A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

Is there a possibility that P-glycoprotein reduces reproductive toxicity in males but breast cancer resistance protein does not?

In traditional understanding, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are regarded as efflux transporters that can decrease the concentration of their substrates in the testis, thereby reducing reproductive toxicity in males (RTM) and protecting spermatogenesis. However, there is currently no direct pharmacological evidence demonstrating that P-gp and BCRP can reduce the occurrence of drug-induced RTM. In this study, we chose small molecule targeted anti-tumor agents as model drugs and systematically retrieved and collected information on the transporters and RTM for these drugs, followed by correlation analysis. The results showed a lower incidence of RTM for P-gp substrate drugs, which aligns with previous knowledge. Surprisingly, BCRP substrate drugs exhibited higher rates of RTM in various dimensions, contradicting previous notions. This discrepancy may be attributed to the differential distribution and transport directions of P-gp and BCRP on the blood-testis barrier (BTB). For the first time, this study may provide clues that BCRP may facilitate the passage of exogenous compounds across the BTB, increasing the occurrence of RTM, rather than protecting spermatogenesis as traditionally believed. Furthermore, this study provides the first direct verification of the role of P-gp in reducing RTM and protecting spermatogenesis.

Efficacy and Safety of Sacubitril/Allisartan for the Treatment of Primary Hypertension.

Background: The prevalence of hypertension still increases with the very rapidly increasing longevity in some countries, such as China. The control rate remains low. Objectives: This randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, compared with olmesartan in Chinese patients with mild-to-moderate hypertension. Methods: Eligible patients aged 18 to 75 years (n = 1,197) with mild-to-moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n = 399), sacubitril/allisartan 480 mg (n = 399), or olmesartan 20 mg (n = 399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n = 1,084) and 28-week prolonged treatment (n = 189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline at 12 weeks. Results: Sacubitril/allisartan 240 mg/d provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: -1.9 mm Hg [95% CI: -4.2 to 0.4 mm Hg]; P = 0.0007, for noninferiority). Sacubitril/allisartan 480 mg/d provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: -5.0 mm Hg [95% CI: -7.3 to -2.8 mm Hg]; P < 0.001, for superiority). Greater reductions in 24-hour, and daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P ≤ 0.001 for 480 mg/d). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. Conclusions: Sacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

SAL0114: a novel deuterated dextromethorphan-bupropion combination with improved antidepressant efficacy and safety profile.

Background: Esketamine, the first Food and Drug Administration-approved fast-acting antidepressant, has limited use because of its addictive properties. Although the combination of dextromethorphan and bupropion partially addresses the limitations of esketamine, concerns remain regarding neurologic side effects related to dextromethorphan metabolites, and seizure risks associated with high-dose bupropion. SAL0114, a novel formulation combining deuterated dextromethorphan (in which hydrogen atoms are replaced with deuterium) with bupropion, seeks to enhance dextromethorphan stability through deuteration of its metabolic sites. This approach is expected to increase antidepressant efficacy, reduce metabolite-induced safety issues, and allow for lower bupropion dosages. Methods: Radioligand competition binding assays were used to evaluate the impact of deuterium substitution on the in vitro activity of dextromethorphan and its metabolite, dextrorphan. In vitro hepatic microsomal stability and in vivo mouse pharmacokinetic assays were performed to assess the effects of deuteration on dextromethorphan stability. Two mouse models of behavioral despair were used to determine the antidepressant and synergistic effects of deuterated dextromethorphan and bupropion. Additionally, a reserpine-induced hypothermia rat model and an ammonia-induced cough mouse model were used to assess the in vivo effects from a pathological perspective. Results: Deuterated dextromethorphan maintained the same in vitro activity as dextromethorphan while exhibiting twice the metabolic stability both in vitro and in vivo. Combination with bupropion further improved its in vivo stability, increasing the exposure by 2.4 times. The combination demonstrated efficacy and synergistic effects in all tested animal models, showing superior efficacy compared with the dextromethorphan-bupropion combination. Conclusion: Deuteration improved dextromethorphan metabolic stability without altering its in vitro activity. Bupropion enhanced this stability and synergistically boosted the antidepressant effect by increasing deuterated dextromethorphan exposure in vivo. This enhanced metabolic stability suggests a reduction in dextromethorphan metabolites associated with clinical neurological side effects. Consequently, SAL0114 is hypothesized to offer improved efficacy and safety compared with the non-deuterated combination, potentially allowing for lower bupropion dosages. Further clinical studies are required to confirm these preclinical findings.

Association of Admission Hyperglycemia with Clinical Outcomes in Patients with Symptomatic Intracranial Hemorrhage After Endovascular Treatment for Large Vessel Occlusive Stroke.

Background: Symptomatic intracranial hemorrhage (sICH) is a fatal complication after endovascular treatment (EVT) for acute large vessel occlusive (LVO) stroke. The aim of this study was to investigate the association between hyperglycemia and outcomes in patients with postprocedural sICH. Methods: Of the 2567 patients with AIS who underwent EVT from two large multicenter randomized trials and two prospective multicenter registry studies, 324 patients occurred sICH with documented admission glucose were included in this study. The primary outcome was functional independence (defined as a modified Rankin Scale score of 0 to 2) at 90 days. Secondary outcomes included mRS score of 0 to 3, 0 to 1, and mRS score at 90 days. Safety outcome was the mortality within 90 days. Admission hyperglycemia was defined as a plasma blood glucose ≥7.8 mmol/L (140 mg/dL) in our analysis. Results: Of 324 eligible participants included in this study, hyperglycemia was observed in 130 (40.1%) patients. The median age was 67 (IQR, 58-75) years, and median blood glucose level was 7.1 (IQR, 6.0-9.3) mmol/L. After adjusting for confounding variables, admission hyperglycemia was associated with decreased odds of functional independence (adjusted odds ratio[OR] 0.34; 95% CI 0.17-0.68; P= 0.003), decreased odds of favorable outcome (adjusted OR 0.31; 95% CI 0.16-0.58; P < 0.001) and increased odds of mortality (adjusted OR 2.56; 95% CI 1.47-4.45; P = 0.001) at 90 days. After 1:1 propensity score matching analysis, the results were consistent with multivariable logistic regression analysis. Conclusion: In patients who suffered sICH after EVT for acute large vessel occlusive stroke, hyperglycemia is a strong predictor of poor clinical outcome and mortality at 90 days.

Pseudomonas aeruginosa exotoxin A as a novel allergen induced Non-TH2 inflammation in a murine model of steroid-insensitive asthma.

Background: Despite the immediate in vivo occurrence of anaphylactic and allergic reactions following treatment with Pseudomonas aeruginosa exotoxin A (PEA)-based immunotoxins, the immunological role of PEA in asthma pathogenesis remains unclear. Objective: This study investigated the allergenic potential of PEA and the specific type of asthma induced. Methods: Recombinant PEA (rPEA) lacking domain Ia (to eliminate non-specific cytotoxicity) was expressed, purified, and employed to detect serum PEA-specific IgE levels in asthmatic patients. Competitive ELISA assays were used to assess rPEA's IgE binding capacity and allergenicity. Additionally, rPEA-challenged C57BL/6 mice were subjected to inflammatory endotyping and therapeutic assays to characterize the allergic nature of PEA. Results: PEA-specific IgE was identified in 17 (14.2 %) of 120 asthma patients. The rPEA-sensitized and challenged mice had increased PEA-specific immunoglobulins (such as IgE, IgG1 and IgG2a) and developed asthma-like phenotypes with airway hyperresponsiveness, severe airway inflammation, and airway remodeling. Lungs from these mice displayed significant increases in neutrophils and IL-17A+ cells. Innate lymphoid cells (ILCs) produced type 2 cytokines (IL-4, IL-5, and IL-13), whereas Th cells did not. Nonetheless, airway inflammation, rather than hyperresponsiveness, was elicited in non-sensitized mice upon challenge with rPEA. Importantly, rPEA-induced asthmatic mice were unresponsive to dexamethasone treatment. Conclusion: PEA is a novel allergen that sensitizes asthmatic patients. Furthermore, mice developed steroid-resistant asthma, characterized by an atypical cytokine profile associated with non-TH2 inflammation, only after being sensitized and challenged with rPEA. These findings suggest a potentially significant role for PEA in asthma development, warranting consideration in clinical diagnosis and treatment strategies.

The effect of service outsourcing on labor income share: Measuring labor income share from the global value chains perspective.

Inspired by the positive impact of service outsourcing in Chery and other enterprises on human resources, this paper explores the impact of service outsourcing on labor income share. This paper introduces a framework to analyze how value added is distributed between capital and labor along the mix of inputs from different countries and sectors participating in global value chains and examines the effect of service outsourcing on the labor share income. Using the World Input-Output Database (WIOD) and OECD Inter-Country Input-Output (OECD- ICIO) table, this paper utilizes the WWZ decomposition method of global value chains (GVCs) to quantify labor share income. The results show that: (1) service outsourcing significantly contributes to the increase in labor share income; (2) Offshore outsourcing had a statistically stronger effect on labor share income after the financial crisis, both compared to the past and to onshore outsourcing; (3) Offshore outsourcing has a higher coefficient in countries with low technology. For ease of comparison, only onshore outsourcing shows a statistically significant difference among various service types; (4) The analysis using Chinese data reveals that the coefficient of offshore outsourcing is negative and statistically significant, indicating that industries with higher levels of service outsourcing have a lower labor share income.

A retrospective study of resting energy expenditure in children hospitalized with different nutritional status.

Background: Resting energy expenditure (REE) refers to the energy consumption of the body in a resting state without skeletal muscle activity. This study aimed to examine the REE among children hospitalized with varying nutritional status. Methods: This was a retrospective study. We enrolled 109 pediatric cases that underwent indirect calorimetry (IC) and divided into four groups: mild malnutrition group (15 cases), moderate malnutrition group (30 cases), severe malnutrition group (32 cases), and obesity group (32 cases). We compared and analyzed the measured REE (mREE) using IC with the predicted REE (pREE) using five energy equations. The paired t-test was used to compare the results of two samples. Pearson analysis was used to assess the correlation between two values. The agreement analysis was performed using the Bland-Altman method. Results: There was no significant difference in mREE between the mild, moderate, and severe malnutrition groups, but each differed significantly from the obesity group. All populations exhibited significant correlation between the mREEs and all five energy equations, and the equation with the highest predictive accuracy was the Schofield equation, which achieved an accuracy of 47.7%. In subgroup analysis, there was no significant difference between mREE and pREE for each of the five equations in the mild, moderate malnutrition groups. Only the prediction result of the Liu equation was not significantly different from the mREE in the severe malnutrition group. The prediction accuracy of the Liu equation was relatively the highest (34.4%). However, in the obese group, there were significant differences in pREE and mREE between the Liu equation and Mifflin equation. Under different nutritional statuses, the results of the Bland-Altman analysis suggested that deviation values between REEs predicted by each equation and mREE were greater than ±10%. Conclusions: There were differences in REE among children with different nutritional status. The results obtained from the five predictive energy equations deviated from the IC results. When REE cannot be measured by IC, it is essential to choose an appropriate predictive energy equation based on the nutritional status of the individual.

Single-molecule force spectroscopy reveals intra- and intermolecular interactions of Caenorhabditis elegans HMP-1 during mechanotransduction.

The Caenorhabditis elegans HMP-2/HMP-1 complex, akin to the mammalian [Formula: see text]-catenin-[Formula: see text]-catenin complex, serves as a critical mechanosensor at cell-cell adherens junctions, transducing tension between HMR-1 (also known as cadherin in mammals) and the actin cytoskeleton. Essential for embryonic development and tissue integrity in C. elegans, this complex experiences tension from both internal actomyosin contractility and external mechanical microenvironmental perturbations. While offering a valuable evolutionary comparison to its mammalian counterpart, the impact of tension on the mechanical stability of HMP-1 and HMP-2/HMP-1 interactions remains unexplored. In this study, we directly quantified the mechanical stability of full-length HMP-1 and its force-bearing modulation domains (M1-M3), as well as the HMP-2/HMP-1 interface. Notably, the M1 domain in HMP-1 exhibits significantly higher mechanical stability than its mammalian analog, attributable to interdomain interactions with M2-M3. Introducing salt bridge mutations in the M3 domain weakens the mechanical stability of the M1 domain. Moreover, the intermolecular HMP-2/HMP-1 interface surpasses its mammalian counterpart in mechanical stability, enabling it to support the mechanical activation of the autoinhibited M1 domain for mechanotransduction. Additionally, the phosphomimetic mutation Y69E in HMP-2 weakens the mechanical stability of the HMP-2/HMP-1 interface, compromising the force-transmission molecular linkage and its associated mechanosensing functions. Collectively, these findings provide mechanobiological insights into the C. elegans HMP-2/HMP-1 complex, highlighting the impact of salt bridges on mechanical stability in [Formula: see text]-catenin and demonstrating the evolutionary conservation of the mechanical switch mechanism activating the HMP-1 modulation domain for protein binding at the single-molecule level.

Greetings from virologists to mycologists: A review outlining viruses that live in fungi.

Viruses are genetic elements that parasitize self-replicating cells. Therefore, organisms parasitized by viruses are not limited to animals and plants but also include microorganisms. Among these, viruses that parasitize fungi are known as mycoviruses. Mycoviruses with an RNA genome persistently replicate inside fungal cells and coevolve with their host cells, similar to a cellular organelle. Within host cells, mycoviruses can modulate various fungal characteristics and activities, including pathogenicity and the production of enzymes and secondary metabolites. In this review, we provide an overview of the mycovirus research field as introduction to fungal researchers. Recognition of all genetic elements in fungi aids towards better understanding and control of fungi, and makes fungi a significant model system for studying microorganisms containing multiple genetic elements.

Role of auxin and gibberellin under low light in enhancing saffron corm starch degradation during sprouting.

The mechanisms by which low light accelerates starch macromolecules degradation by auxin and gibberellin (GA) in geophytes during sprouting remain largely unknown. This study investigated these mechanisms in saffron, grown under low light (50 µmol m-2 s-1) and optimal light (200 µmol m-2 s-1) during the sprouting phase. Low light reduced starch concentration in corms by 34.0 % and increased significantly sucrose levels in corms, leaves, and leaf sheaths by 19.2 %, 9.8 %, and 134.5 %, respectively. This was associated with a 33.3 % increase in GA3 level and enhanced auxin signaling. Leaves synthesized IAA under low light, which was transported to the corms to promote GA synthesis, facilitating starch degradation through a 228.7 % increase in amylase activity. Exogenous applications of GA and IAA, as well as the use of their synthesis or transport inhibitors, confirmed the synergistic role of these phytohormones in starch metabolism. The unigenes associated with GA biosynthesis and auxin signaling were upregulated under low light, highlighting the IAA-GA module role in starch degradation. Moreover, increased respiration rate and invertase activity, crucial for ATP biosynthesis and the tricarboxylic acid cycle, were consistent with the upregulation of related unigenes, suggesting that auxin signaling accelerates starch degradation by promoting energy metabolism. Upregulated of auxin signaling (CsSAUR32) and starch metabolism (CsSnRK1) genes under low light suggests that auxin directly regulate starch degradation in saffron corms. This study elucidates that low light modulates auxin and GA interactions to accelerate starch degradation in saffron corms during sprouting, offering insights for optimizing agricultural practices under suboptimal light conditions.

Interleukin(IL)-37 attenuates isoproterenol (ISO)-induced cardiac hypertrophy by suppressing JAK2/STAT3-signaling associated inflammation and oxidative stress.

BACKGROUND: Inflammation and oxidative stress have drawn more and more interest in the realm of cardiovascular disease. In many different disorders, IL-37 acts as an anti-inflammatory and suppressor of inflammation. This study aimed to investigate whether IL-37 could alleviate cardiac hypertrophy by reducing inflammation and oxidative stress. METHODS: In vivo, a cardiac hypertrophy model was induced by 14 d of daily isoproterenol (ISO, 30 mg/kg/d) injection, followed by weeks of treatment with recombinant human IL-37 (1000 ng/animal), administered three times weekly. Assessments concentrated on markers of inflammation and oxidative stress, apoptosis, myocardial disease, and cardiac shape and function. In vitro, neonatal rat cardiomyocytes (NRCMs) were subjected to ISO (10 µM) to establish a cardiomyocytes hypertrophy model. Subsequent IL-37 treatment (100 ng/ml) was applied to determine its cardioprotective efficacy and to elucidate further the underlying mechanisms involved. RESULTS: Significant cardioprotective benefits of IL-37 were seen (in vitro as well as in vivo), primarily through the reduction of oxidative stress, inflammation, apoptosis, and heart hypertrophy markers. Furthermore, IL-37 treatment was associated with a decrease in JAK2 and STAT3 phosphorylation. It is interesting to note that WP1066, a JAK2/STAT3 inhibitor, exhibited antioxidant and anti-inflammatory properties comparable to IL-37, as well as synergistic effects when mixed with the latter. CONCLUSION: ISO-induced cardiac hypertrophy is lessened by IL-37 through the reduction of oxidative stress and inflammation. Additionally, the effects of IL-37 are closely related to inactivation of the JAK2/STAT3 signaling pathway. It is anticipated that IL-37 will one day be used to treat cardiovascular illnesses such as heart hypertrophy.

Organic Polymer-Based Photodiodes for Optoelectronic Reservoir Computing with Time-Based Coding.

The integration of optoelectronic devices with reservoir computing offers a novel and effective approach to in-sensor computing. This work presents a hybrid digital-physical solution that leverages the high-performance poly[(bithiophene)-alternate-(2,5-di(2-octyldodecyl)-3,6-di(thienyl)-pyrrolyl pyrrolidone)] (DPPT-TT) organic polymer-based photodiodes for the hardware implementation of reservoir computing system. The photodiodes demonstrate nonlinear photoelectric responses, fading memory, and cyclical stability, in relation to the temporal information on light stimuli. These attributes enable effective mapping, historical context sensitivity, and consistent performance, with time-encoded inputs, which are particularly essential for accurate and continuous processing of time series data. The optoelectronic reservoir computing system with pulse width modulation (PWM) coding demonstrates impressive performance in the prediction of chaotic sequences, achieving a normalized root-mean-square error as low as 0.095 with optimized parameters. The DPPT-TT-based photodiodes and time-based coding offer a hardware-efficient solution for reservoir computing, significantly advancing Internet of Things applications.

Unveiling the Interplay Between Depressive Symptoms' Alleviation and Quality of Life Improvement in Major Depressive Disorder: A Network Analysis Based on Longitudinal Data.

Background: Understanding the dynamic relationship between depressive symptoms and quality of life (QOL) is essential in improving long-term outcomes for patients with Major Depressive Disorder (MDD). While previous studies often relied on cross-sectional data, there is a pressing need for stronger evidence based on longitudinal data to better inform the development of effective clinical interventions. By focusing on key depressive symptoms, such interventions have the potential to ultimately enhance QOL in individuals with MDD. Methods: This multi-center prospective study, conducted between 2016 and 2020, enrolled outpatients and inpatients diagnosed with MDD across twelve psychiatric hospitals in China. Longitudinal data on Patient Health Questionnaire - 9 (PHQ-9) and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) was analyzed using an Extended Bayesian Information Criterion (EBIC) graphical least absolute shrinkage and selection operator (gLASSO) network model to explore the connections between depressive symptom changes and QOL changes. Flow network was applied to investigate relationships between individual symptom changes and overall QOL score change, as well as daily functional independence. Results: This study included 818 participants with complete data after 8-week antidepressant treatment. Apart from the overlapping items from PHQ-9 and Q-LES-Q-SF, the three edges between "mood" (delta-QLES2) and "anhedonia" (delta-DEP1), between "physical health" (delta-QLES1) and "sleep problems" (delta-DEP3), and between "physical health" (delta-QLES1) and "sad mood" (delta-DEP2) were the most strong bridges between the cluster of depressive symptoms alleviation and the cluster of QOL change. "Anhedonia" (delta-DEP1), "sad mood" (delta-DEP2) and "loss of energy" (delta-DEP4) had the highest bridge strength between the alleviations of depressive symptoms and the total score change of Q-LES-Q-SF. Anhedonia had the greatest connection with participants' satisfaction with function in daily life. Conclusion: This study highlighted the potential for developing highly effective interventions by targeting on central symptoms, thereby to ultimately improve QOL for patients with MDD.

Effects of postprandial exercise timing on blood glucose and fluctuations in patients with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to assess how moderate-intensity aerobic exercise performed 45 minutes and 90 minutes after a meal affects blood glucose levels and fluctuations in individuals diagnosed with type 2 diabetes mellitus (T2DM). METHODS: Twenty-two patients with T2DM, who were solely receiving oral hypoglycemic medication, were enrolled and divided randomly into two categories: those exercising 45 minutes after a meal (45-minute postprandial exercise group) and those exercising 90 minutes post-meal (90-minute postprandial exercise group). Both groups engaged in a 30-minute session of moderate-intensity aerobic stationary bike exercise following breakfast. This aerobic exercise regimen consisted of two stages, with the groups switching exercise timings after the initial phase. Continuous glucose monitoring (CGM) was utilized to evaluate the blood glucose levels and fluctuations in the participants. RESULTS: After breakfast, both overall daily blood glucose levels and the area under the curve for blood glucose following breakfast were reduced in the 45-minute postprandial exercise group compared to the 90-minute postprandial exercise group. The 45-minute postprandial exercise group demonstrated greater time spent within the target glucose range and less time above the target range than the 90-minute postprandial exercise group. Additionally, measures such as standard deviation, mean amplitude of glycemic excursions, largest amplitude of glycemic excursions, and postprandial glucose excursion for breakfast, peak postprandial glucose levels, and duration of elevated glucose levels were all lower in the 45-minute postprandial exercise group compared to the 90-minute postprandial exercise group. CONCLUSIONS: Moderate-intensity aerobic exercise lasting 45 minutes after meals was found to be more efficient in decreasing blood glucose levels and minimizing fluctuations compared to exercising 90 minutes after meals in patients with T2DM. Additionally, it notably reduced the peak in blood glucose levels after meals.

Dietary curcumin supplementation enhances growth performance and anti-inflammatory functions by modulating gut microbiota, microbiota-derived metabolites, and expression of inflammation-related genes in broilers.

Curcumin (CUR) is a natural polyphenolic substance that has been widely used since ancient times for its multiple beneficial functions. However, whether CUR affects growth performance of broilers by altering gut microbiota and metabolite and the underlying mechanism are largely unknown. This study was conducted to evaluate the effect of dietary CUR supplementation on growth performance, anti-inflammatory function, intestinal morphology and barrier, cecum microbiota and metabolite profile of broilers. Sixty 1-day-old male broilers were randomly divided into control group (CON, fed a control diet) and CUR group (fed a control diet supplemented with 200 mg/kg CUR) after 2 days of adaptation. Results showed that after feeding to 52-day-old, compared with CON broilers, the CUR broilers showed improved feed utilization efficiency and growth performance. Furthermore, the CUR broilers showed an improved intestinal morphology, which was demonstrated by a lower crypt depth in the jejunum. The 16S rRNA gene sequencing and non-targeted metabonomics (LC-MS/MS) analysis results showed that the cecum microbiota ecology and function were significantly improved, and the abundance of beneficial flora and metabolites were increased, while the harmful bacteria and metabolites were significantly decreased. In addition, RT-qPCR results showed that CUR significantly reduced inflammatory responses, promoted the formation of the mucosal barrier and enhanced digestion, absorption and transport of lipids and glucose related genes expression in the intestine. These above findings demonstrated that dietary CUR supplementation improved growth performance, intestinal morphology and anti-inflammatory functions, mainly by manipulating cecum microbiota and microbiota-derived metabolites, which provides a credible explanation for the growth-promoting effect and anti-inflammatory functions of CUR and aids our understanding of the mechanisms underlying.

Endocytosis-Inspired Zwitterionic Gel Tape for High-Efficient and Sustainable Underoil Adhesion.

Marine oil exploration is important yet greatly increases the risk of oil leakage, which will result in severe environment pollution and economic losses. It is an urgent need to develop effective underoil adhesives. However, realizing underoil adhesion is even harder than those underwater, due to the stubborn attachment of a highly viscous oil layer on target surface. Here, inspired by endocytosis, a tough gel tape composed of zwitterionic polymer network and zwitterionic surfactants is developed. The amphiphilic surfactants can form micelle to capture the oil droplets and transport them from the interface to gel via electrostatic attraction of polymer backbone, mimicking the endocytosis and achieving robust underoil adhesion. Benefiting from the oil-resistance of polymer backbone, the gel further realizes a combination of i) long-term adhesion with high durability, ii) repeated adhesion in oil, and iii) renewable adhesion efficiency after exhausted use. The tape exhibits an ultra-high adhesive toughness of 2446.86 J m-2 to stainless steel in silicone oil after 30 days' oil-exposure; such value of adhesive toughness surpasses many of those achieved in underwater adhesion and is greater than underoil adhesion performance of commercial tape. The strategy illustrated here will motivate the design of sustainable and efficient adhesives for wet environments.

Exploring the association between activities of daily living ability and injurious falls in older stroke patients with different activity ranges.

Injurious falls pose a significant threat to the safety of stroke patients, particularly among older adults. While the influence of activities of daily living (ADL) on falls is acknowledged, the precise connection between ADL ability and fall-related injuries in older stroke patients undergoing rehabilitation, particularly those with varying mobility levels, remains unclear. This multicenter cross-sectional study in China recruited 741 stroke patients aged 65 years and above, categorized into bedridden, domestic, and community groups based on their mobility levels using the Longshi Scale. ADL ability was assessed using the Barthel Index. Logistic regression models, generalized additive models, smoothed curve-fitting, and threshold effect analysis were employed to explore the relationship between ADL ability and injurious falls across the three mobility groups. Results revealed an inverted U-shaped relationship between ADL ability and injurious falls among patients in the domestic group (p = 0.011). Below the inflection point of 35 on the Barthel Index, the likelihood of injurious falls increased by 14% with each unit increase in ADL ability (OR = 1.14, 95% CI 1.010-1.29, p = 0.0331), while above the inflection point, it decreased by 3% per unit increase (OR = 0.97, 95% CI 0.95-0.99, p = 0.0013). However, no significant association between ADL ability and injurious falls was observed in either the bedridden or community groups (p > 0.05). These findings suggest that only older stroke patients capable of engaging in activities at home demonstrate a correlation between ADL ability and injurious falls. The identified inverted U-shaped relationship may aid in identifying fall injury risk in this population.

Dissection of potential anti-osteoporosis mechanism of isopsoralen - a quality control marker in Psoraleae Fructus - by metabolite profiling and network pharmacology.

RATIONALE: Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. METHODS: The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. RESULTS: A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.

Regulation mechanism of GPS2 on PGC-1α/Drp1-mediated mitochondrial dynamics in inflammation of acute lung injury.

Acute lung injury (ALI) has been a hot topic in the field of critical care research in recent years. Mitochondrial dynamics consists of mitochondrial fusion and mitochondrial fission. Dynamin-related protein 1 (Drp1), a key molecule that regulates mitochondrial fission, is important in the oxidative stress and inflammatory response to ALI. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a core protein that mediates mitochondrial biogenesis. G-protein pathway suppressor 2 (GPS2) acts as a transcriptional cofactor with regulatory effects on nuclear-encoded mitochondrial genes. This study aimed to investigate the mechanism of PGC-1α/Drp1-mediated mitochondrial dynamics involved in ALI and to demonstrate the protective mechanism of GPS2 in regulating mitochondrial structure and function and inflammation in ALI. The ALI model was constructed using LPS-induced wild-type mice and human pulmonary microvascular endothelial cells (HPMVECs). It was found that lung injury, oxidative stress and inflammation were exacerbated in the mice ALI model and that mitochondrial structure and function were disrupted in HPMVECs. In vitro studies revealed that LPS led to the upregulated expression of Drp1 and the downregulated expression of PGC-1α and GPS2. Mitochondrial division was reduced and respiratory function was restored in Drp1 knockdown cells, which inhibited oxidative stress and inflammatory response. In addition, the overexpression of PGC-1α and GPS2 significantly inhibited the expression of Drp1, mitochondrial function was restored, and inhibited reactive oxygen species (ROS) production and inflammatory factor release. Moreover, the overexpression of GPS2 promoted the upregulated expression of PGC-1α. This mechanism was also validated in vivo, in which the low expression of GPS2 in mice resulted in the upregulated expression of Drp1 and the downregulated expression of PGC-1α, and further exacerbated LPS-induced ALI. In the present study, we also found that LPS-induced the downregulated expression of GPS2 may be associated with its increased degradation by the proteasome. Therefore, these findings revealed that GPS2 inhibited oxidative stress and inflammation by modulating PGC-1α/Drp1-mediated mitochondrial dynamics to alleviate LPS-induced ALI, which may provide a new approach to the therapeutic orientation for LPS-induced ALI.