes in our daily life, especially in human mobility since 2020. As the major component of the integrated transport system in most cities, taxi trips represent a large portion of residents' urban mobility. Thus, quantifying the impacts of COVID-19 on city-wide taxi demand can help to better understand the reshaped travel patterns, optimize public-transport operational strategies, and gather emergency experience under the pressure of this pandemic. To achieve the objectives, the Geographically and Temporally Weighted Regression (GTWR) model is used to analyze the impact mechanism of COVID-19 on taxi demand in this study. City-wide taxi trip data from August 1st, 2020 to July 31st, 2021 in New York City was collected as model's dependent variables, and COVID-19 case rate, population density, road density, station density, points of interest (POI) were selected as the independent variables. By comparing GTWR model with traditional ordinary least square (OLS) model, temporally weighted regression model (TWR) and geographically weighted regression (GWR) model, a significantly better goodness of fit on spatial-temporal taxi data was observed for GTWR. Furthermore, temporal analysis, spatial analysis and the epidemic marginal effect were developed on the GTWR model results. The conclusions of this research are shown as follows: (1) The virus and health care become the major restraining and stimulative factors of taxi demand in post epidemic era. (2) The restraining level of COVID-19 on taxi demand is higher in cold weather. (3) The restraining level of COVID-19 on taxi demand is severely influenced by the curfew policy. (4) Although this virus decreases taxi demand in most of time and places, it can still increase taxi demand in some specific time and places. (5) Along with COVID-19, sports facilities and tourism become obstacles on increasing taxi demand in most of places and time in post epidemic era. The findings can provide useful insights for policymakers and stakeholders to improve the taxi operational efficiency during the remainder of the COVID-19 pandemic.

Exploring the effects of the dietary fiber compound mediated by a longevity dietary pattern on antioxidation, characteristic bacterial genera, and metabolites based on fecal metabolomics.

BACKGROUND: Age-related dysbiosis of the microbiota has been linked to various negative health outcomes. This study aims to investigate the effects of a newly discovered dietary fiber compound (DFC) on aging, intestinal microbiota, and related metabolic processes. The DFC was identified through in vitro fermentation screening experiments, and its dosage and composition were determined based on a longevity dietary pattern. METHODS: Aged SPF C57BL/6 J mice (65 weeks old) and young mice (8 weeks old) were divided into three groups: a subgroup without dietary fiber (NDF), a low DFC dose subgroup (LDF, 10% DFC), and a high DFC dose subgroup (HDF, 20% DFC). The total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) content, and glutathione peroxidase (GSH-Px) activity in liver and serum samples of the mice were measured according to the manufacturer's protocol. The expression levels of characteristic bacterial genera and fecal metabolite concentrations in mice were determined using quantitative real-time PCR (qPCR) and nuclear magnetic resonance hydrogen spectroscopy (1H NMR). Metabolomics analysis was further conducted to identify biological functions and potential pathways related to aging. RESULTS: After an 8-weeks dietary intervention, DFC supplementation significantly attenuated age-related weight loss, organ degeneration, and oxidative stress. And promoted the growth of Lactobacillus and Bifidobacterium and inhibited the growth of Escherichia coli (E. coli) and Bacteroides (p < 0.05) in the intestinal tracts of aged mice. Metabolomic analysis identified glycolipid and amino acid metabolic pathway biomarkers associated with aging that were differentially regulated by DFC consumption. Correlation analysis between the identified microbial flora and the biomarkers revealed potential mechanistic links between altered microbial composition and metabolic activity with aging markers. CONCLUSIONS: In conclusion, this study revealed an important mechanism by which DFC consumption impacts healthspan and longevity, shedding light on optimizing dietary fiber or developing fiber-based interventions to improve human health.

Binding properties of chemosensory protein 4 in Riptortus pedestris to aggregation pheromones.

In insects, chemosensory proteins (CSPs) play an important role in the perception of the external environment and have been widely used for protein-binding characterization. Riptortus pedestris has received increased attention as a potential cause of soybean staygreen syndrome in recent years. In this study, we found that RpedCSP4 expression in the antennae of adult R. pedestris increased with age, with no significant difference in expression level observed between males and females, as determined through quantitative real-time polymerase chain reaction (qRT-PCR). Subsequently, we investigated the ability of RpedCSP4 to bind various ligands (five aggregated pheromone components and 13 soybean volatiles) using a prokaryotic expression system and fluorescence competitive binding assays. We found that RpedCSP4 binds to three aggregated pheromone components of R. pedestris, namely, ((E)-2-hexenyl (Z)-3-hexenoate (E2Z3), (E)-2-hexenyl (E)-2-hexenoate (E2E2), and (E)-2-hexenyl hexenoate (E2HH)), and that its binding capacities are most stable under acidic condition. Finally, the structure and protein-ligand interactions of RpedCSP4 were further analyzed via homology modeling, molecular docking, and targeted mutagenesis experiments. The L29A mutant exhibited a loss of binding ability to these three aggregated pheromone components. Our results show that the olfactory function of RpedCSP4 provides new insights into the binding mechanism of RpedCSPs to aggregation pheromones and contributes to discover new target candidates that will provide a theoretical basis for future population control of R. pedestris.

CB1 Receptor Negative Allosteric Modulators as a Potential Tool to Reverse Cannabinoid Toxicity.

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications-and deaths-every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or 'waiting it out' to treat these patients. We have shown that the canonical synthetic 'designer' cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds-RTICBM189 and PSNCBAM1-blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity.

Nicotinamide mononucleotide maintains cytoskeletal stability and fortifies mitochondrial function to mitigate oocyte damage induced by Triocresyl phosphate.

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.